Theranostic Applications of Carbon Nanomaterials in Cancer: Focus on Imaging and Cargo Delivery Daiqin Chen, Casey A. Dougherty, Kaicheng Zhu, Hao Hong PII: DOI: Reference:
S0168-3659(15)00251-5 doi: 10.1016/j.jconrel.2015.04.021 COREL 7642
To appear in:
Journal of Controlled Release
Received date: Revised date: Accepted date:
7 March 2015 17 April 2015 18 April 2015
Please cite this article as: Daiqin Chen, Casey A. Dougherty, Kaicheng Zhu, Hao Hong, Theranostic Applications of Carbon Nanomaterials in Cancer: Focus on Imaging and Cargo Delivery, Journal of Controlled Release (2015), doi: 10.1016/j.jconrel.2015.04.021
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Theranostic Applications of Carbon Nanomaterials in Cancer: Focus on Imaging and Cargo Delivery
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Daiqin Chen1,2, Casey A. Dougherty1,2, Kaicheng Zhu1,2, Hao Hong1,2,3*
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Center for Molecular Imaging, University of Michigan Health Systems, Ann Arbor, Michigan 48109, United States 2
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Department of Radiology, University of Michigan Health Systems, Ann Arbor, Michigan 48109, United States 3
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University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, United States
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Requests for reprints: Hao Hong, PhD, Departments of Radiology, University of Michigan Health Systems, Room A520, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. Fax: 1-734-763-5447 Tel: 1-734-615-4634 E-mail: [email protected]
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ACCEPTED MANUSCRIPT Contents 1. Introduction ............................................................................................................................ 4 2. Functionalization of carbon nanomaterials ............................................................................ 6
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3. Theranostic applications of fullerenes (nontubular type) ...................................................... 7 3.1 Cancer imaging with fullerenes ........................................................................................ 8
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3.2 Cargo delivery to cancer with fullerenes .......................................................................... 9 4. Theranostic applications of carbon nanotubes ....................................................................... 9
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4.1 Cancer imaging with fullerenes ...................................................................................... 10 4.2 Cargo delivery to cancer with fullerenes ........................................................................ 12
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5. Theranostic applications of single-walled carbon nanohorns .............................................. 12 5.1 Cancer imaging with SWNHs ........................................................................................ 13
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5.2 Cargo delivery to cancer with SWNHs .......................................................................... 14 6. Theranostic applications of nanodiamonds .......................................................................... 14 6.1 Cancer imaging with nanodiamonds .............................................................................. 14
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6.2 Cargo delivery to cancer with nanodiamonds ................................................................ 16
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7. Theranostic applications of carbon nanodots ....................................................................... 16 7.1 Cancer imaging with carbon nanodots ........................................................................... 16 7.2 Cargo delivery to cancer with carbon nanodots ............................................................. 17
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8. Theranostic applications of nanographenes ......................................................................... 18 8.1 Cancer imaging with nanographenes ............................................................................. 18 8.2 Cargo delivery to cancer with nanographenes................................................................ 20 9. Conclusions and future perspectives .................................................................................... 22 Acknowledgments.................................................................................................................... 23 References ................................................................................................................................ 24
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ACCEPTED MANUSCRIPT ABSTRACT: Carbon based nanomaterials have attracted significant attention over the past decades due
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to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of
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carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials
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will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene
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derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging
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(fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.)
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and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and
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the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional
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carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer.
KEYWORDS: carbon nanomaterials, theranostics, cancer, molecular imaging, drug delivery
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ACCEPTED MANUSCRIPT 1. INTRODUCTION With an estimation of 1,658,370 new cases and 589,430 deaths in the United States in
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2015, cancer is considered as the second leading health threat [1]. Despite great progress made in the past few decades, early diagnosis and efficient treatment of cancer are still challenges to
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overcome [2, 3]. The current standard management of cancer patients involves stage
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determination (by imaging or biopsies), chemo/radiation therapy, and/or surgical resection.
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Molecular imaging, a useful tool to monitor in vivo biochemical events, can provide invaluable insights into both cancer diagnosis and therapeutic response monitoring [4]. Different molecular
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imaging techniques, including optical imaging (fluorescence/bioluminescence/Raman), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET),
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single photon emission computed tomography (SPECT), and ultrasound (US), have furthered our
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understanding of cancer initiation, progression, and metastasis.
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Post cancer diagnosis/detection, chemotherapy is the most frequently used method for cancer treatment. In order to obtain the best curative effect while avoiding negative side effects, it is important to develop drug delivery systems with strong cancer targeting abilities, as well as controllable/on-demand release properties. Nanomaterials have been stated to be one of the most promising platforms for cancer imaging and drug delivery since they have the ability to synergistically combine diagnosis and therapy into one material [5, 6]. A material that combines diagnosis and therapy has been termed a “theranostic” [7, 8].
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ACCEPTED MANUSCRIPT Nanomaterials can be generally classified into organic nanomaterials, inorganic nanomaterials and hybrid nanomaterials [9-11]. The theranostic applications of organic
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nanomaterials (primarily including liposomes, micelles, dendrimers, and protein-based
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nanomaterials) in cancer have been previously summarized elsewhere [12, 13]. Inorganic nanomaterials (e.g. silica nanoparticles, gold nanoparticles, iron oxide nanoparticles and
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carbonaceous nanomaterials etc.) are more actively being used for cancer theranostic
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applications due to their unique physical properties (which usually improve the therapeutic outputs) and comparatively lower production cost [14-16]. Among these inorganic nanomaterials,
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carbonaceous nanomaterials are rising stars due to their excellent mechanical, thermal and optical properties (Figure 1) [17, 18]. For instance, most of these carbonaceous nanomaterials
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possess strong absorption in the infrared (IR) or near infrared (NIR) regions, which is useful for photothermal therapy (PTT) of cancer. Some inorganic nanomaterials (e.g. carbon nanotubes or
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nanodots) can also produce fluorescence in the visible and infrared regions for fluorescence imaging [19, 20]. In addition, carbonaceous nanomaterials are able to transform the energy from a laser into acoustic signals, which makes them promising agents for photoacoustic imaging (PAI) [21, 22]. Finally, intrinsic Raman vibration signals from carbonaceous materials can also provide a reliable method to monitor their distribution and metabolism in vivo [23, 24].
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ACCEPTED MANUSCRIPT Figure 1 Radioisotopes
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Chemo drugs
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Carbon nanomaterials
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Genes
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Polymer functionalization
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PDT & photothermal
Image-guided cancer therapy Targeting ligands
Imaging labels
Legend to Figure 1. The schematic illustration of theranostic applications of carbon nanomaterials in cancer.
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ACCEPTED MANUSCRIPT Due to the unique sp2 carbon structure and inherent hydrophobic nature of carbonaceous nanomaterials, the nanomaterials have the potential to be useful drug delivery vectors. Multiple
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copies of drugs or DNA/RNA molecules can easily be absorbed onto their surface through
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hydrophobic interactions or π-π stacking [25-27]. After loading the drugs/genes, the carbonaceous nanomaterials (or their assemblies) can accumulate into tumors in vivo through
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either “active” targeting (by introduction of a targeting ligand for overexpressed receptors in
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tumor/vasculatures) or by the enhanced permeability and retention (EPR) effect. Drug/gene cargos on carbonaceous nanomaterials possess distinct pharmacokinetic behavior compared to
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free molecules, which may not only enhance the tumor killing efficiency but also decrease toxicity in surrounding healthy tissue. In some cases, carbonaceous nanomaterials (e.g. fullerene)
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can also be used as anticancer agents themselves and provide synergetic antitumor effects with a given drug [28]. Moreover, the addition of stimuli (e.g. light or heat) responsive polymers to
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carbonaceous nanomaterials can also be extremely useful for selective and controllable drug release [29, 30].
Much research effort has been devoted to carbonaceous nanomaterials as platforms for cancer diagnosis and drug delivery due to their many aforementioned advantages, leading to the goal of personalized cancer therapy [7, 31]. By combining imaging labels with therapeutics in the same platform, the location of the tumor can be precisely delineated, and the optimal drug doses as well as therapeutic time frame can be determined by acquiring the real-time drug distribution information in vivo. Image-guided carbonaceous nanomaterials can evaluate the therapeutic efficacy of a given treatment by monitoring the abundance fluctuation of target proteins/receptors as well. Theranostic applications of carbonaceous nanomaterials will be discussed in the current review article. They will be categorized into fullerenes, nanotubes, 7
ACCEPTED MANUSCRIPT nanohorns, nanodiamond, nanodots and graphene derivatives according to their morphologies. The functionalization (i.e. chemical modification) of these materials before their biomedical uses
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will be briefly introduced. The molecular imaging and cargo delivery applications of these
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materials will be the major focus. Lastly, the safety/toxicity concerns of each carbonaceous
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nanomaterial will be covered.
2. FUNCTIONALIZATION OF CARBON NANOMATERIALS
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Since most of pristine carbonaceous nanomaterials are highly hydrophobic (due to the sp2 carbon nanostructure), proper functionalization is necessary before their biomedical applications.
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Generally speaking, there are two primary strategies of functionalization: covalent or noncovalent (Table 1). Covalent modifications usually involve introduction of hydrophilic
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functional groups (e.g. hydroxyl groups, carboxyl groups, or amino groups) for the further conjugation of protecting polymers (such as poly(ethylene glycol) [PEG]), targeting ligands, or
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drug/gene cargos [32-35]. For example, carboxyl groups (-COOH) can be formed by oxidation by agents like nitric acid. Besides oxidation, the cycloaddition reaction is another covalent approach to modify carbonaceous nanomaterials, in which the aromatic rings inside the material structures are used as the reaction target [27].
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ACCEPTED MANUSCRIPT Table 1 Functionalization strategies for carbonaceous nanomaterials Functionalization molecule(s)
Major Purpose(s)
Potential toxicity concerns
Representative References
PEG derivatives Chitosan
Stabilization Stabilization and gene delivery Stabilization and gene delivery Imaging label
Biocompatible Biocompatible
[63, 95, 174] [96, 210, 231]
BSA M13 phage
DNA DNA/siRNA Nanostructures (IONP, QDs, gold NPs etc.) Gadolinium (Gd) Chemo drugs Photosensitizers 9
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Imaging label
Mostly biocompatible
[73, 161]
Biocompatible Potential immune response
[95, 178, 242] [100, 164]
Biocompatible Biocompatible
[243] [119]
Biocompatible Potential immune response
[123] [70, 71]
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Pluronic F127 Chitosan
[85, 161] [132]
Stabilization Stabilization and gene delivery Stabilization Stabilization and gene loading Stabilization Stabilization and tumor targeting Stabilization
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PEG derivatives Polyethylenimine (PEI)
[104, 146, 209]
Toxicity from premature release Tumor therapy Toxicity from premature release Tumor Potential immune targeting response
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Antibodies, proteins, or peptides Fluorophores Noncovalent
Radiation exposure
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Chemo drugs
Imaging label
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Radioisotopes and chelators Gadolinium (Gd)
Potential immune response
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Polyethylenimine (PEI)
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Covalent
Potential immune response Gene therapy Gene inhibition in normal tissues Imaging label, MPS capture and PDT, and PTT potential metal contamination Imaging label Toxicity from premature release Tumor therapy Toxicity from premature release PDT Damage to normal tissues by ROS
[57, 97] [47, 97, 104, 174, 221]
[207] [122, 164, 212] [63, 72, 147, 203]
[116, 204] [56, 57, 119] [55, 102, 103, 121, 168, 223]
ACCEPTED MANUSCRIPT The covalently functionalized carbonaceous nanomaterials are usually stable. However, the limitation lies in that this type of functionalization method inevitably destroys partial material
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structure causing the loss of certain intrinsic properties (e.g. photothermal capacities). Compared
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with covalent functionalization, the reaction condition of noncovalent functionalization is comparatively mild, which involves coating the carbonaceous nanomaterials with amphiphilic
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molecules. The hydrophobic motifs of the amphiphilic molecules could be anchored onto the
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material’s surface with the hydrophilic ends extending to the aqueous solution and maintaining the stability of the whole material. Noncovalent interactions include electrostatic forces, π-π
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interactions, hydrogen bonding, or van der Waals forces [36, 37]. As we can expect, lower stability of noncovalent conjugates is the major concern for this type of functionalization. For
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example, Chung et al. attempted to conjugate lysozyme onto the surface of nanodiamonds via electrostatic interactions [38]. Although direct absorption based on electrostatic interactions was
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observed to be fast and easy, the stability of formed conjugates was far from satisfactory. A lot of thought about stability and design of the nanomaterial must be taken into account before choosing an appropriate functionalization method for any carbonaceous nanomaterial. A balance between stability and structural integrity must be maintained before any further biomedical applications. The functionalization strategy is one of the most significant factors that can control the subsequent loading efficiency of drug/gene/imaging labels. For those materials which are not sensitive to structural alteration (e.g. carbon nanotube, nanodiamonds, or nanographene oxide), a covalent functionalization can be preferred, but other factors (e.g. effective cargo release, circulation half-life, or reagent availability) must be considered. Carbonaceous nanomaterials are only effective for cancer theranostic applications once the correct functionalization strategy is chosen and applied. 10
ACCEPTED MANUSCRIPT 3. THERANOSTIC APPLICATIONS OF FULLERENES (NONTUBULAR TYPE) Fullerene is the first category of carbonaceous nanomaterial frequently used for cancer
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theranostic applications. Since the initial discovery of the first fullerene, C60, in 1985, the fullerene family has been expanding rapidly with more members being identified [39]. Among
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these fullerene derivatives, C60 (OH)x and C82 (OH)22 are two of the most investigated fullerene
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species [40]. Their unique structures provide fullerenes with some very attractive and unique
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properties [27]. For example, gadolinium ions (Gd, T1-weighted) can be incorporated into the carbon cage of the C82 molecules, making Gd@C82 derivatives promising MRI contrast agents
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[41]. Photodynamic therapy (PDT) relies on reactive oxygen species (ROS, e.g. singlet oxygen) to be emitted from a photosensitizer (PS) under laser irradiation to destroy cancer cells [42].
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Many fullerene derivatives can serve as effective photosensitizers for PDT under laser irradiation
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and work as a “radical sponge”, demonstrating anticancer properties by themselves [43].
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Fullerenes are also reported to be excellent cargo delivering vectors for anticancer drugs and genes (DNA/RNA) – both enhanced cytotoxicity and gene transfection efficiency are observed with the use of fullerenes as a non-viral vector [44]. 3.1. Cancer imaging with fullerenes The most dominant utilization of fullerene in cancer imaging is for MRI. To be more specific, metallofullerene complexes (e.g. gadolinium-containing or iron oxide nanoparticle [IONP, T2-weighted]-containing) are generally considered to be good MRI contrast agents [45]. In
one
study,
a
water-soluble
gadolinium
endohedral
fulleride,
Gd@C82O6(OH)16-
(NHCH2CH2COOH)8 (AAD-EMFs) was synthesized with good stability and water proton relaxivity [46], which is ideal for MRI applications. In a follow-up report, these AAD-EMFs were further conjugated with an antibody against green fluorescence protein (GFP) [47]. With the assistance of GFP, the cellular distribution of AAD-EMFs can be more accurately detected. 11
ACCEPTED MANUSCRIPT Other groups also explored the morphological impact of the gadolinium-fullerene complex to MR relaxation behavior [48, 49]. Details of other gadolinium-fullerene complexes and their MR
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relaxation behavior can be found in references [50, 51]. IONP-decorated fullerene represents
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another category of T2-weighted MRI agents. A recent study used IONP-C60 composite for MRI, PDT, and PTT triple applications [52]. Adopting folic acid (FA) as the tumor targeting molecule,
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this hybrid IONP-C60 could not only visualize tumor in vivo (Figure 2A), but also provided
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synergistic PDT/PTT for effective and selective ablation of tumor.
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Figure 2
Folic acid (FA)
(A)
IONP
(B)
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C60 fullerene PEG Control
C60-IONP-PEG C60-IONP-PEG C60-IONP-PEG -FA + magnet -FA
PEI
DOX
DOX
Free DOX
C60-PEI-DOX
ROS
Control Control
C60-PEI-DOX + laser
C60-PEI-DOX + laser
Legend to Figure 2. (A) Structure of C60-IONP-PEG-FA and its application as an MRI-guidable PDT/PTT agent for tumors. Significant “darkening” of tumor area based on T2-weighted MR images indicated selective accumulation of C60-IONP-PEG-FA from folate receptor targeting and magnetic attraction. Adapted with permission from reference [52]. (B) Structure and application of C60-PEI-DOX for synergistic cancer therapy by DOX and PDT. C60-PEI-DOX demonstrated good uptake in melanoma cells and significant production of cellular ROS after laser irradiation. Histological examination also confirmed that treatment with C60-PEI-DOX plus laser irradiation produced maximal cancer cell killing efficiency. Adapted with permission from reference [57].
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ACCEPTED MANUSCRIPT Fullerene derivatives are also useful for fluorescence imaging of cancer. One example is a hyaluronated (for CD44-targeting) C60 fullerene with a strong intrinsic NIR fluorescence
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emission. The hyaluranoted C60 fullerene was used for both in vivo fluorescence imaging of
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HCT-116 tumors (CD44+) and photodynamic killing of tumors [53]. Since the intrinsic fluorescence signal from fullerene is not very strong, external fluorophores could also be
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attached to facilitate the visualization of fullerene complexes in vivo. For example, a hybrid
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nanoconjugate was formed from the condensation between hyaluronated C60 fullerene and upconversion nanocrystals [54]. Although only cell imaging and ROS validation were carried out
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in this study, this fullerene complex could be potentially used for in vivo fluorescence imaging and PDT.
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Despite their usefulness as imaging contrast agents, fullerene derivatives are rarely adopted solely for cancer imaging/detection purposes. With synergistic integration into other
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applications (e.g. drug delivery), imaging can also provide guidance to assess delivery efficiency or therapeutic responses.
3.2. Cargo delivery to cancer with fullerenes The unique structure of fullerene derivatives render them broadly useful for delivery of different cargos. Recently, an Asn-Gly-Arg (NGR, against CD13 on the tumor cells) functionalized
C60 fullerene was used as a targeted delivery system for a PDT agent (2-
methoxyestradiol [2-ME]) [55]. Joint photosensitization effects were witnessed for C60 fullerene to boost the cell apoptosis efficacy of 2-ME on MCF-7 breast cancer cells. Other chemotherapy drugs, such as doxorubicin (DOX) and pacilitaxel, were also loaded into C60 [56, 57], which was confirmed to possess enhanced tumor killing capacity over free individual drug. In one of these studies, cancer cell death was the consequence from synergistic pH-sensitive DOX release and PDT-mediated ROS (Figure 2B) [57]. 13
ACCEPTED MANUSCRIPT With the introduction of proper cationic groups, fullerenes can also be attractive carriers for gene delivery due to the carbon cages inside fullerene [58, 59], which can stabilize DNA-
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fullerene complexes. A cationic tetra (piperazino) fullerene epoxide (TPFE) was synthesized as
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an in vivo gene delivery carrier [59]. The initial validation was carried out after loading the fullerene with DNA encoding enhanced green fluorescent protein gene (EGFP). The gene
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delivery by TPFE was efficient and organ selective, causing no noticeable toxicity. Although
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cancer-selective gene delivery (e.g. therapeutic siRNA) with nontubular fullerenes has not been carried out to date, these studies validated the value of using fullerenes as a gene delivery vector
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for cancer treatment.
Various fullerene-based multifunctional vectors (e.g. combination of drug delivery with
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imaging or PDT/PTT) have been developed recently [52, 60-62]. One recent example was the utilization of a PEGylated fullerene decorated with IONPs for targeted delivery of PDT-sensitive
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hematoporphyrin monomethyl ether (HMME), readily monitored by MRI [63]. The PDT efficacy of HMME delivered by this composite was dramatically improved both in vitro and in vivo when compared with that of free HMME, monitored by MRI and other evidences. 4. THERANOSTIC APPLICATIONS OF CARBON NANOTUBES Although strictly speaking, carbon nanotubes (CNTs) belong to a sub-category of fullerene derivatives, their wide-spread biomedical applications necessitate a separate section to illustrate their leading role for cancer theranostics inside the whole carbon nanomaterial family. CNTs are carbon allotropes which possess a cylindrical nanostructure with a very high length-to-diameter ratio. According to the numbers of sheets of sp2 carbon atoms, CNTs can be generally categorized into single-walled nanotubes (SWNTs) and multi-walled nanotubes (MWNTs). CNTs retain several unique properties, including strong resonant Raman scattering and photoluminescence in the NIR region, and good laser-to-acoustic transferring capacity [64]. The 14
ACCEPTED MANUSCRIPT strong NIR absorption of CNTs enables them to be used as a potential candidate for cancer PTT. The large area inside and outside CNTs provide tremendous accommodation to various
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therapeutic molecules [25].
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4.1. Cancer imaging with CNTs
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We will focus on the updates within the passing five years since the progress in molecular imaging with SWNTs has been summarized previously [65]. Among all the imaging
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techniques, fluorescence imaging is the most frequently adopted for CNTs in cancer imaging/detection. The intrinsic emission in the second NIR region (1100-1400 nm, NIRII) from
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CNTs could be readily used for in vivo tumor detection [66, 67]. Since the initial success of CNT imaging producing high-resolution tumor vessel visualization [19], different studies have
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confirmed that CNTs do in fact produce high signal-to-noise ratios. Most organisms investigated have extremely low absorption in the second NIR wavelength region [68, 69]. In an interesting
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study, M13 phage-conjugated SWNTs with stable display of tumor-targeting sequence were used for NIR fluorescence imaging of prostate tumors in mice [70]. The same group improved their results by adopting a new tumor-targeting sequence on M13-SWNTs, which could facilitate the detection and excision of tumors with submillimeter diameters (Figure 3A) [71]. At the same time, CNTs could also be conjugated with multiple fluorophores with different emission wavelengths (e.g. quantum dots [QD] and polydiacetylene) [72, 73] for fluorescence imaging of cancer cells based on fluorescence resonance energy transfer (FRET). Besides fluorescence imaging, bioluminescence imaging was also used recently to monitor the distribution of CNTs in vivo after conjugation of a thermostable luciferase onto CNTs [74].
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ACCEPTED MANUSCRIPT Figure 3 Unguided M13-SWNT guided tumor excision
M13-SWNT guided
Post-surgery (unguided)
(B)
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1h
4h
Post-surgery (M13-SWNT guided)
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Pre-surgery
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(A)
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SWNT-PEI /siRNA
SWNT-PEI /siRNA/NGR
Upper: SWNT-PEI/siRNA/NGR Down: SWNT-PEI/siRNA/NGR + laser
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Legend to Figure 3. (A) The use of M13 functionalized SWNTs for NIR fluorescence-guided tumor excision. Peptide sequence targeting secreted protein, acidic and rich in cysteines (SPARC) was displayed on M13. The fluorescence from M13-SWNTs was successfully used for detection and excision of submillimeter tumors which were not removable without M13-SWNTs guidance. SBP stands for SPARC binding peptide. Adapted with permission from reference [71]. (B) The structure of SWNT-PEI and its application for siRNA/PDT synergistic therapy of prostate tumors. SWNT-PEI loaded with siRNA (with or without NGR targeting peptide) could enter nucleus of PC-3 cells for effective siRNA delivery at 4 h post-treatment. In vivo siRNA/PTT demonstrated significantly beneficial therapeutic response when compared with only RNA interference induced by siRNA loaded, NGR conjugated SWNT-PEI (SWNTPEI/siRNA/NGR). Adapted with permission from reference [104]. Another primary application for CNTs in cancer imaging is to serve as an ultrasound contrast agent [75, 76] or a PAI agent [77, 78]. PAI detects the ultrasound signals excited by optical lasers, and it promises to have much higher spatial resolution over fluorescence imaging since ultrasound is less scatterable than photons [79]. The initial PAI study of CNTs was carried out in 2008, in which cyclic Arg-Gly-Asp (RGD) functionalized SWNTs showed strong accumulation into the tumor [21]. Afterwards, different strategies were used to improve PAI contrast for CNTs. For example, SWNTs were recently conjugated with indocyanine green (ICG) and used to identify sentinel lymph nodes (SLNs), with approximately four folds of signal enhancement being observed after ICG conjugation [80]. Another research group doped silicacoated gold nanorods (GNRs) onto the surface of MWNTs to boost PAI signals for gastric cancer delineation [81]. 16
ACCEPTED MANUSCRIPT The Raman scattering is useful for long term monitoring of CNTs since it is durable and resistant to photo-bleaching. Multicolor Raman imaging of live cells has been reported using C) and a single laser excitation [23]. By
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C/13C isotope compositions, five-color Raman imaging with SWNTs was done in a
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changing
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SWNTs containing different carbon isotopes (12C or
follow-up study [82]. The same research group also reported the first ex vivo and in vivo Raman
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imaging of CNTs [21, 24]. With the support of Raman imaging, the intracellular distribution of
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CNTs could be determined post treatment in cancer cells [83]. With the coating of noble metals
imaging and photothermal therapy [84].
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(e.g. gold or silver), CNTs can also be used for both surface enhanced Raman scattering (SERS)
Due to the chemical versatility and structural uniqueness, CNTs can be also used in other
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imaging techniques, including PET [85], MRI [86, 87], or multimodality imaging [88-91].
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4.2 Cargo delivery to cancer with CNTs CNTs have been intensively investigated as drug carriers, with DOX being the most common model drug [92]. DOX-loaded CNTs have a potent accumulation in different tumor types and the on-demand release of DOX is witnessed upon the delivery of CNTs to the tumor [93]. Stimuli-responsive cargo delivery (e.g. promotion of drug uptake/release in tumor by a laser) into tumors is also achievable by utilization of CNTs’ unique optical properties [94]. The aforementioned imaging capacity of CNTs allows them to be used as imaging guided therapeutic platforms for cancer as well. When accompanied with a targeting ligand (i.e. a molecule with strong affinity against a given receptor overexpressed in a tumor), CNTs could be adopted as tumor-selective delivery vectors. Functionalized MWNTs were used for the delivery of DOX to glioma by utilization of angiopep-2 (ANG) as the targeting ligand (for low-density lipoprotein receptor-related protein [LRP] overexpressed in glioma) [95]. Improved therapeutic efficacy was observed for DOX17
ACCEPTED MANUSCRIPT MWNTs-PEG-ANG when compared with free DOX. Another example of targeted delivery of DOX is the use of chitosan modified SWNTs conjugated with folic acid (FA) in order to target
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folate receptor (FR) positive cancer cells [96]. The SWNTs effectively inhibited the growth of
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hepatocellular carcinoma with less observable side effects over free DOX. In most cases, anticancer drugs were loaded onto CNTs through noncovalent interactions, although covalent
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binding can also be employed for hydrophilic drugs. For example, cisplatin and epidermal
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growth factor (EGF) were covalently attached to SWNTs and had enhanced killing efficacy of cancer cells that were positive for EGF receptors [97].
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With proper functionalization, CNTs can also be a good gene delivery vector of plasmid DNA, small interfering RNA (siRNA), and micro RNA [98, 99]. For example, SWNTs were
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functionalized non-covalently with succinated polyethyleimine (PEI-SA) in one study and loaded with siRNA for transdermal siRNA delivery in a murine melanoma model with an attenuated
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tumor growth being observed [100]. CNTs have also been used for thermal therapy [101] and PDT agent delivery [102, 103]. A recent trend has been to combine different cargo loadings into CNTs to maximize the therapeutic response. SWNTs were functionalized in one recent report with PEI as well as tumor-targeting NGR peptide for both siRNA delivery and PTT [104]. In tumor-bearing mice the delivery system exhibited potent tumor accumulation without obvious toxicity in main organs, and the combination of RNAi and PTT significantly enhanced the therapeutic output (Figure 3B).
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ACCEPTED MANUSCRIPT 5. THERANOSTIC APPLICATIONS OF SINGLE WALLED CARBON NANOHORNS As a close relative (with conical structure) to CNTs, carbon nanohorns (CNHs) have certain
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unique and attractive properties, although their use in biomedical applications is still at a preliminary stage. Single walled carbon nanohorns (SWNHs) are the chief member of the CNH
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family – defined as an assembly of tubular units that are 2-5 nm in diameter and 40-50 nm in
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length [105, 106]. According to the different morphologies of these aggregates, SWNHs can be
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classified into either dahlia-like type, bud-like type or seed-like type [32]. The dahlia-like SWNHs were most frequently used for cancer theranostic applications, which are composed of
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nearly 2,000 tubular unites and have a spherical structure with a diameter of 80-100 nm [107, 108]. SWNHs have many properties in common with SWNTs due to structural similarity.
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However, SWNHs have several advantages over SWNTs including more uniform and
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controllable morphology [109], easier large-scale production and free of metal contamination
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(considered to be the main attribution to CNTs’ toxicity) [110], and improved biocompatibility [111]. Hence, SWNHs are considered to have a higher potential for clinical use [112]. 5.1. Cancer imaging with SWNHs As a comparatively new material for biomedical applications, cancer imaging studies with SWNHs are quite limited. The primary imaging techniques adopted is MRI since SWNHs can be easily complexed with gadolinium [113, 114] or IONPs [115] (this property is shared by other carbon nanomaterials with similar structure such as fullerene or CNTs). For example, Gd3N@C80@SWNHs was coupled with QDs in one study to visualize U87 tumors in the mouse brain with MRI [116]. IONPs have also been stably attached onto SWNHs with holes opened (SWNHox) via a thermal transformation [117] – the as-prepared IONP-functionalized SWNHox was very stable and had clear detection in the T2-weighted MRI images.
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ACCEPTED MANUSCRIPT Recently, SWNHs were used as a PAI guided PTT platform [118]. A PEG derivative, poly(maleic anhydride-alt-1-octadecene-PEG) (C18PMH-PEG), was utilized to functionalize
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SWNHs (Figure 4A). The obtained SWNHs/C18PMH-PEG was highly dispersible and stable in
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aqueous solutions. With strong absorbance in the NIR region, it could be used for synergistic PAI/PTT. After the accumulation of SWNHs/C18PMH-PEG in the peripheric vessels of the
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tumor, the boundary of tumor was clearly delineated in PAI to achieve more accurate tumor
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ablation.
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Figure 4
Legend to Figure 4. (A) The structure and application of SWNHs/C18 PMH-PEG for PAI guided PTT. The PA images of tumor sites at different time were shown for mouse injected with SWNHs/C18 PMH-PEG. Whole animal images before and after laser irradiation were also shown for mouse injected with SWNHs/C18 PMH-PEG or saline. Adapted with permission from reference [118]. (B) The schematic illustration of SWNHs used as a tool for photothermally enhanced DOX release in tumor. Thermal images and histological examination confirmed the temperature rise in tumor area, which demonstrated the boosted cancer killing efficacy from both DOX and PTT. Adapted with permission from reference [119].
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ACCEPTED MANUSCRIPT 5.2. Cargo delivery to cancer with SWNHs The large areas both outside and inside the horn structure of SWNHs allow for
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accommodation of different cargo molecules [107, 108]. Recently, DOX-loaded SWNHs (DOXSWNHs) were used for photothermal enhanced chemotherapy [119]. After stabilization with
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chitosan, the obtained complex demonstrated good biocompatibility and photothermal properties.
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A mild heating from the laser irradiation was found to effectively promote the release of DOX from the complex, therefore effectively enhancing the toxicity of DOX to cancer cells (Figure
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4B). Another example of SWNH drug loading is cisplatin loaded in SWNHox via a solvent
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evaporation procedure [120]. The incorporated cisplatin was completely released from SWNHox resulting in increased anticancer efficacy. The same group has used SWNHox for loading zinc
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phthalocyanine (ZnPc) for synergistic PDT/PTT [121]. After subsequent functionalization with
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BSA, a single 670 nm laser was used to trigger PDT/PTT at the same time. Almost full tumor
phototherapy.
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disappearance post treatment was observed, confirming the potential of SWNHs in cancer
SWNHs have shown promise as effective gene carriers as well [108]. Polyamidoamine (PAMAM) modified SWNHs were used to deliver siRNA into prostate cancer cells (PC-3), and the results showed initial evidence of gene transfection by SWNHs with decreased toxicity to normal cells [122]. This hybrid platform possesses several advantages: the PAMAM functionalization provides strong electrostatic interactions with DNA/RNA, the PAMAM functionality also provides good solubility while decreasing toxicity, and the PAMAM allows for further biological modifications. Another application of SWNHs in gene therapy is to utilize the photothermal effect induced by SWNHs for regulation of gene expression [123]. For example, BSA modified SWNHs were combined with NIR laser irradiation to trigger heat shock
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ACCEPTED MANUSCRIPT promoter-mediated gene expression. The positive results of this study provide an important insight in the development of light-triggered gene manipulation.
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6. THERANOSTIC APPLICATIONS OF CARBON NANODIAMONDS As another important member of carbonaceous nanomaterial family, nanodiamond
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(ND) has an octahedral architecture ranging in size from 5-50nm. NDs are becoming
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increasingly useful in therapeutic and diagnostic applications due to their biocompatibility,
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scalability, and easy surface modification [124]. NDs also possesses an inherent stable fluorescence with the introduction of nitrogen into its internal structure.
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6.1. Cancer imaging with nanodiamonds
NDs are effective imaging agents due to their bright intrinsic fluorescence after the
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N or
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C, for fluorescence imaging or MRI [124]. The amount of nitrogen
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isotopes, such as
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addition of nitrogen and easy modification with an organic fluorophore or MRI detectable
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implemented into the ND allows for control over the fluorescence intensity and emission [125], which could be used for single molecule tracking inside a cell. The inherent fluorescence intensity from an ND is significantly higher compared to an AlexFluor dye at the same wavelength, so the ND does not need to be further functionalized in order to have strong imaging capabilities [126]. This strong fluorescence from NDs is particularly useful for low-background imaging in vivo [127]. In order to obtain even higher brightness from the fluorescence of the ND, helium has been used to bombard the ND powder [128]. With a larger degree of vacancy caused by helium ions inside the ND, more nitrogen was introduced, increasing the fluorescence intensity observed from the ND. Despite the active research into ND fluorescence, it was not until recently that fluorescent NDs were used for in vivo tracking of cancer cells in a murine model (Figure 5A) [129].
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ACCEPTED MANUSCRIPT Figure 5
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Legend to Figure 5. (A) Fluorescent NDs were used for in vivo lung cancer cell tracking in a murine model Adapted with permission from reference [129]. (B) DOX-loaded ND could prevent DOX from efflux from cancer cells and boost the therapeutic response in a murine liver cancer model. Adapted with permission from reference [137].
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ACCEPTED MANUSCRIPT There has been no report to date adopting magnetic NDs for in vivo detection of cancer, although some researchers claimed that Gd-NDs conjugates could be considered “game
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changing” and provide dramatically enhanced MR signal intensity [130-132]. To prepare NDs
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for cancer detection/imaging applications, various imaging labels were simultaneously incorporated into NDs. For example, one early study explored the in vivo distribution pattern of
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amino-functionalized NDs by using the positron-emitting isotope
18
F (t1/2 = 110 min) as the
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imaging label [133]. Iron nanoparticle (ferrocene) bound NDs were used in another study for fluorescence and MRI based cancer cell tracking [134]. Also, a new imaging concept, based on
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the optical detection of NDs in a magnetic field gradient, was proposed recently to achieve higher sensitivity and ND detection with better spatial resolution [135]. This imaging method has
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been named “nanodiamond imaging”, and it could be extremely useful for applications such as circulating tumor cell (CTC) tracking or stem cell tracking in vivo.
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6.2. Cargo delivery to cancer with nanodiamonds NDs can be useful vectors to provide cancer-targeted drug delivery with adjustable blood circulation and potentially decrease drug resistance of cancer cells. It was shown that NDs conjugated with DOX embedded in a microfilm produced a long term slow release of DOX for over a month [136].
ND-DOX conjugates were recently used in murine models of mammary and liver cancer to determine their distribution compared to free DOX [137]. The ND-DOX conjugates showed increased tumor growth inhibition and apoptosis compared to typical DOX treatment (Figure 5B) with decreased chemotherapeutic toxicity. Consistent therapeutic effect with better kidney and liver tolerance was confirmed in another report [138], and similar results were also obtained in a lung cancer model [139]. Other ND-drug conjugates also have shown improved tumor therapy efficacy, including 10-hydroxycampotothecin (HCPT) [140] and daunorubicin [141]. 24
ACCEPTED MANUSCRIPT Besides the loading of chemotherapeutic drugs, NDs can also be used for carrying proteins [142] or genes [143-146]. After conjugation with cationic compounds such as PEI [146],
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protamine sulfate [145], or cationic polymers [143, 144], NDs demonstrated potent siRNA
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delivery efficiency into various types of tumors. Unlike previously mentioned carbon nanomaterials, NDs are not intrinsically usable for PDT or PTT of cancer, but NDs can still be
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used for delivering PTT/PDT agents to cancer cells after proper hybridization. For example, NDs
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were complexed with gold/silver nanoparticles and used for efficient photothermal killing of
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cancer cells [147].
7. THERANOSTIC APPLICATIONS OF CARBON NANODOTS
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Carbon nanodots (C-dots) are quantum sized carbon analogues with bright and tunable
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photoluminescence [148]. Interestingly, the C-dots are photoluminescent only after surface passivation. Massive research efforts have been devoted to utilize the bright and colorful
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luminescent agents for imaging applications [149-152]. Unlike other carbonaceous nanomaterials, the C-dots have inherent aqueous solubility: no complicated functionalization is necessary for CDots to be stabilized in buffers. Large scale production of C-dots could be economically practical since many cheap and widely available materials can be used for C-dot synthesis [153-155]. Cdots are considered much more biocompatible compared to other materials, such as quantum dots, since heavy metal catalysts is not required in their synthesis.
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ACCEPTED MANUSCRIPT 7.1. Cancer imaging with carbon nanodots Like NDs, the intrinsic photoluminescence in C-dots allows the material to be used as an
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imaging agent. Produced initially by laser ablation and nitric acid treatment [148], C-dots possess bright and colorful luminescence with a strong dependence (tunable) on the excitation
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wavelength. The first in vivo imaging of these materials used C-dots doped with ZnS in order to
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increase their fluorescence [156]. It was found that C-dots retained their strong
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photoluminescence in vivo with no observable acute toxicity to the tested mice. In another study, identical C-dots with diameters of 3–4 nm were obtained from carbon nanotubes and graphite
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[157]. Fluorescence imaging was also carried out to study the distribution of these C-dots. C-dots have also been applied in cancer cell identification [158] and fluorescence imaging-guided drug
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delivery [159].
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Aside from fluorescence imaging, C-dots can be readily used for multimodal imaging.
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For example, after doping with gadolinium, C-Dots were used for both fluorescence imaging and MRI [160]. In another report, the distribution, clearance and tumor uptake of C-dots were systematically investigated by fluorescence and PET (Figure 6A) after conjugation with positron-emitting
64
Cu (t1/2 = 12.7 h) and a NIR fluorophore [161]. The combination of NIR
imaging and PET imaging could provide synergistic information to assess the in vivo fate of Cdots.
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ACCEPTED MANUSCRIPT Figure 6
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0.05 (scaled counts/ g)
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i.v.
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Legend to Figure 6. (A) The schematic structure of C-dots used for in vivo imaging and the fluorescence images of tumor-bearing mice with different administrative ways of C-dots: subcutaneous injection (s.c.), intramuscular (i.m.) injection and intraveneous injection (i.v.). White arrow indicates tumor; red arrow indicates kidney. Adapted with permission from reference [161].
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(B) Scheme for synthesis and theranostic application of CD-Oxa. In vivo fluorescence images and the tumor size of tumor-bearing mouse at different time intervals after injection of CD-Oxa. Adapted with permission from reference [162].
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ACCEPTED MANUSCRIPT 7.2. Cargo delivery to cancer with carbon nanodots C-dots can also serve as a carrier for delivery of cancer therapeutics. One example uses
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C-dots covalently attached to a chemotherapeutic [162]. C-dot oxaliplatin conjugates significantly improved the anticancer efficacy of oxaliplatin. Moreover, the distribution and the
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pharmacokinetics of this C-dot conjugate could be monitored in a real-time scale due to the
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inherent imaging capabilities of C-dots (Figure 6B), which facilitated the optimization of the administration of drugs and the therapeutic evaluation after treatment. Different complexes from
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C-dots (e.g. C-dots@GNRs or C-dots@mesoporous silica nanoparticles) have also been formed
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for the controlled release of DOX [159, 163]. The drug loading efficiency of the C-dot DOX hybrid platforms was very high and the release of DOX was triggered under laser irradiation by
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the photothermal effect [163] or pH-mediated dissociation [159]. The strong inherent
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fluorescence of the C-dots was used for determining the distribution of DOX.
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C-dots can also serve as vectors for transferring DNA/RNA, proteins, or PDT agents. For example, PEI adsorbed C-dots were used in one study to deliver siRNA against survivin into human gastric cancer cells [164]. The C-dot complex induced more than 90% of the target protein knockdown, resulting in significant cell apoptosis. Ribonuclease A was loaded onto Cdots in another study for simultaneous therapy and fluorescence imaging in gastric tumor-bearing mice [165]. After conjugation with a photosensitizer, C-dots were used for simultaneous fluorescence imaging and PDT [166-169]. The C-dots/PS conjugation strategy has several advantages including therapeutic response monitoring [166, 169], extended tissue penetration of conventional PSs [167], and laser power decrease for effective PDT [168].
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ACCEPTED MANUSCRIPT 8. THERANOSTIC APPLICATIONS OF NANOGRAPHENES Another category of carbon nanomaterial is nanosized graphene which includes its
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derivatives graphene oxide (GO), reduced graphene oxide (RGO), and hybrid graphene nanostructures [170-172]. Graphene is a two-dimensional (2d) carbon sheet assembled in a
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honeycomb structure, and it can be used as the basic composing piece for other carbon materials
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of different dimensions [173]. The unique physical and chemical characteristics of graphene (and
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its derivatives), such as ultra-high surface area, robust mechanical strength, rapid electron transfer ability, and versatile surface modification capacity, attracts enormous research interests.
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8.1 Cancer imaging with nanographenes Cancer imaging with nanographenes is as effective as using CNTs. An initial PET
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imaging of cancer study with GO nanosheets used an antibody against CD105 as the targeting
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ligand with 64Cu as a PET label. The targeted GO nanosheet resulted in enhanced tumor uptake.
radiogalium
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To broaden the clinical applicability of the GO conjugates, other PET labels including Ga (t1/2 = 9.3 h) [175] and
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Cu (t1/2 = 3.3 h) [176] were used. In another study,
vascular endothelial growth factor 121 (VEGF121) was selected as a targeting ligand to further improve tumor targeting efficiency (Figure 7A) [177]. The antibody and
64
Cu were attached
onto RGO conjugates with a slightly modified conjugation strategy (i.e. noncovalent stacking of C18PMH-PEG-NH2 was used to functionalize RGO surface instead of covalent binding) [178]. Conjugation strategies of graphene derivatives for biomedical applications have been reviewed in detail [179].
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ACCEPTED MANUSCRIPT Figure 7 NOTA
(A)
(B)
Fluorescence
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64Cu
PAI 64Cu-NOTA-GO-PEG-VEGF
121
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VEGF121
10 %ID/g
Treatment
-VEGF121
0 %ID/g
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64Cu-NOTA-GO-PEG 64 Cu-NOTA-GO-PEG
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100 nm
PDT + PTT
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PTT
Saline
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Legend to Figure 7. (A) The structure and applications of graphene derivatives as a PET imaging contrast agent for tumor detection. Adapted with permission from reference [177].
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(B) An imaging-guided hybrid PDT/PTT therapy nanovector based on graphene oxide. Adapted with permission from reference [228].
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ACCEPTED MANUSCRIPT Researchers from Oxford University conducted the initial research report of using GO as a scaffold to create SPECT imaging agents [180].
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In (t1/2 = 2.8 d) was adopted as the
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radiolabel and its chelator, p–NH2–Bn-DTPA, was introduced onto the surface of GO via π-π
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stacking. An anti-HER2 (human epidermal growth factor receptor 2) antibody, trastuzumab, was also conjugated onto the GO surface to increase uptake in HER2-positive tumors.
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In-GO-
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trastuzumab could not only detect primary tumor site, but also locate metastases in lymph nodes.
199
198,199
Au (t1/2:
198
Au: 2.7 d;
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In a recent report, GO sheets were also shown to be labeled with an
Au: 3.1 d) nanoparticle (named 198,199Au@AF-GO) [181]. In rats bearing fibrosarcoma tumors, Au@AF-GO exhibited fast penetration and strong accumulation (a surprisingly high tumor-
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198,199
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to-muscle ratio of 167 could be obtained at 4 h post-injection).
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Three major types of MR label can be used to produce graphene-based MRI contrast agents – IONPs, manganese (Mn2+), and Gd. Initial production of the different MR labelled
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nanosheets was carried out by decomposition of an iron precursor onto RGO via high temperature [182]. MnFe2O4 nanoparticles were also used to decorate GO to serve as a potential T2 contrast agent for MRI [183]. Mn2+–intercalated graphene nanoplatelets functionalized with dextran has been another potential choice as an MRI agent [184]. Fluorinated GO (FGO) is another interesting category of MRI detectable graphene derivatives [30]. FGO is used as a magnetically responsive drug carrier which can potentially be used for both MRI and photoacoustic imaging [185].
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ACCEPTED MANUSCRIPT Similar to CNTs, nanosized GO produce fluorescence in the visible and IR regions [186]. The IR-A fluorescence emissions (~1100 to 2200 nm) from GO can be detected by an InGaAs
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detector. Despite successful cell imaging with low background, the inherently low quantum yield
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of GO fluorescence hinders its in vivo applications. Adopting direct emission from GO as an imaging label is not optimal due to the limited resources of an InGaAs detector. To address
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direct emission limitations, different fluorophores were conjugated onto graphene derivatives.
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One example is a Cy7 labeled, PEG-functionalized GO nanosheets used for fluorescence tumor detection [187]. From this study, increased uptake was observed in tumors, with relatively low
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accumulation in the mononuclear phagocyte system (MPS). QD-tagged RGOs with bright
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tracking of drug behavior [190].
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fluorescence were also used for live cell imaging [188], tumor imaging and PTT [189], and
Another emerging fluorescent graphene is a graphene quantum dot (GQD), which can be
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produced from a variety of synthetic methods [191, 192]. Compared to “conventional” heavy metal based QDs, these GQDs are chemically inert, and usually possess good solubility, photostability, low toxicity [193], and high quantum-yield fluorescence emissions. Tumortargeting ligands such as hyaluronic acid (for CD44) [194] or folic acid [195] could be easily coupled onto GQDs for tumor targeting. In addition to tumor cell detection and recognition, GQDs can also be useful to monitor biochemical pathways, such as apoptosis [196]. Different GQD based hybrid nanostructures, primarily silica nanomaterials-GQDs [197-199], have also been synthesized for fluorescence imaging and drug delivery applications.
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ACCEPTED MANUSCRIPT GOs were also considered highly promising PA contrast agents [200]. In a more recent study, GO nanosheets were produced with a modified Hummers method by microwave-assisted
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pure nitronium ion oxidation instead of KMnO4. The resulting GO nanosheets exhibited strong
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absorption in the visible and NIR regions and strong PA signals from NIR excitation [201]. Strong NIR absorption and excitation from these materials is useful for long-term tracking of
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cancer cells. BSA was used in another study as both a reductant and stabilizer to a nanosized
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RGO for both PAI and PTT [202].
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8.2 Cargo delivery to cancer with nanographenes The delocalized π electrons and highly available surface area on graphene derivatives provide good loading capacity for various molecules. Despite the fact that they have been
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frequently adopted as drug/gene delivery vectors, in vivo drug delivery with graphene derivatives
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are still in its infancy. The overall benefits of nanographene as delivery vectors of anti-cancer
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drugs and genes have been reviewed elsewhere [26, 171]. DOX was loaded onto GO-IONP-PEG to be used for MRI detectable and magnetically targeted drug delivery [203]. T2 MRI demonstrated accumulation of GO-IONP-PEG in the tumor site: this study for the first time established the role of graphene derivatives as an in vivo drug delivery vector. Following a similar strategy, a GO-based T1 MRI detectable nanoplatform was developed via a GO-gadolinium complex [204], which showed strong uptake and subsequent cytotoxicity in HepG2 cancer cells after DOX loading. By chemical deposition of silver nanoparticles onto GO, GO@Ag was used for DOX loading and selective tumor targeting after NGR peptide (against CD13) conjugation [205]. With better DOX delivery to the tumor and an improved release profile over free DOX, the nanomaterial could serve as an X-ray contrast agent and a platform to combine local chemotherapy with PTT. GO nanosheets with PAI capacity was 33
ACCEPTED MANUSCRIPT also developed with DOX loading, which monitored the therapy response over time and revealed subtle microvascular changes during chemotherapy [206].
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Graphene derivatives are active candidates for directing a gene to the cancerous sites.
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They have been used for delivering DNA [207] or RNA [208] to cancer cells, with PEI [209] or
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chitosan [210] being two primary mediators to improve the DNA/RNA binding and condensation. For example, GO-PEG-PEI was used in a study and showed increased gene
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transfection efficiency as well as reduced cytotoxicity compared to free PEI [211]. Interestingly,
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the authors utilized the NIR absorbance of GO to enhance the cellular uptake of GO-PEG-PEI by using a low power NIR laser irradiation to increase membrane permeability. This GO-PEG-PEI
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was able to deliver siRNA into cells under NIR irradiation with obvious down-regulation of the
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target gene. The use of the NIR laser irradiation is known as “light-controllable gene delivery”. Another study used similarly structured GO conjugates for delivering Stat3-specific siRNA into
[212].
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melanomas to produce significant regression in tumor growth due to increased gene transfection
Nanographenes were demonstrated to have higher heat production capacity when compared with CNTs under the same conditions [213]. An initial PTT study used Cy5 labeled GO nanosheets to determine long circulation time and high tumor accumulation [187]. A laser energy density of ~ 2 W cm-2 was used for tumor irradiation with efficient tumor ablation. GOIONP-Au-PEG was also synthesized with improved photothermal tumor ablation [214]. Another IONP-GO complex was also formed by one-step adherence of IONP to carboxylic GO via hydrophobic interactions [215], which displayed a good photothermal efficiency. Recently, BaGdF5 nanoparticles were attached on the surface of GO nanosheets to form the GO/BaGdF5/PEG [216]. Efficient tumor penetration of GO/BaGdF5/PEG led to efficient 34
ACCEPTED MANUSCRIPT photothermal ablation of tumor in vivo, monitored by MRI and CT. GO nanoconjugates can also be used for diagnosis and ablation of tumor-drained regional lymph nodes [217].
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The reduction of GO can lead to enhanced absorbance in the NIR region [171], so RGOs
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can be considered more ideal for PTT applications. Single-layered RGO nanosheets (~ 20 nm) exhibited 6-fold higher NIR absorption that other non-reduced GO materials [218]. RGO-PEG
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conjugates were used to completely eliminate tumors by low-power laser irradiation in tumor
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area (0.15 W cm-2) post intratumor injection of RGO-PEG [219]. A RGO-IONP-PEG complex was also developed with good tumor targeting and improved PTT tumor ablation over GO [220].
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RGO nanomesh (RGONM) was another recently developed structures of graphene with over 20fold higher NIR absorption [221]. As-synthesized RGONMs were functionalized by PEG, RGD,
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laser power (0.1 W cm-2).
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and Cy7 and completely eliminated U87MG tumors followed by irradiation with an ultralow
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The first study of PDT with graphene derivatives used ZnPc as a PS [222]. The GO-ZnPc complex was internalized in MCF-7 cells, exhibiting a pronounced cytotoxicity under Xe light irradiation. Adopting a similar PS-attaching strategy, a folic acid-conjugated GO was used to load chlorin e6 (Ce6) for selective PDT in tumor cells [223]. Clinical translation of current PDT agents are often limited by their low singlet oxygen (1O2) quantum yields. One GQD-based PDT agent could produce 1O2 via a multistate sensitization process, resulting in a quantum yield of ~1.3, the highest recorded for PDT agents [224]. The fluorescence of PSs are often drastically quenched via an energy/charge transfer process after their interactions with graphene derivatives, which sometimes limits their detectability. To solve this problem, a PTT agent was prepared from sinoporphyrin sodium (DVDMS) loaded, PEGylated GO (named GO-PEG-DVDMS) which possessed more stable fluorescence for imaging guided PDT [225]. The uniqueness of 35
ACCEPTED MANUSCRIPT DVDMS is that its fluorescence could be enhanced via intramolecular charge transfer post loading onto GO-PEG. Another PS molecule, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-
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alpha (HPPH), was loaded onto PEG-GO. In vivo distribution and delivery of the obtained 64
Cu
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complex could be tracked by both fluorescence imaging and PET after radiolabeling with [226]. Improved cancer cell killing efficacy was witnessed in all of these reports.
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Graphene-based nanoplatforms are useful for multiple hybrid therapies, such as
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PDT/PTT and PTT/chemotherapy. Carboxylated graphene nanodots (cGdots) has been used for imaging-guided PDT/PTT without requirement of an extra PS [227]. cGdots have shown to
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effectively shrink MDA-MB-231 tumors compared with a saline-treated control group upon NIR laser irradiation. The luminescence emission from cGdots enabled visualization of tumor tissue
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to better interpret the treatment efficacy in mice. DVDMS-loaded GO-PEG (GO-PEG-DVDMS) was also used in another study for combined PDT and PTT [228]. The synergistic PDT/PTT
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efficacy was monitored by fluorescence/PA dual-modal imaging (Figure 7B). One graphene based nanohybrid was engineered via a facile one-pot process consisting of Fe3O4, Pluronic F127 (PF127), and graphene nanosheets [229]. DOX-loaded nanohybrids showed a significant cytotoxicity to HeLa cells, which could be intensified post laser irradiation. Another peptidemodified magnetic graphene-based mesoporous silica was synthesized with good NIR absorbance, facile magnetic separation, large T2 relaxation rates, and a high DOX loading capacity [230]. With DOX loading, it could integrate MRI, magnetic targeting and receptormediated active targeting, and chemo-photothermal therapy for a synergistic therapy of glioma.
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ACCEPTED MANUSCRIPT Graphene derivatives are also good choices for hybrid cargo loading. For example, a chitosan functionalized magnetic graphene nanoparticle (CMG) was used for simultaneous gene
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and drug delivery [231]. After intravenous administration of GFP-plasmid encapsulated within
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DOX-CMGs into lung tumor-bearing mice, both GFP expression and DOX accumulation at the tumor site were shown. In another study, PAMAM-grafted Gd-GO nanoparticles were evaluated
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as carriers to deliver both chemotherapeutic drugs and miRNAs to cancer cells [232].
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9. CONCLUSIONS AND FUTURE PERSEPCTIVES As we can draw a preliminary conclusion based on aforementioned summarized research
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progress, carbonaceous nanomaterials are extremely useful tools for theranostic applications in cancer. The unique physical properties (e.g. intrinsic fluorescence or NIR absorbance), chemical
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versatility, and superior cargo loading capacity are the prerequisite for them to be used as potent
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cancer therapeutics. The cancer imaging and cargo delivery applications of six leading players
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(with CNTs and nanographenes as two leading horses) from carbonaceous nanomaterial family were discussed in this review article. We are fully aware that there are still other existing carbon nanostructures (e.g. carbon nano-onions [233]), which may be useful for theranostic applications in cancer. However, their limited case numbers restrained the devotion of a separate section for illustration – interested readers can refer to literature [234] for details. The structural integrity is critical for certain carbonaceous nanomaterials (e.g. fullerenes or CNHs), thus suitable medication/functionalization methods should be chosen carefully to improve their biocompatibility, solubility, and cargo loading efficiency (Table 1). Continued research into optimized surface modifications will allow for more effective loading and release of relevant moieties. The future research should be directed on development of functionalization strategies which can result in accurate release of the cargo from the vector. Although concepts such as “stimuli-responsive” drug delivery have been proposed utilizing the heat-driving cargo 37
ACCEPTED MANUSCRIPT release from carbonaceous nanomaterials [29, 94], the ability to control the system is still comparatively low (e.g. with limited tissue penetration), with inevitable heat damage to
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surrounding fragile tissues. To partially address this dilemma, drug loading with an environment
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sensitive chemical bond (e.g. pH-sensitive) can be helpful [235].
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With the increasing complexity of carbonaceous nanomaterials, knowledge of their in vivo kinetics is crucial to boost their performance. Imaging techniques are powerful tools to
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determine in vivo kinetics since they can not only provide the precise distribution profile of
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carbonaceous nanomaterials, but also give evaluation on therapeutic response [6]. However, each individual imaging technique has its pros and cons. For example, optical imaging
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(fluorescence/bioluminescence/Raman) is highly sensitive and cost-effective with good security,
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but their tissue penetration is rather limited. MRI possesses high spatial resolution for tissues with good penetration depth, while its detection sensitivity for a given molecule is not optimal.
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PET or SPECT imaging can provide highly sensitive and quantitative detection of trace materials, but the radiation exposure and relatively limited spatial resolution are major disadvantages. The integration of multi-modalities into a single platform may provide an answer to partially solve this conundrum – with different imaging modalities synergistically combined (e.g. MRI/PET to provide both high-resolution images and accurate molecular profile) in different studies for carbonaceous nanomaterials, more precise information can be collected to prepare them as the “next-generation” delivering vectors for cancer therapy.
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ACCEPTED MANUSCRIPT To minimize the impact of carbonaceous nanomaterials to normal tissues/organs, their toxicity should be properly evaluated [236, 237]. As most reports claimed that carbonaceous
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nanomaterials are quite biocompatible after proper functionalization, skepticism can be raised
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due to their accumulation in cells from MPS (e.g. macrophages), incomplete excretion from the test subjects, and limited biodegradability. For example, induction of ROS from carbonaceous
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nanomaterials (especially with a tubular morphology) could be one leading factor to cause cell
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death [238]. At the same time, as metal catalysts are needed in the production of some carbonaceous nanomaterials (e.g. CNTs), heavy metal ions release from the material even after
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functionalization could be another source of toxicity. Combined with toxicological assessment methods, imaging techniques could be used to provide a better insight into their distribution,
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pharmacokinetic behavior, and eventually long-term toxicity. Some carbonaceous nanomaterials with small sizes, like fullerene, C-dots, were able to be cleared completely within weeks and do
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not have long term toxicity concerns [27, 239]. There has also been some recent progress on the development of a “biodegradable” carbonaceous nanomaterial [240, 241], and will hopefully design a “deliver and degrade” vector with carbonaceous nanomaterials for ideal pharmacokinetic behavior and low long term toxicity. There is potential for future clinical usage of carbonaceous nanomaterials. With the multi-functionality of these materials, future developments can involve the production of carbonaceous nanomaterials with the capacity of detecting and responding to the dynamic changes of proteins or DNA/RNA in living systems (i.e. a “smart” surgeon-like material). Joint efforts from scientists and continued research can further develop advanced carbonaceous nanomaterials for cancer theranostic applications.
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS The authors acknowledge financial support from the Department of Radiology at
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University of Michigan Health Systems.
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Graphical abstract
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S0168-3659(15)00251-5 doi: 10.1016/j.jconrel.2015.04.021 COREL 7642
To appear in:
Journal of Controlled Release
Received date: Revised date: Accepted date:
7 March 2015 17 April 2015 18 April 2015
Please cite this article as: Daiqin Chen, Casey A. Dougherty, Kaicheng Zhu, Hao Hong, Theranostic Applications of Carbon Nanomaterials in Cancer: Focus on Imaging and Cargo Delivery, Journal of Controlled Release (2015), doi: 10.1016/j.jconrel.2015.04.021
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Theranostic Applications of Carbon Nanomaterials in Cancer: Focus on Imaging and Cargo Delivery
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Daiqin Chen1,2, Casey A. Dougherty1,2, Kaicheng Zhu1,2, Hao Hong1,2,3*
1
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Center for Molecular Imaging, University of Michigan Health Systems, Ann Arbor, Michigan 48109, United States 2
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Department of Radiology, University of Michigan Health Systems, Ann Arbor, Michigan 48109, United States 3
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University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, United States
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Requests for reprints: Hao Hong, PhD, Departments of Radiology, University of Michigan Health Systems, Room A520, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. Fax: 1-734-763-5447 Tel: 1-734-615-4634 E-mail: [email protected]
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ACCEPTED MANUSCRIPT Contents 1. Introduction ............................................................................................................................ 4 2. Functionalization of carbon nanomaterials ............................................................................ 6
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3. Theranostic applications of fullerenes (nontubular type) ...................................................... 7 3.1 Cancer imaging with fullerenes ........................................................................................ 8
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3.2 Cargo delivery to cancer with fullerenes .......................................................................... 9 4. Theranostic applications of carbon nanotubes ....................................................................... 9
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4.1 Cancer imaging with fullerenes ...................................................................................... 10 4.2 Cargo delivery to cancer with fullerenes ........................................................................ 12
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5. Theranostic applications of single-walled carbon nanohorns .............................................. 12 5.1 Cancer imaging with SWNHs ........................................................................................ 13
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5.2 Cargo delivery to cancer with SWNHs .......................................................................... 14 6. Theranostic applications of nanodiamonds .......................................................................... 14 6.1 Cancer imaging with nanodiamonds .............................................................................. 14
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6.2 Cargo delivery to cancer with nanodiamonds ................................................................ 16
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7. Theranostic applications of carbon nanodots ....................................................................... 16 7.1 Cancer imaging with carbon nanodots ........................................................................... 16 7.2 Cargo delivery to cancer with carbon nanodots ............................................................. 17
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8. Theranostic applications of nanographenes ......................................................................... 18 8.1 Cancer imaging with nanographenes ............................................................................. 18 8.2 Cargo delivery to cancer with nanographenes................................................................ 20 9. Conclusions and future perspectives .................................................................................... 22 Acknowledgments.................................................................................................................... 23 References ................................................................................................................................ 24
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ACCEPTED MANUSCRIPT ABSTRACT: Carbon based nanomaterials have attracted significant attention over the past decades due
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to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of
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carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials
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will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene
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derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging
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(fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.)
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and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and
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the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional
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carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer.
KEYWORDS: carbon nanomaterials, theranostics, cancer, molecular imaging, drug delivery
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ACCEPTED MANUSCRIPT 1. INTRODUCTION With an estimation of 1,658,370 new cases and 589,430 deaths in the United States in
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2015, cancer is considered as the second leading health threat [1]. Despite great progress made in the past few decades, early diagnosis and efficient treatment of cancer are still challenges to
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overcome [2, 3]. The current standard management of cancer patients involves stage
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determination (by imaging or biopsies), chemo/radiation therapy, and/or surgical resection.
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Molecular imaging, a useful tool to monitor in vivo biochemical events, can provide invaluable insights into both cancer diagnosis and therapeutic response monitoring [4]. Different molecular
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imaging techniques, including optical imaging (fluorescence/bioluminescence/Raman), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET),
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single photon emission computed tomography (SPECT), and ultrasound (US), have furthered our
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understanding of cancer initiation, progression, and metastasis.
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Post cancer diagnosis/detection, chemotherapy is the most frequently used method for cancer treatment. In order to obtain the best curative effect while avoiding negative side effects, it is important to develop drug delivery systems with strong cancer targeting abilities, as well as controllable/on-demand release properties. Nanomaterials have been stated to be one of the most promising platforms for cancer imaging and drug delivery since they have the ability to synergistically combine diagnosis and therapy into one material [5, 6]. A material that combines diagnosis and therapy has been termed a “theranostic” [7, 8].
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ACCEPTED MANUSCRIPT Nanomaterials can be generally classified into organic nanomaterials, inorganic nanomaterials and hybrid nanomaterials [9-11]. The theranostic applications of organic
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nanomaterials (primarily including liposomes, micelles, dendrimers, and protein-based
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nanomaterials) in cancer have been previously summarized elsewhere [12, 13]. Inorganic nanomaterials (e.g. silica nanoparticles, gold nanoparticles, iron oxide nanoparticles and
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carbonaceous nanomaterials etc.) are more actively being used for cancer theranostic
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applications due to their unique physical properties (which usually improve the therapeutic outputs) and comparatively lower production cost [14-16]. Among these inorganic nanomaterials,
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carbonaceous nanomaterials are rising stars due to their excellent mechanical, thermal and optical properties (Figure 1) [17, 18]. For instance, most of these carbonaceous nanomaterials
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possess strong absorption in the infrared (IR) or near infrared (NIR) regions, which is useful for photothermal therapy (PTT) of cancer. Some inorganic nanomaterials (e.g. carbon nanotubes or
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nanodots) can also produce fluorescence in the visible and infrared regions for fluorescence imaging [19, 20]. In addition, carbonaceous nanomaterials are able to transform the energy from a laser into acoustic signals, which makes them promising agents for photoacoustic imaging (PAI) [21, 22]. Finally, intrinsic Raman vibration signals from carbonaceous materials can also provide a reliable method to monitor their distribution and metabolism in vivo [23, 24].
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ACCEPTED MANUSCRIPT Figure 1 Radioisotopes
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Chemo drugs
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Carbon nanomaterials
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Genes
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Polymer functionalization
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PDT & photothermal
Image-guided cancer therapy Targeting ligands
Imaging labels
Legend to Figure 1. The schematic illustration of theranostic applications of carbon nanomaterials in cancer.
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ACCEPTED MANUSCRIPT Due to the unique sp2 carbon structure and inherent hydrophobic nature of carbonaceous nanomaterials, the nanomaterials have the potential to be useful drug delivery vectors. Multiple
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copies of drugs or DNA/RNA molecules can easily be absorbed onto their surface through
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hydrophobic interactions or π-π stacking [25-27]. After loading the drugs/genes, the carbonaceous nanomaterials (or their assemblies) can accumulate into tumors in vivo through
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either “active” targeting (by introduction of a targeting ligand for overexpressed receptors in
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tumor/vasculatures) or by the enhanced permeability and retention (EPR) effect. Drug/gene cargos on carbonaceous nanomaterials possess distinct pharmacokinetic behavior compared to
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free molecules, which may not only enhance the tumor killing efficiency but also decrease toxicity in surrounding healthy tissue. In some cases, carbonaceous nanomaterials (e.g. fullerene)
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can also be used as anticancer agents themselves and provide synergetic antitumor effects with a given drug [28]. Moreover, the addition of stimuli (e.g. light or heat) responsive polymers to
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carbonaceous nanomaterials can also be extremely useful for selective and controllable drug release [29, 30].
Much research effort has been devoted to carbonaceous nanomaterials as platforms for cancer diagnosis and drug delivery due to their many aforementioned advantages, leading to the goal of personalized cancer therapy [7, 31]. By combining imaging labels with therapeutics in the same platform, the location of the tumor can be precisely delineated, and the optimal drug doses as well as therapeutic time frame can be determined by acquiring the real-time drug distribution information in vivo. Image-guided carbonaceous nanomaterials can evaluate the therapeutic efficacy of a given treatment by monitoring the abundance fluctuation of target proteins/receptors as well. Theranostic applications of carbonaceous nanomaterials will be discussed in the current review article. They will be categorized into fullerenes, nanotubes, 7
ACCEPTED MANUSCRIPT nanohorns, nanodiamond, nanodots and graphene derivatives according to their morphologies. The functionalization (i.e. chemical modification) of these materials before their biomedical uses
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will be briefly introduced. The molecular imaging and cargo delivery applications of these
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materials will be the major focus. Lastly, the safety/toxicity concerns of each carbonaceous
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nanomaterial will be covered.
2. FUNCTIONALIZATION OF CARBON NANOMATERIALS
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Since most of pristine carbonaceous nanomaterials are highly hydrophobic (due to the sp2 carbon nanostructure), proper functionalization is necessary before their biomedical applications.
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Generally speaking, there are two primary strategies of functionalization: covalent or noncovalent (Table 1). Covalent modifications usually involve introduction of hydrophilic
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functional groups (e.g. hydroxyl groups, carboxyl groups, or amino groups) for the further conjugation of protecting polymers (such as poly(ethylene glycol) [PEG]), targeting ligands, or
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drug/gene cargos [32-35]. For example, carboxyl groups (-COOH) can be formed by oxidation by agents like nitric acid. Besides oxidation, the cycloaddition reaction is another covalent approach to modify carbonaceous nanomaterials, in which the aromatic rings inside the material structures are used as the reaction target [27].
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ACCEPTED MANUSCRIPT Table 1 Functionalization strategies for carbonaceous nanomaterials Functionalization molecule(s)
Major Purpose(s)
Potential toxicity concerns
Representative References
PEG derivatives Chitosan
Stabilization Stabilization and gene delivery Stabilization and gene delivery Imaging label
Biocompatible Biocompatible
[63, 95, 174] [96, 210, 231]
BSA M13 phage
DNA DNA/siRNA Nanostructures (IONP, QDs, gold NPs etc.) Gadolinium (Gd) Chemo drugs Photosensitizers 9
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Imaging label
Mostly biocompatible
[73, 161]
Biocompatible Potential immune response
[95, 178, 242] [100, 164]
Biocompatible Biocompatible
[243] [119]
Biocompatible Potential immune response
[123] [70, 71]
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Pluronic F127 Chitosan
[85, 161] [132]
Stabilization Stabilization and gene delivery Stabilization Stabilization and gene loading Stabilization Stabilization and tumor targeting Stabilization
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PEG derivatives Polyethylenimine (PEI)
[104, 146, 209]
Toxicity from premature release Tumor therapy Toxicity from premature release Tumor Potential immune targeting response
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Antibodies, proteins, or peptides Fluorophores Noncovalent
Radiation exposure
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Chemo drugs
Imaging label
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Radioisotopes and chelators Gadolinium (Gd)
Potential immune response
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Polyethylenimine (PEI)
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Covalent
Potential immune response Gene therapy Gene inhibition in normal tissues Imaging label, MPS capture and PDT, and PTT potential metal contamination Imaging label Toxicity from premature release Tumor therapy Toxicity from premature release PDT Damage to normal tissues by ROS
[57, 97] [47, 97, 104, 174, 221]
[207] [122, 164, 212] [63, 72, 147, 203]
[116, 204] [56, 57, 119] [55, 102, 103, 121, 168, 223]
ACCEPTED MANUSCRIPT The covalently functionalized carbonaceous nanomaterials are usually stable. However, the limitation lies in that this type of functionalization method inevitably destroys partial material
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structure causing the loss of certain intrinsic properties (e.g. photothermal capacities). Compared
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with covalent functionalization, the reaction condition of noncovalent functionalization is comparatively mild, which involves coating the carbonaceous nanomaterials with amphiphilic
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molecules. The hydrophobic motifs of the amphiphilic molecules could be anchored onto the
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material’s surface with the hydrophilic ends extending to the aqueous solution and maintaining the stability of the whole material. Noncovalent interactions include electrostatic forces, π-π
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interactions, hydrogen bonding, or van der Waals forces [36, 37]. As we can expect, lower stability of noncovalent conjugates is the major concern for this type of functionalization. For
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example, Chung et al. attempted to conjugate lysozyme onto the surface of nanodiamonds via electrostatic interactions [38]. Although direct absorption based on electrostatic interactions was
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observed to be fast and easy, the stability of formed conjugates was far from satisfactory. A lot of thought about stability and design of the nanomaterial must be taken into account before choosing an appropriate functionalization method for any carbonaceous nanomaterial. A balance between stability and structural integrity must be maintained before any further biomedical applications. The functionalization strategy is one of the most significant factors that can control the subsequent loading efficiency of drug/gene/imaging labels. For those materials which are not sensitive to structural alteration (e.g. carbon nanotube, nanodiamonds, or nanographene oxide), a covalent functionalization can be preferred, but other factors (e.g. effective cargo release, circulation half-life, or reagent availability) must be considered. Carbonaceous nanomaterials are only effective for cancer theranostic applications once the correct functionalization strategy is chosen and applied. 10
ACCEPTED MANUSCRIPT 3. THERANOSTIC APPLICATIONS OF FULLERENES (NONTUBULAR TYPE) Fullerene is the first category of carbonaceous nanomaterial frequently used for cancer
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theranostic applications. Since the initial discovery of the first fullerene, C60, in 1985, the fullerene family has been expanding rapidly with more members being identified [39]. Among
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these fullerene derivatives, C60 (OH)x and C82 (OH)22 are two of the most investigated fullerene
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species [40]. Their unique structures provide fullerenes with some very attractive and unique
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properties [27]. For example, gadolinium ions (Gd, T1-weighted) can be incorporated into the carbon cage of the C82 molecules, making Gd@C82 derivatives promising MRI contrast agents
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[41]. Photodynamic therapy (PDT) relies on reactive oxygen species (ROS, e.g. singlet oxygen) to be emitted from a photosensitizer (PS) under laser irradiation to destroy cancer cells [42].
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Many fullerene derivatives can serve as effective photosensitizers for PDT under laser irradiation
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and work as a “radical sponge”, demonstrating anticancer properties by themselves [43].
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Fullerenes are also reported to be excellent cargo delivering vectors for anticancer drugs and genes (DNA/RNA) – both enhanced cytotoxicity and gene transfection efficiency are observed with the use of fullerenes as a non-viral vector [44]. 3.1. Cancer imaging with fullerenes The most dominant utilization of fullerene in cancer imaging is for MRI. To be more specific, metallofullerene complexes (e.g. gadolinium-containing or iron oxide nanoparticle [IONP, T2-weighted]-containing) are generally considered to be good MRI contrast agents [45]. In
one
study,
a
water-soluble
gadolinium
endohedral
fulleride,
Gd@C82O6(OH)16-
(NHCH2CH2COOH)8 (AAD-EMFs) was synthesized with good stability and water proton relaxivity [46], which is ideal for MRI applications. In a follow-up report, these AAD-EMFs were further conjugated with an antibody against green fluorescence protein (GFP) [47]. With the assistance of GFP, the cellular distribution of AAD-EMFs can be more accurately detected. 11
ACCEPTED MANUSCRIPT Other groups also explored the morphological impact of the gadolinium-fullerene complex to MR relaxation behavior [48, 49]. Details of other gadolinium-fullerene complexes and their MR
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relaxation behavior can be found in references [50, 51]. IONP-decorated fullerene represents
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another category of T2-weighted MRI agents. A recent study used IONP-C60 composite for MRI, PDT, and PTT triple applications [52]. Adopting folic acid (FA) as the tumor targeting molecule,
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this hybrid IONP-C60 could not only visualize tumor in vivo (Figure 2A), but also provided
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synergistic PDT/PTT for effective and selective ablation of tumor.
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Figure 2
Folic acid (FA)
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IONP
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C60 fullerene PEG Control
C60-IONP-PEG C60-IONP-PEG C60-IONP-PEG -FA + magnet -FA
PEI
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ROS
Control Control
C60-PEI-DOX + laser
C60-PEI-DOX + laser
Legend to Figure 2. (A) Structure of C60-IONP-PEG-FA and its application as an MRI-guidable PDT/PTT agent for tumors. Significant “darkening” of tumor area based on T2-weighted MR images indicated selective accumulation of C60-IONP-PEG-FA from folate receptor targeting and magnetic attraction. Adapted with permission from reference [52]. (B) Structure and application of C60-PEI-DOX for synergistic cancer therapy by DOX and PDT. C60-PEI-DOX demonstrated good uptake in melanoma cells and significant production of cellular ROS after laser irradiation. Histological examination also confirmed that treatment with C60-PEI-DOX plus laser irradiation produced maximal cancer cell killing efficiency. Adapted with permission from reference [57].
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ACCEPTED MANUSCRIPT Fullerene derivatives are also useful for fluorescence imaging of cancer. One example is a hyaluronated (for CD44-targeting) C60 fullerene with a strong intrinsic NIR fluorescence
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emission. The hyaluranoted C60 fullerene was used for both in vivo fluorescence imaging of
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HCT-116 tumors (CD44+) and photodynamic killing of tumors [53]. Since the intrinsic fluorescence signal from fullerene is not very strong, external fluorophores could also be
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attached to facilitate the visualization of fullerene complexes in vivo. For example, a hybrid
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nanoconjugate was formed from the condensation between hyaluronated C60 fullerene and upconversion nanocrystals [54]. Although only cell imaging and ROS validation were carried out
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in this study, this fullerene complex could be potentially used for in vivo fluorescence imaging and PDT.
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Despite their usefulness as imaging contrast agents, fullerene derivatives are rarely adopted solely for cancer imaging/detection purposes. With synergistic integration into other
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applications (e.g. drug delivery), imaging can also provide guidance to assess delivery efficiency or therapeutic responses.
3.2. Cargo delivery to cancer with fullerenes The unique structure of fullerene derivatives render them broadly useful for delivery of different cargos. Recently, an Asn-Gly-Arg (NGR, against CD13 on the tumor cells) functionalized
C60 fullerene was used as a targeted delivery system for a PDT agent (2-
methoxyestradiol [2-ME]) [55]. Joint photosensitization effects were witnessed for C60 fullerene to boost the cell apoptosis efficacy of 2-ME on MCF-7 breast cancer cells. Other chemotherapy drugs, such as doxorubicin (DOX) and pacilitaxel, were also loaded into C60 [56, 57], which was confirmed to possess enhanced tumor killing capacity over free individual drug. In one of these studies, cancer cell death was the consequence from synergistic pH-sensitive DOX release and PDT-mediated ROS (Figure 2B) [57]. 13
ACCEPTED MANUSCRIPT With the introduction of proper cationic groups, fullerenes can also be attractive carriers for gene delivery due to the carbon cages inside fullerene [58, 59], which can stabilize DNA-
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fullerene complexes. A cationic tetra (piperazino) fullerene epoxide (TPFE) was synthesized as
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an in vivo gene delivery carrier [59]. The initial validation was carried out after loading the fullerene with DNA encoding enhanced green fluorescent protein gene (EGFP). The gene
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delivery by TPFE was efficient and organ selective, causing no noticeable toxicity. Although
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cancer-selective gene delivery (e.g. therapeutic siRNA) with nontubular fullerenes has not been carried out to date, these studies validated the value of using fullerenes as a gene delivery vector
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for cancer treatment.
Various fullerene-based multifunctional vectors (e.g. combination of drug delivery with
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imaging or PDT/PTT) have been developed recently [52, 60-62]. One recent example was the utilization of a PEGylated fullerene decorated with IONPs for targeted delivery of PDT-sensitive
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hematoporphyrin monomethyl ether (HMME), readily monitored by MRI [63]. The PDT efficacy of HMME delivered by this composite was dramatically improved both in vitro and in vivo when compared with that of free HMME, monitored by MRI and other evidences. 4. THERANOSTIC APPLICATIONS OF CARBON NANOTUBES Although strictly speaking, carbon nanotubes (CNTs) belong to a sub-category of fullerene derivatives, their wide-spread biomedical applications necessitate a separate section to illustrate their leading role for cancer theranostics inside the whole carbon nanomaterial family. CNTs are carbon allotropes which possess a cylindrical nanostructure with a very high length-to-diameter ratio. According to the numbers of sheets of sp2 carbon atoms, CNTs can be generally categorized into single-walled nanotubes (SWNTs) and multi-walled nanotubes (MWNTs). CNTs retain several unique properties, including strong resonant Raman scattering and photoluminescence in the NIR region, and good laser-to-acoustic transferring capacity [64]. The 14
ACCEPTED MANUSCRIPT strong NIR absorption of CNTs enables them to be used as a potential candidate for cancer PTT. The large area inside and outside CNTs provide tremendous accommodation to various
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therapeutic molecules [25].
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4.1. Cancer imaging with CNTs
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We will focus on the updates within the passing five years since the progress in molecular imaging with SWNTs has been summarized previously [65]. Among all the imaging
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techniques, fluorescence imaging is the most frequently adopted for CNTs in cancer imaging/detection. The intrinsic emission in the second NIR region (1100-1400 nm, NIRII) from
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CNTs could be readily used for in vivo tumor detection [66, 67]. Since the initial success of CNT imaging producing high-resolution tumor vessel visualization [19], different studies have
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confirmed that CNTs do in fact produce high signal-to-noise ratios. Most organisms investigated have extremely low absorption in the second NIR wavelength region [68, 69]. In an interesting
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study, M13 phage-conjugated SWNTs with stable display of tumor-targeting sequence were used for NIR fluorescence imaging of prostate tumors in mice [70]. The same group improved their results by adopting a new tumor-targeting sequence on M13-SWNTs, which could facilitate the detection and excision of tumors with submillimeter diameters (Figure 3A) [71]. At the same time, CNTs could also be conjugated with multiple fluorophores with different emission wavelengths (e.g. quantum dots [QD] and polydiacetylene) [72, 73] for fluorescence imaging of cancer cells based on fluorescence resonance energy transfer (FRET). Besides fluorescence imaging, bioluminescence imaging was also used recently to monitor the distribution of CNTs in vivo after conjugation of a thermostable luciferase onto CNTs [74].
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ACCEPTED MANUSCRIPT Figure 3 Unguided M13-SWNT guided tumor excision
M13-SWNT guided
Post-surgery (unguided)
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Pre-surgery
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Legend to Figure 3. (A) The use of M13 functionalized SWNTs for NIR fluorescence-guided tumor excision. Peptide sequence targeting secreted protein, acidic and rich in cysteines (SPARC) was displayed on M13. The fluorescence from M13-SWNTs was successfully used for detection and excision of submillimeter tumors which were not removable without M13-SWNTs guidance. SBP stands for SPARC binding peptide. Adapted with permission from reference [71]. (B) The structure of SWNT-PEI and its application for siRNA/PDT synergistic therapy of prostate tumors. SWNT-PEI loaded with siRNA (with or without NGR targeting peptide) could enter nucleus of PC-3 cells for effective siRNA delivery at 4 h post-treatment. In vivo siRNA/PTT demonstrated significantly beneficial therapeutic response when compared with only RNA interference induced by siRNA loaded, NGR conjugated SWNT-PEI (SWNTPEI/siRNA/NGR). Adapted with permission from reference [104]. Another primary application for CNTs in cancer imaging is to serve as an ultrasound contrast agent [75, 76] or a PAI agent [77, 78]. PAI detects the ultrasound signals excited by optical lasers, and it promises to have much higher spatial resolution over fluorescence imaging since ultrasound is less scatterable than photons [79]. The initial PAI study of CNTs was carried out in 2008, in which cyclic Arg-Gly-Asp (RGD) functionalized SWNTs showed strong accumulation into the tumor [21]. Afterwards, different strategies were used to improve PAI contrast for CNTs. For example, SWNTs were recently conjugated with indocyanine green (ICG) and used to identify sentinel lymph nodes (SLNs), with approximately four folds of signal enhancement being observed after ICG conjugation [80]. Another research group doped silicacoated gold nanorods (GNRs) onto the surface of MWNTs to boost PAI signals for gastric cancer delineation [81]. 16
ACCEPTED MANUSCRIPT The Raman scattering is useful for long term monitoring of CNTs since it is durable and resistant to photo-bleaching. Multicolor Raman imaging of live cells has been reported using C) and a single laser excitation [23]. By
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C/13C isotope compositions, five-color Raman imaging with SWNTs was done in a
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changing
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SWNTs containing different carbon isotopes (12C or
follow-up study [82]. The same research group also reported the first ex vivo and in vivo Raman
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imaging of CNTs [21, 24]. With the support of Raman imaging, the intracellular distribution of
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CNTs could be determined post treatment in cancer cells [83]. With the coating of noble metals
imaging and photothermal therapy [84].
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(e.g. gold or silver), CNTs can also be used for both surface enhanced Raman scattering (SERS)
Due to the chemical versatility and structural uniqueness, CNTs can be also used in other
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imaging techniques, including PET [85], MRI [86, 87], or multimodality imaging [88-91].
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4.2 Cargo delivery to cancer with CNTs CNTs have been intensively investigated as drug carriers, with DOX being the most common model drug [92]. DOX-loaded CNTs have a potent accumulation in different tumor types and the on-demand release of DOX is witnessed upon the delivery of CNTs to the tumor [93]. Stimuli-responsive cargo delivery (e.g. promotion of drug uptake/release in tumor by a laser) into tumors is also achievable by utilization of CNTs’ unique optical properties [94]. The aforementioned imaging capacity of CNTs allows them to be used as imaging guided therapeutic platforms for cancer as well. When accompanied with a targeting ligand (i.e. a molecule with strong affinity against a given receptor overexpressed in a tumor), CNTs could be adopted as tumor-selective delivery vectors. Functionalized MWNTs were used for the delivery of DOX to glioma by utilization of angiopep-2 (ANG) as the targeting ligand (for low-density lipoprotein receptor-related protein [LRP] overexpressed in glioma) [95]. Improved therapeutic efficacy was observed for DOX17
ACCEPTED MANUSCRIPT MWNTs-PEG-ANG when compared with free DOX. Another example of targeted delivery of DOX is the use of chitosan modified SWNTs conjugated with folic acid (FA) in order to target
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folate receptor (FR) positive cancer cells [96]. The SWNTs effectively inhibited the growth of
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hepatocellular carcinoma with less observable side effects over free DOX. In most cases, anticancer drugs were loaded onto CNTs through noncovalent interactions, although covalent
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binding can also be employed for hydrophilic drugs. For example, cisplatin and epidermal
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growth factor (EGF) were covalently attached to SWNTs and had enhanced killing efficacy of cancer cells that were positive for EGF receptors [97].
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With proper functionalization, CNTs can also be a good gene delivery vector of plasmid DNA, small interfering RNA (siRNA), and micro RNA [98, 99]. For example, SWNTs were
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functionalized non-covalently with succinated polyethyleimine (PEI-SA) in one study and loaded with siRNA for transdermal siRNA delivery in a murine melanoma model with an attenuated
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tumor growth being observed [100]. CNTs have also been used for thermal therapy [101] and PDT agent delivery [102, 103]. A recent trend has been to combine different cargo loadings into CNTs to maximize the therapeutic response. SWNTs were functionalized in one recent report with PEI as well as tumor-targeting NGR peptide for both siRNA delivery and PTT [104]. In tumor-bearing mice the delivery system exhibited potent tumor accumulation without obvious toxicity in main organs, and the combination of RNAi and PTT significantly enhanced the therapeutic output (Figure 3B).
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ACCEPTED MANUSCRIPT 5. THERANOSTIC APPLICATIONS OF SINGLE WALLED CARBON NANOHORNS As a close relative (with conical structure) to CNTs, carbon nanohorns (CNHs) have certain
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unique and attractive properties, although their use in biomedical applications is still at a preliminary stage. Single walled carbon nanohorns (SWNHs) are the chief member of the CNH
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family – defined as an assembly of tubular units that are 2-5 nm in diameter and 40-50 nm in
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length [105, 106]. According to the different morphologies of these aggregates, SWNHs can be
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classified into either dahlia-like type, bud-like type or seed-like type [32]. The dahlia-like SWNHs were most frequently used for cancer theranostic applications, which are composed of
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nearly 2,000 tubular unites and have a spherical structure with a diameter of 80-100 nm [107, 108]. SWNHs have many properties in common with SWNTs due to structural similarity.
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However, SWNHs have several advantages over SWNTs including more uniform and
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controllable morphology [109], easier large-scale production and free of metal contamination
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(considered to be the main attribution to CNTs’ toxicity) [110], and improved biocompatibility [111]. Hence, SWNHs are considered to have a higher potential for clinical use [112]. 5.1. Cancer imaging with SWNHs As a comparatively new material for biomedical applications, cancer imaging studies with SWNHs are quite limited. The primary imaging techniques adopted is MRI since SWNHs can be easily complexed with gadolinium [113, 114] or IONPs [115] (this property is shared by other carbon nanomaterials with similar structure such as fullerene or CNTs). For example, Gd3N@C80@SWNHs was coupled with QDs in one study to visualize U87 tumors in the mouse brain with MRI [116]. IONPs have also been stably attached onto SWNHs with holes opened (SWNHox) via a thermal transformation [117] – the as-prepared IONP-functionalized SWNHox was very stable and had clear detection in the T2-weighted MRI images.
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ACCEPTED MANUSCRIPT Recently, SWNHs were used as a PAI guided PTT platform [118]. A PEG derivative, poly(maleic anhydride-alt-1-octadecene-PEG) (C18PMH-PEG), was utilized to functionalize
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SWNHs (Figure 4A). The obtained SWNHs/C18PMH-PEG was highly dispersible and stable in
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aqueous solutions. With strong absorbance in the NIR region, it could be used for synergistic PAI/PTT. After the accumulation of SWNHs/C18PMH-PEG in the peripheric vessels of the
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tumor, the boundary of tumor was clearly delineated in PAI to achieve more accurate tumor
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ablation.
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Figure 4
Legend to Figure 4. (A) The structure and application of SWNHs/C18 PMH-PEG for PAI guided PTT. The PA images of tumor sites at different time were shown for mouse injected with SWNHs/C18 PMH-PEG. Whole animal images before and after laser irradiation were also shown for mouse injected with SWNHs/C18 PMH-PEG or saline. Adapted with permission from reference [118]. (B) The schematic illustration of SWNHs used as a tool for photothermally enhanced DOX release in tumor. Thermal images and histological examination confirmed the temperature rise in tumor area, which demonstrated the boosted cancer killing efficacy from both DOX and PTT. Adapted with permission from reference [119].
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ACCEPTED MANUSCRIPT 5.2. Cargo delivery to cancer with SWNHs The large areas both outside and inside the horn structure of SWNHs allow for
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accommodation of different cargo molecules [107, 108]. Recently, DOX-loaded SWNHs (DOXSWNHs) were used for photothermal enhanced chemotherapy [119]. After stabilization with
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chitosan, the obtained complex demonstrated good biocompatibility and photothermal properties.
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A mild heating from the laser irradiation was found to effectively promote the release of DOX from the complex, therefore effectively enhancing the toxicity of DOX to cancer cells (Figure
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4B). Another example of SWNH drug loading is cisplatin loaded in SWNHox via a solvent
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evaporation procedure [120]. The incorporated cisplatin was completely released from SWNHox resulting in increased anticancer efficacy. The same group has used SWNHox for loading zinc
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phthalocyanine (ZnPc) for synergistic PDT/PTT [121]. After subsequent functionalization with
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BSA, a single 670 nm laser was used to trigger PDT/PTT at the same time. Almost full tumor
phototherapy.
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disappearance post treatment was observed, confirming the potential of SWNHs in cancer
SWNHs have shown promise as effective gene carriers as well [108]. Polyamidoamine (PAMAM) modified SWNHs were used to deliver siRNA into prostate cancer cells (PC-3), and the results showed initial evidence of gene transfection by SWNHs with decreased toxicity to normal cells [122]. This hybrid platform possesses several advantages: the PAMAM functionalization provides strong electrostatic interactions with DNA/RNA, the PAMAM functionality also provides good solubility while decreasing toxicity, and the PAMAM allows for further biological modifications. Another application of SWNHs in gene therapy is to utilize the photothermal effect induced by SWNHs for regulation of gene expression [123]. For example, BSA modified SWNHs were combined with NIR laser irradiation to trigger heat shock
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ACCEPTED MANUSCRIPT promoter-mediated gene expression. The positive results of this study provide an important insight in the development of light-triggered gene manipulation.
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6. THERANOSTIC APPLICATIONS OF CARBON NANODIAMONDS As another important member of carbonaceous nanomaterial family, nanodiamond
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(ND) has an octahedral architecture ranging in size from 5-50nm. NDs are becoming
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increasingly useful in therapeutic and diagnostic applications due to their biocompatibility,
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scalability, and easy surface modification [124]. NDs also possesses an inherent stable fluorescence with the introduction of nitrogen into its internal structure.
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6.1. Cancer imaging with nanodiamonds
NDs are effective imaging agents due to their bright intrinsic fluorescence after the
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N or
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C, for fluorescence imaging or MRI [124]. The amount of nitrogen
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isotopes, such as
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addition of nitrogen and easy modification with an organic fluorophore or MRI detectable
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implemented into the ND allows for control over the fluorescence intensity and emission [125], which could be used for single molecule tracking inside a cell. The inherent fluorescence intensity from an ND is significantly higher compared to an AlexFluor dye at the same wavelength, so the ND does not need to be further functionalized in order to have strong imaging capabilities [126]. This strong fluorescence from NDs is particularly useful for low-background imaging in vivo [127]. In order to obtain even higher brightness from the fluorescence of the ND, helium has been used to bombard the ND powder [128]. With a larger degree of vacancy caused by helium ions inside the ND, more nitrogen was introduced, increasing the fluorescence intensity observed from the ND. Despite the active research into ND fluorescence, it was not until recently that fluorescent NDs were used for in vivo tracking of cancer cells in a murine model (Figure 5A) [129].
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ACCEPTED MANUSCRIPT Figure 5
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Legend to Figure 5. (A) Fluorescent NDs were used for in vivo lung cancer cell tracking in a murine model Adapted with permission from reference [129]. (B) DOX-loaded ND could prevent DOX from efflux from cancer cells and boost the therapeutic response in a murine liver cancer model. Adapted with permission from reference [137].
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ACCEPTED MANUSCRIPT There has been no report to date adopting magnetic NDs for in vivo detection of cancer, although some researchers claimed that Gd-NDs conjugates could be considered “game
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changing” and provide dramatically enhanced MR signal intensity [130-132]. To prepare NDs
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for cancer detection/imaging applications, various imaging labels were simultaneously incorporated into NDs. For example, one early study explored the in vivo distribution pattern of
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amino-functionalized NDs by using the positron-emitting isotope
18
F (t1/2 = 110 min) as the
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imaging label [133]. Iron nanoparticle (ferrocene) bound NDs were used in another study for fluorescence and MRI based cancer cell tracking [134]. Also, a new imaging concept, based on
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the optical detection of NDs in a magnetic field gradient, was proposed recently to achieve higher sensitivity and ND detection with better spatial resolution [135]. This imaging method has
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been named “nanodiamond imaging”, and it could be extremely useful for applications such as circulating tumor cell (CTC) tracking or stem cell tracking in vivo.
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6.2. Cargo delivery to cancer with nanodiamonds NDs can be useful vectors to provide cancer-targeted drug delivery with adjustable blood circulation and potentially decrease drug resistance of cancer cells. It was shown that NDs conjugated with DOX embedded in a microfilm produced a long term slow release of DOX for over a month [136].
ND-DOX conjugates were recently used in murine models of mammary and liver cancer to determine their distribution compared to free DOX [137]. The ND-DOX conjugates showed increased tumor growth inhibition and apoptosis compared to typical DOX treatment (Figure 5B) with decreased chemotherapeutic toxicity. Consistent therapeutic effect with better kidney and liver tolerance was confirmed in another report [138], and similar results were also obtained in a lung cancer model [139]. Other ND-drug conjugates also have shown improved tumor therapy efficacy, including 10-hydroxycampotothecin (HCPT) [140] and daunorubicin [141]. 24
ACCEPTED MANUSCRIPT Besides the loading of chemotherapeutic drugs, NDs can also be used for carrying proteins [142] or genes [143-146]. After conjugation with cationic compounds such as PEI [146],
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protamine sulfate [145], or cationic polymers [143, 144], NDs demonstrated potent siRNA
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delivery efficiency into various types of tumors. Unlike previously mentioned carbon nanomaterials, NDs are not intrinsically usable for PDT or PTT of cancer, but NDs can still be
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used for delivering PTT/PDT agents to cancer cells after proper hybridization. For example, NDs
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were complexed with gold/silver nanoparticles and used for efficient photothermal killing of
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cancer cells [147].
7. THERANOSTIC APPLICATIONS OF CARBON NANODOTS
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Carbon nanodots (C-dots) are quantum sized carbon analogues with bright and tunable
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photoluminescence [148]. Interestingly, the C-dots are photoluminescent only after surface passivation. Massive research efforts have been devoted to utilize the bright and colorful
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luminescent agents for imaging applications [149-152]. Unlike other carbonaceous nanomaterials, the C-dots have inherent aqueous solubility: no complicated functionalization is necessary for CDots to be stabilized in buffers. Large scale production of C-dots could be economically practical since many cheap and widely available materials can be used for C-dot synthesis [153-155]. Cdots are considered much more biocompatible compared to other materials, such as quantum dots, since heavy metal catalysts is not required in their synthesis.
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ACCEPTED MANUSCRIPT 7.1. Cancer imaging with carbon nanodots Like NDs, the intrinsic photoluminescence in C-dots allows the material to be used as an
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imaging agent. Produced initially by laser ablation and nitric acid treatment [148], C-dots possess bright and colorful luminescence with a strong dependence (tunable) on the excitation
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wavelength. The first in vivo imaging of these materials used C-dots doped with ZnS in order to
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increase their fluorescence [156]. It was found that C-dots retained their strong
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photoluminescence in vivo with no observable acute toxicity to the tested mice. In another study, identical C-dots with diameters of 3–4 nm were obtained from carbon nanotubes and graphite
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[157]. Fluorescence imaging was also carried out to study the distribution of these C-dots. C-dots have also been applied in cancer cell identification [158] and fluorescence imaging-guided drug
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delivery [159].
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Aside from fluorescence imaging, C-dots can be readily used for multimodal imaging.
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For example, after doping with gadolinium, C-Dots were used for both fluorescence imaging and MRI [160]. In another report, the distribution, clearance and tumor uptake of C-dots were systematically investigated by fluorescence and PET (Figure 6A) after conjugation with positron-emitting
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Cu (t1/2 = 12.7 h) and a NIR fluorophore [161]. The combination of NIR
imaging and PET imaging could provide synergistic information to assess the in vivo fate of Cdots.
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ACCEPTED MANUSCRIPT Figure 6
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Legend to Figure 6. (A) The schematic structure of C-dots used for in vivo imaging and the fluorescence images of tumor-bearing mice with different administrative ways of C-dots: subcutaneous injection (s.c.), intramuscular (i.m.) injection and intraveneous injection (i.v.). White arrow indicates tumor; red arrow indicates kidney. Adapted with permission from reference [161].
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(B) Scheme for synthesis and theranostic application of CD-Oxa. In vivo fluorescence images and the tumor size of tumor-bearing mouse at different time intervals after injection of CD-Oxa. Adapted with permission from reference [162].
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ACCEPTED MANUSCRIPT 7.2. Cargo delivery to cancer with carbon nanodots C-dots can also serve as a carrier for delivery of cancer therapeutics. One example uses
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C-dots covalently attached to a chemotherapeutic [162]. C-dot oxaliplatin conjugates significantly improved the anticancer efficacy of oxaliplatin. Moreover, the distribution and the
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pharmacokinetics of this C-dot conjugate could be monitored in a real-time scale due to the
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inherent imaging capabilities of C-dots (Figure 6B), which facilitated the optimization of the administration of drugs and the therapeutic evaluation after treatment. Different complexes from
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C-dots (e.g. C-dots@GNRs or C-dots@mesoporous silica nanoparticles) have also been formed
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for the controlled release of DOX [159, 163]. The drug loading efficiency of the C-dot DOX hybrid platforms was very high and the release of DOX was triggered under laser irradiation by
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the photothermal effect [163] or pH-mediated dissociation [159]. The strong inherent
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fluorescence of the C-dots was used for determining the distribution of DOX.
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C-dots can also serve as vectors for transferring DNA/RNA, proteins, or PDT agents. For example, PEI adsorbed C-dots were used in one study to deliver siRNA against survivin into human gastric cancer cells [164]. The C-dot complex induced more than 90% of the target protein knockdown, resulting in significant cell apoptosis. Ribonuclease A was loaded onto Cdots in another study for simultaneous therapy and fluorescence imaging in gastric tumor-bearing mice [165]. After conjugation with a photosensitizer, C-dots were used for simultaneous fluorescence imaging and PDT [166-169]. The C-dots/PS conjugation strategy has several advantages including therapeutic response monitoring [166, 169], extended tissue penetration of conventional PSs [167], and laser power decrease for effective PDT [168].
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ACCEPTED MANUSCRIPT 8. THERANOSTIC APPLICATIONS OF NANOGRAPHENES Another category of carbon nanomaterial is nanosized graphene which includes its
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derivatives graphene oxide (GO), reduced graphene oxide (RGO), and hybrid graphene nanostructures [170-172]. Graphene is a two-dimensional (2d) carbon sheet assembled in a
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honeycomb structure, and it can be used as the basic composing piece for other carbon materials
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of different dimensions [173]. The unique physical and chemical characteristics of graphene (and
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its derivatives), such as ultra-high surface area, robust mechanical strength, rapid electron transfer ability, and versatile surface modification capacity, attracts enormous research interests.
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8.1 Cancer imaging with nanographenes Cancer imaging with nanographenes is as effective as using CNTs. An initial PET
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imaging of cancer study with GO nanosheets used an antibody against CD105 as the targeting
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ligand with 64Cu as a PET label. The targeted GO nanosheet resulted in enhanced tumor uptake.
radiogalium
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To broaden the clinical applicability of the GO conjugates, other PET labels including Ga (t1/2 = 9.3 h) [175] and
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Cu (t1/2 = 3.3 h) [176] were used. In another study,
vascular endothelial growth factor 121 (VEGF121) was selected as a targeting ligand to further improve tumor targeting efficiency (Figure 7A) [177]. The antibody and
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Cu were attached
onto RGO conjugates with a slightly modified conjugation strategy (i.e. noncovalent stacking of C18PMH-PEG-NH2 was used to functionalize RGO surface instead of covalent binding) [178]. Conjugation strategies of graphene derivatives for biomedical applications have been reviewed in detail [179].
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ACCEPTED MANUSCRIPT Figure 7 NOTA
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Fluorescence
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64Cu
PAI 64Cu-NOTA-GO-PEG-VEGF
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VEGF121
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64Cu-NOTA-GO-PEG 64 Cu-NOTA-GO-PEG
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Legend to Figure 7. (A) The structure and applications of graphene derivatives as a PET imaging contrast agent for tumor detection. Adapted with permission from reference [177].
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(B) An imaging-guided hybrid PDT/PTT therapy nanovector based on graphene oxide. Adapted with permission from reference [228].
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ACCEPTED MANUSCRIPT Researchers from Oxford University conducted the initial research report of using GO as a scaffold to create SPECT imaging agents [180].
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In (t1/2 = 2.8 d) was adopted as the
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radiolabel and its chelator, p–NH2–Bn-DTPA, was introduced onto the surface of GO via π-π
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stacking. An anti-HER2 (human epidermal growth factor receptor 2) antibody, trastuzumab, was also conjugated onto the GO surface to increase uptake in HER2-positive tumors.
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In-GO-
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trastuzumab could not only detect primary tumor site, but also locate metastases in lymph nodes.
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198,199
Au (t1/2:
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Au: 2.7 d;
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In a recent report, GO sheets were also shown to be labeled with an
Au: 3.1 d) nanoparticle (named 198,199Au@AF-GO) [181]. In rats bearing fibrosarcoma tumors, Au@AF-GO exhibited fast penetration and strong accumulation (a surprisingly high tumor-
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198,199
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to-muscle ratio of 167 could be obtained at 4 h post-injection).
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Three major types of MR label can be used to produce graphene-based MRI contrast agents – IONPs, manganese (Mn2+), and Gd. Initial production of the different MR labelled
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nanosheets was carried out by decomposition of an iron precursor onto RGO via high temperature [182]. MnFe2O4 nanoparticles were also used to decorate GO to serve as a potential T2 contrast agent for MRI [183]. Mn2+–intercalated graphene nanoplatelets functionalized with dextran has been another potential choice as an MRI agent [184]. Fluorinated GO (FGO) is another interesting category of MRI detectable graphene derivatives [30]. FGO is used as a magnetically responsive drug carrier which can potentially be used for both MRI and photoacoustic imaging [185].
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ACCEPTED MANUSCRIPT Similar to CNTs, nanosized GO produce fluorescence in the visible and IR regions [186]. The IR-A fluorescence emissions (~1100 to 2200 nm) from GO can be detected by an InGaAs
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detector. Despite successful cell imaging with low background, the inherently low quantum yield
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of GO fluorescence hinders its in vivo applications. Adopting direct emission from GO as an imaging label is not optimal due to the limited resources of an InGaAs detector. To address
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direct emission limitations, different fluorophores were conjugated onto graphene derivatives.
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One example is a Cy7 labeled, PEG-functionalized GO nanosheets used for fluorescence tumor detection [187]. From this study, increased uptake was observed in tumors, with relatively low
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accumulation in the mononuclear phagocyte system (MPS). QD-tagged RGOs with bright
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tracking of drug behavior [190].
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fluorescence were also used for live cell imaging [188], tumor imaging and PTT [189], and
Another emerging fluorescent graphene is a graphene quantum dot (GQD), which can be
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produced from a variety of synthetic methods [191, 192]. Compared to “conventional” heavy metal based QDs, these GQDs are chemically inert, and usually possess good solubility, photostability, low toxicity [193], and high quantum-yield fluorescence emissions. Tumortargeting ligands such as hyaluronic acid (for CD44) [194] or folic acid [195] could be easily coupled onto GQDs for tumor targeting. In addition to tumor cell detection and recognition, GQDs can also be useful to monitor biochemical pathways, such as apoptosis [196]. Different GQD based hybrid nanostructures, primarily silica nanomaterials-GQDs [197-199], have also been synthesized for fluorescence imaging and drug delivery applications.
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ACCEPTED MANUSCRIPT GOs were also considered highly promising PA contrast agents [200]. In a more recent study, GO nanosheets were produced with a modified Hummers method by microwave-assisted
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pure nitronium ion oxidation instead of KMnO4. The resulting GO nanosheets exhibited strong
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absorption in the visible and NIR regions and strong PA signals from NIR excitation [201]. Strong NIR absorption and excitation from these materials is useful for long-term tracking of
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cancer cells. BSA was used in another study as both a reductant and stabilizer to a nanosized
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RGO for both PAI and PTT [202].
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8.2 Cargo delivery to cancer with nanographenes The delocalized π electrons and highly available surface area on graphene derivatives provide good loading capacity for various molecules. Despite the fact that they have been
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frequently adopted as drug/gene delivery vectors, in vivo drug delivery with graphene derivatives
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are still in its infancy. The overall benefits of nanographene as delivery vectors of anti-cancer
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drugs and genes have been reviewed elsewhere [26, 171]. DOX was loaded onto GO-IONP-PEG to be used for MRI detectable and magnetically targeted drug delivery [203]. T2 MRI demonstrated accumulation of GO-IONP-PEG in the tumor site: this study for the first time established the role of graphene derivatives as an in vivo drug delivery vector. Following a similar strategy, a GO-based T1 MRI detectable nanoplatform was developed via a GO-gadolinium complex [204], which showed strong uptake and subsequent cytotoxicity in HepG2 cancer cells after DOX loading. By chemical deposition of silver nanoparticles onto GO, GO@Ag was used for DOX loading and selective tumor targeting after NGR peptide (against CD13) conjugation [205]. With better DOX delivery to the tumor and an improved release profile over free DOX, the nanomaterial could serve as an X-ray contrast agent and a platform to combine local chemotherapy with PTT. GO nanosheets with PAI capacity was 33
ACCEPTED MANUSCRIPT also developed with DOX loading, which monitored the therapy response over time and revealed subtle microvascular changes during chemotherapy [206].
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Graphene derivatives are active candidates for directing a gene to the cancerous sites.
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They have been used for delivering DNA [207] or RNA [208] to cancer cells, with PEI [209] or
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chitosan [210] being two primary mediators to improve the DNA/RNA binding and condensation. For example, GO-PEG-PEI was used in a study and showed increased gene
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transfection efficiency as well as reduced cytotoxicity compared to free PEI [211]. Interestingly,
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the authors utilized the NIR absorbance of GO to enhance the cellular uptake of GO-PEG-PEI by using a low power NIR laser irradiation to increase membrane permeability. This GO-PEG-PEI
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was able to deliver siRNA into cells under NIR irradiation with obvious down-regulation of the
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target gene. The use of the NIR laser irradiation is known as “light-controllable gene delivery”. Another study used similarly structured GO conjugates for delivering Stat3-specific siRNA into
[212].
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melanomas to produce significant regression in tumor growth due to increased gene transfection
Nanographenes were demonstrated to have higher heat production capacity when compared with CNTs under the same conditions [213]. An initial PTT study used Cy5 labeled GO nanosheets to determine long circulation time and high tumor accumulation [187]. A laser energy density of ~ 2 W cm-2 was used for tumor irradiation with efficient tumor ablation. GOIONP-Au-PEG was also synthesized with improved photothermal tumor ablation [214]. Another IONP-GO complex was also formed by one-step adherence of IONP to carboxylic GO via hydrophobic interactions [215], which displayed a good photothermal efficiency. Recently, BaGdF5 nanoparticles were attached on the surface of GO nanosheets to form the GO/BaGdF5/PEG [216]. Efficient tumor penetration of GO/BaGdF5/PEG led to efficient 34
ACCEPTED MANUSCRIPT photothermal ablation of tumor in vivo, monitored by MRI and CT. GO nanoconjugates can also be used for diagnosis and ablation of tumor-drained regional lymph nodes [217].
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The reduction of GO can lead to enhanced absorbance in the NIR region [171], so RGOs
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can be considered more ideal for PTT applications. Single-layered RGO nanosheets (~ 20 nm) exhibited 6-fold higher NIR absorption that other non-reduced GO materials [218]. RGO-PEG
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conjugates were used to completely eliminate tumors by low-power laser irradiation in tumor
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area (0.15 W cm-2) post intratumor injection of RGO-PEG [219]. A RGO-IONP-PEG complex was also developed with good tumor targeting and improved PTT tumor ablation over GO [220].
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RGO nanomesh (RGONM) was another recently developed structures of graphene with over 20fold higher NIR absorption [221]. As-synthesized RGONMs were functionalized by PEG, RGD,
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laser power (0.1 W cm-2).
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and Cy7 and completely eliminated U87MG tumors followed by irradiation with an ultralow
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The first study of PDT with graphene derivatives used ZnPc as a PS [222]. The GO-ZnPc complex was internalized in MCF-7 cells, exhibiting a pronounced cytotoxicity under Xe light irradiation. Adopting a similar PS-attaching strategy, a folic acid-conjugated GO was used to load chlorin e6 (Ce6) for selective PDT in tumor cells [223]. Clinical translation of current PDT agents are often limited by their low singlet oxygen (1O2) quantum yields. One GQD-based PDT agent could produce 1O2 via a multistate sensitization process, resulting in a quantum yield of ~1.3, the highest recorded for PDT agents [224]. The fluorescence of PSs are often drastically quenched via an energy/charge transfer process after their interactions with graphene derivatives, which sometimes limits their detectability. To solve this problem, a PTT agent was prepared from sinoporphyrin sodium (DVDMS) loaded, PEGylated GO (named GO-PEG-DVDMS) which possessed more stable fluorescence for imaging guided PDT [225]. The uniqueness of 35
ACCEPTED MANUSCRIPT DVDMS is that its fluorescence could be enhanced via intramolecular charge transfer post loading onto GO-PEG. Another PS molecule, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-
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alpha (HPPH), was loaded onto PEG-GO. In vivo distribution and delivery of the obtained 64
Cu
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complex could be tracked by both fluorescence imaging and PET after radiolabeling with [226]. Improved cancer cell killing efficacy was witnessed in all of these reports.
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Graphene-based nanoplatforms are useful for multiple hybrid therapies, such as
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PDT/PTT and PTT/chemotherapy. Carboxylated graphene nanodots (cGdots) has been used for imaging-guided PDT/PTT without requirement of an extra PS [227]. cGdots have shown to
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effectively shrink MDA-MB-231 tumors compared with a saline-treated control group upon NIR laser irradiation. The luminescence emission from cGdots enabled visualization of tumor tissue
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to better interpret the treatment efficacy in mice. DVDMS-loaded GO-PEG (GO-PEG-DVDMS) was also used in another study for combined PDT and PTT [228]. The synergistic PDT/PTT
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efficacy was monitored by fluorescence/PA dual-modal imaging (Figure 7B). One graphene based nanohybrid was engineered via a facile one-pot process consisting of Fe3O4, Pluronic F127 (PF127), and graphene nanosheets [229]. DOX-loaded nanohybrids showed a significant cytotoxicity to HeLa cells, which could be intensified post laser irradiation. Another peptidemodified magnetic graphene-based mesoporous silica was synthesized with good NIR absorbance, facile magnetic separation, large T2 relaxation rates, and a high DOX loading capacity [230]. With DOX loading, it could integrate MRI, magnetic targeting and receptormediated active targeting, and chemo-photothermal therapy for a synergistic therapy of glioma.
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ACCEPTED MANUSCRIPT Graphene derivatives are also good choices for hybrid cargo loading. For example, a chitosan functionalized magnetic graphene nanoparticle (CMG) was used for simultaneous gene
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and drug delivery [231]. After intravenous administration of GFP-plasmid encapsulated within
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DOX-CMGs into lung tumor-bearing mice, both GFP expression and DOX accumulation at the tumor site were shown. In another study, PAMAM-grafted Gd-GO nanoparticles were evaluated
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as carriers to deliver both chemotherapeutic drugs and miRNAs to cancer cells [232].
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9. CONCLUSIONS AND FUTURE PERSEPCTIVES As we can draw a preliminary conclusion based on aforementioned summarized research
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progress, carbonaceous nanomaterials are extremely useful tools for theranostic applications in cancer. The unique physical properties (e.g. intrinsic fluorescence or NIR absorbance), chemical
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versatility, and superior cargo loading capacity are the prerequisite for them to be used as potent
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cancer therapeutics. The cancer imaging and cargo delivery applications of six leading players
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(with CNTs and nanographenes as two leading horses) from carbonaceous nanomaterial family were discussed in this review article. We are fully aware that there are still other existing carbon nanostructures (e.g. carbon nano-onions [233]), which may be useful for theranostic applications in cancer. However, their limited case numbers restrained the devotion of a separate section for illustration – interested readers can refer to literature [234] for details. The structural integrity is critical for certain carbonaceous nanomaterials (e.g. fullerenes or CNHs), thus suitable medication/functionalization methods should be chosen carefully to improve their biocompatibility, solubility, and cargo loading efficiency (Table 1). Continued research into optimized surface modifications will allow for more effective loading and release of relevant moieties. The future research should be directed on development of functionalization strategies which can result in accurate release of the cargo from the vector. Although concepts such as “stimuli-responsive” drug delivery have been proposed utilizing the heat-driving cargo 37
ACCEPTED MANUSCRIPT release from carbonaceous nanomaterials [29, 94], the ability to control the system is still comparatively low (e.g. with limited tissue penetration), with inevitable heat damage to
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surrounding fragile tissues. To partially address this dilemma, drug loading with an environment
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sensitive chemical bond (e.g. pH-sensitive) can be helpful [235].
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With the increasing complexity of carbonaceous nanomaterials, knowledge of their in vivo kinetics is crucial to boost their performance. Imaging techniques are powerful tools to
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determine in vivo kinetics since they can not only provide the precise distribution profile of
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carbonaceous nanomaterials, but also give evaluation on therapeutic response [6]. However, each individual imaging technique has its pros and cons. For example, optical imaging
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(fluorescence/bioluminescence/Raman) is highly sensitive and cost-effective with good security,
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but their tissue penetration is rather limited. MRI possesses high spatial resolution for tissues with good penetration depth, while its detection sensitivity for a given molecule is not optimal.
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PET or SPECT imaging can provide highly sensitive and quantitative detection of trace materials, but the radiation exposure and relatively limited spatial resolution are major disadvantages. The integration of multi-modalities into a single platform may provide an answer to partially solve this conundrum – with different imaging modalities synergistically combined (e.g. MRI/PET to provide both high-resolution images and accurate molecular profile) in different studies for carbonaceous nanomaterials, more precise information can be collected to prepare them as the “next-generation” delivering vectors for cancer therapy.
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ACCEPTED MANUSCRIPT To minimize the impact of carbonaceous nanomaterials to normal tissues/organs, their toxicity should be properly evaluated [236, 237]. As most reports claimed that carbonaceous
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nanomaterials are quite biocompatible after proper functionalization, skepticism can be raised
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due to their accumulation in cells from MPS (e.g. macrophages), incomplete excretion from the test subjects, and limited biodegradability. For example, induction of ROS from carbonaceous
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nanomaterials (especially with a tubular morphology) could be one leading factor to cause cell
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death [238]. At the same time, as metal catalysts are needed in the production of some carbonaceous nanomaterials (e.g. CNTs), heavy metal ions release from the material even after
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functionalization could be another source of toxicity. Combined with toxicological assessment methods, imaging techniques could be used to provide a better insight into their distribution,
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pharmacokinetic behavior, and eventually long-term toxicity. Some carbonaceous nanomaterials with small sizes, like fullerene, C-dots, were able to be cleared completely within weeks and do
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not have long term toxicity concerns [27, 239]. There has also been some recent progress on the development of a “biodegradable” carbonaceous nanomaterial [240, 241], and will hopefully design a “deliver and degrade” vector with carbonaceous nanomaterials for ideal pharmacokinetic behavior and low long term toxicity. There is potential for future clinical usage of carbonaceous nanomaterials. With the multi-functionality of these materials, future developments can involve the production of carbonaceous nanomaterials with the capacity of detecting and responding to the dynamic changes of proteins or DNA/RNA in living systems (i.e. a “smart” surgeon-like material). Joint efforts from scientists and continued research can further develop advanced carbonaceous nanomaterials for cancer theranostic applications.
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS The authors acknowledge financial support from the Department of Radiology at
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University of Michigan Health Systems.
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