Drug Metabolism Reviews

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Nanomaterials for targeted drug delivery to cancer stem cells Anamaria Orza, Daniel Casciano & Alexandru Biris To cite this article: Anamaria Orza, Daniel Casciano & Alexandru Biris (2014) Nanomaterials for targeted drug delivery to cancer stem cells, Drug Metabolism Reviews, 46:2, 191-206, DOI: 10.3109/03602532.2014.900566 To link to this article: http://dx.doi.org/10.3109/03602532.2014.900566

Published online: 04 Apr 2014.

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Date: 11 December 2016, At: 03:41

http://informahealthcare.com/dmr ISSN: 0360-2532 (print), 1097-9883 (electronic) Drug Metab Rev, 2014; 46(2): 191–206 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03602532.2014.900566


Nanomaterials for targeted drug delivery to cancer stem cells Anamaria Orza*, Daniel Casciano, and Alexandru Biris Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR, USA



Recent developments in cancer biology have identified the existence of a sub-poplulation of cells – cancer stem cells (CSC) that are resistant to most traditional therapies (e.g. chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. These findings have necessitated a break with traditional oncology management and encouraged new perspectives concerning cancer treatment. Understanding the functional biology of CSCs – especially the signaling pathways that are involved in their self-renewal mechanisms – is crucial for discovering new forms of treatment. In this review, we highlight current and future prospects for potential cancer therapies based on the use of nano-sized materials. Nanomaterials could revolutionize cancer management because of their distinctive features – unique surface chemistry, strong electronic, optic, and magnetic properties – that are found neither in bulk materials nor in single molecules. Based on these distinct properties, we believe that nanomaterials could be excellent candidates for use in CSC research in order to optimize cancer therapeutics. Moreover, we propose these nanomaterials for the inhibition of the selfrenewal pathways of CSCs by focusing on the Hedgehog, Notch, and Wnt/b-catenin selfrenewal mechanisms. By introducing these methods for the detection, targeting, and destruction of CSCs, an efficient alternative treatment for the incurable disease of cancer could be provided.

Cancer stem cells, drug delivery, gold nanostructures, specific delivery

Despite significant progress in the development of innovative technologies, cancer remains a significant global health problem. According to the Center for Disease Control and Prevention (CDC), more than 7.5 million people die from cancer annually, and that number is expected to increase by nearly 80% by 2030 (CDC, 2012). One of the possible reasons for the failure of the present therapeutic regimens is the existence of a relatively rare cell population known as cancer stem cells (CSCs) that are resistant to or not targeted by present therapeutic modalities. There are considerable data indicating that CSCs could be responsible for complex tumor biology, including initiation, growth, and regeneration. In 1997, Bonnet & Dick (1997) published their findings concerning the existence of CSCs, by isolating a subpopulation of leukemic cells. Further, several other groups have identified them in various solid tumors: brain (Singh et al., 2003), breast (Al-Hajj et al., 2003), colon (O’Brien et al., 2007), ovary (Zhang et al., 2008), pancreas (Li et al., 2007), prostate (Maitland & Collins, 2008; Lang et al., 2009), *Current address: Radiology Department, Emory University, Wesley Woods Health Centre, 1841 Clifton Road, Atlanta, GA 30329, USA Address for correspondence: Dr. Anamaria Orza, Radiology Department, Emory University, Wesley Woods Health Centre, 1841 Clifton Road, Atlanta, GA 30329, USA. E-mail: [email protected], [email protected] emory.edu

Received 27 February 2014 Accepted 28 February 2014 Published online 4 April 2014

melanoma (Boiko et al., 2010; Civenni et al., 2011; Schatton et al., 2008; Schmidt et al., 2011), and multiple myeloma (Matsui et al., 2004, 2008). CSCs exhibit certain properties, such as high expression of various anti-apoptotic proteins, expression of ABC pumps, and others, that would allow them to resist chemotherapeutic agents (Li et al., 2008) and ionizing radiations (Diehn et al., 2009). Nanomaterials, such as nanotubes, nanoparticles, and polymers, are promising materials that need to be explored with increased attention owing to their potential as components of an alternative treatment approach for tumors and CSCs (Orza et al., 2013; Tomuleasa et al., 2012). A variety of organic and inorganic nanomaterials of various sizes and with various molecules attached to their surfaces can be easily prepared for use in CSC therapy. Nanomaterials have unique properties, such as a large number of surface atoms that confer excellent surface chemistry, allowing various biomolecules/drugs inhibitor molecules to be attached, while exhibiting quantum-size effects and unique electronic structures (Whitesides et al., 1991). Taking advantage of these properties will provide solutions for the detection, as well as the targeted and controlled destruction of CSCs. Nanomaterials decorated with targeting molecules (Iancu et al., 2011; Mocan et al., 2011), active ingredients (pharmacological molecules), and bio-active molecules (genes, receptors, si-RNA, etc.) – along with emerging technologies, such as Raman (Biris et al., 2009a, b;

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Karmakar et al., 2012), photothermal–photoacoustic (PT/PA) (Huang et al., 2006), lasers excitation (Biris et al., 2011), etc. – offer promising means for finding solutions for high-sensitivity detection, specific targeting, and the complete destruction of CSCs. Unlike traditional chemotherapeutic agents, nanomaterial– drug systems can selectively deliver therapeutic drugs by entering weakened vascular structures and accumulating in the desired solid tumor site (Bae & Park, 2011). Using nanoparticles – such as noble nanoparticles, magnetic, polymeric, etc. – carbon nanotubes, and liposomes as agents for the specific delivery to CSCs of various targeted biomolecules (drugs, genes, receptors, antibody oncolytic virus, siARN, etc.) holds great promise for improving cancer therapy (Yu et al., 2010). Many of the currently proposed delivery agents – the majority of which contain a combination of standard chemotherapeutics (e.g. cisplatin and doxorubicin; Park et al., 2006) – have proceeded to clinical applications; however, an efficient treatment has yet to be fully developed. An important problem confronting targeted therapy is the specific delivery of chemotherapeutic drugs in order to reduce their clinical side effects. Therefore, it is urgent to understand the complex biology of CSC in order to identify new therapies that can target specific markers using molecular approaches (Table 1). The purpose of this review is to highlight current challenges associated with existing treatments for cancer with a focus on stem cells and their capacity to evade and resist destruction by chemotherapeutics and radiation, given their ability to repair damaged DNA. Moreover, this review proposes the use of nanostructural materials as a complex new therapeutic approach for the detection, targeting, and destruction of CSC and to help overcome the barriers created by the high expression of membrane efflux pumps. A combination of targeting molecules (different receptors for targeting CSCs and molecules for targeting their self-renewal pathways), active ingredients (pharmacological molecules), bio-active molecules (other biological molecules that can reduce and limit their proliferation), and nanomaterials could be the key to finding new advanced therapeutics.

Nanomaterials for CSC detection, targeting, and destruction Nanomaterials are a novel class of materials that have attracted widespread attention during the past few decades owing to their unique chemical, electronic, and optical properties (Manchikanti & Bandopadhyay, 2010). Based on these properties, they can be applied in a range of fields: catalysis (David, 2007; Diao & Cao, 2011), biosensors (Orza et al., 2010), targeted drug delivery (Kumar et al., 2012), cancer cell detection (Galanzha et al., 2013; Lu et al., 2010), and so forth. Their novel characteristics are primarily associated with their large number of surface atoms, which is significantly greater in nanomaterials compared to their bulk counterparts. Such properties confer excellent chemical surface characteristics that can be utilized for the attachment of drugs or a variety of active agents commonly used in cancer biology for the targeting and the destruction of CSCs.

Drug Metab Rev, 2014; 46(2): 191–206

Among all nanomaterials, gold nanoparticles are among the best candidates for use in biological applications due to their chemical inertness and optical properties (Alkilany & Murphy, 2010). The most commonly used methods for the synthesis of such nanomaterials are chemical reductions – to reduce a metal salt in the presence of a surface agent to prevent further aggregation of the colloids. The first synthesis of gold colloids was made by Michael Faraday (1857), and, since then, a large number of synthesis methods that generate tunable shapes and sizes have been presented in the literature. Turkevich et al. (1951) was the first to propose the reduction of a gold salt complex with sodium citrate. The formation of gold colloids can be visually inspected given the color change (from yellow to dark blue to red) as the colloids start to form. The final color indicates the formation of nanoparticles in the range of 5–50 nm. This method produces 5–30 nm nanoparticles that are fairly mono-dispersed with spherical shapes. However, it was shown that nanoparticles with size distributions larger than 30 nm present deviations from the spherical shape (Kimling et al., 2006). In Turkevich’s reaction, the citrate acts both as a stabilizing agent and a reduction agent; therefore, the average particle diameter can be controlled by varying the molar ratio between the gold salt and the citrate, itself: the higher the ratio, the larger the average diameter (in the range 8–25 nm; Frens, 1973). The stability of gold colloids is generally achieved due to electrostatic repulsions. An electrochemical double layer of negatively charged particles and positively charged ions from the solution is formed; as a result, Coulombic repulsion will occur between the nanoparticles. Such methods for the preparation of gold nanostructural materials are very popular due to the ease of preparation and the ability to decorate the nanoparticles with a large variety of functional groups. The above procedure has a potential limitation related to particle concentration: the highest concentration that can be achieved is around 2 nM. This limitation can be overcome by using bis(p-sulfonatophenyl)phenylphosphane dehydrate dipotassium salt (BSPP) as a capping agent capable of replacing the citrate from the surface of the particles (Hao et al., 2004). The resulting particles having BSPP on the surface are highly stable in higher ionic strength solutions, and the BSPP can be further substituted, for example, with thiols (Balasubramanian et al., 2005; Ionita et al., 2004). The disadvantages of the synthesis of gold colloids in aqueous solution are related to their increased ionic strength that leads to agglomeration (Jiang et al., 2009). To overcome this inconvenient result, the synthesis of nanoparticles in organic solutions has been proposed. In this respect, the seminal work of Schmidt et al. (2011) and the two-phase reaction of Brust et al. (1994) have proven to be the most promising. The method proposed by Brust et al. generates nanoparticles with diameters ranging between 1 and 3 nm surrounded by a monolayer cluster of thiols. The nanoparticles are highly stable under ambient conditions, and they can exist in solvent free form, which makes it possible to dissolve, precipitate, and re-dissolve them without altering their properties. The alkanethiol layer can be replaced by other thiols in order to confer to the

None None None None None CD44 CD44 CD44 CD133 HER2 receptor EGF receptor Biotin receptor Folate receptor Apolipoprotein B receptor Mitochondria None None None VEGF and TG2 receptors Biotin receptor None None CD44 CD71, gastrin and Tf receptors CD133 P-gp HER2 and PAM4 receptors

Lipid nano complex of anti-P-gp siRNA + paclitaxel Liposomes with anti-MGMT siRNA for oral temozolomide therapy Liposome-polycation formulations of anti-P-gp siRNA Anti-TG-2 siRNA in neutral DOPC liposomes + gemcitabine Biotin-treated nanoparticles for anti-P-gp siRNA + paclitaxel therapy Drug-loaded nanoparticles and pulsed ultrasound treatment Alginate-PVA nanoparticles for chemo- and photo-dynamic therapy Ag–Au core–hyaluronan shell nanogels for photothermal treatment Indocyanine green-silicate nanoparticles for photodynamic therapy mAb-vectorized SWNT for hypothermic treatment mAb-functionalized carbon nanotubes Targeted gold nanoparticles and radio frequency-based therapy

Tumor targeting

Curcumin-loaded nanoparticles Nanomicelles plus paclitaxel Triblock polymeric micelles with doxorubicin Stealth liposomal daunorubicin + tamoxifen Stealth liposomes with all-trans retinoic acid Poly(benzylglutamate)–hyaluronan polymerosomes with doxorubicin Paclitaxel–hyaluronan bioconjugate Hyaluronic acid-nanoparticles mAb-modified lipid nanocapsules mAb-vectorized PLGA nanoparticles loaded with doxorubicin Targeted PEG–PLGA nanoparticles of paclitaxel/lonidamine Biotin-treated nanoparticles with paclitaxel + tariquidar Notch signaling GSI-loaded mesoporous silica nanoparticles Drug delivery using synthetic low-density lipoprotein particles Liposomes with dequalinium + daunorubicin + quinacrine

Nanodelivery approach

Adapted from Future Nanomedicine. (2012) 7(4), 597-615 with permission of Future Medicine Ltd.

Drug delivery Brain Breast Breast Breast Breast Breast Ovarian Skin (squamous) Colon Ovarian/uterine Breast/ovarian Breast Cervical Leukemia Breast Targeting genes active in CSCs Colon Brain Ovarian Pancreatic Breast Destruction of CSCs/niche Breast Breast Melanoma Leukemia Brain Leukemia Pancreatic

Cancer type

Table 1. Summary of several nanosystems used in CSC research until 2012.

Grainger et al. (2010) Khdair et al. (2010) Wu et al. (2010, 2011) Barth et al. (2011) Wang et al. (2011) Li et al. (2010) Glazer et al. (2010)

Liu et al. (2009) Kato et al. (2010) Chen et al. (2010) Verma et al. (2008) Patil et al. (2010)

Lim et al. (2011) Yao et al. (2011) Kim et al. (2010) Guo et al. (2010) Li et al. (2011) Upadhyay et al. (2010) Banzato et al. (2008) Choi et al. (2010) Bourseau-Guilmain et al. (2011) Lei et al. (2011) Milane et al. (2011) Patil et al. (2009) Mamaeva et al. (2011) Zhou et al. (2010) Zhang et al. (2012)


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particle superior solubility for biological applications (Agasti et al., 2008). To enable their use in the destruction of CSCs, nanoparticles must be functionalized with the desired molecules. There are at least four methods of functionalization: (i) Synthesis directly in the presence of a functional thiol, where the nanoparticle’s surface is decorated with thiolended ligands such as glutathione (Schaaf et al., 1998), tiopronin (Templeton et al., 1999a, b), thiolated derivatives of polyethylene glycol(PEG) (Kanaras et al., 2002; Wuelfing et al., 1998), (-mercaptopropyl) trimethyloxysilane (Storhoff et al., 1998), arenthiolates (Brust et al., 1995; Chen & Murray, 1999), and coenzyme A (CoA; Taton et al., 2000). (ii) Ligand exchange or the Murray ligand exchange method (Hostetler et al., 1999), which consists of two steps, i.e. direct synthesis of the particles with a ‘‘standard thiol’’ ligand shell, followed by its usually partial displacement by another thiol ligand that carries the desired functional group. The primary advantage of this method is the possibility of introducing functional groups that would not be compatible with the reaction conditions of the synthetic step. (iii) Post-synthetic modification of the pendant functionalities by an interfacial reaction. This procedure involves the direct synthesis of nanoparticles that are stable enough to sustain the subsequent reactions required for the introduction of new chemical functionalities on the surface of the particles. Examples of modification reactions include polymerizations (Kamata et al., 2003; Li & Neaves, 2006; Li et al., 2006), coupling reactions (Prasad et al., 2005; Templeton et al., 1998, 1999a,1999b), and the transformation of an existing functional group (Dai et al., 2005; Latham & Williams, 2006; Shenoy et al., 2006). (iv) Coupling biomolecules through non-specific electrostatic interactions.

Figure 1. Complex methods for cancer treatment based on CSC targeting, detection, alteration, and destruction by using multifunctional nanosystems.

Drug Metab Rev, 2014; 46(2): 191–206

The most important goal in the synthesis of complex nanosystems with controllable properties concerns their versatility in cancer biology and treatment research. Recent advances in this area have demonstrated the existence of a sub-population of cancer cells (CSCs) that, based on their unique properties, have the ability to resist conventional chemotherapeutics and ionizing radiation (Clevers, 2011). The traditional treatments have not provided an efficient solution for cancer treatment. In order to achieve highly sensitive detection of CSCs, the nanomaterial should be functionalized with specific molecules to selectively target those cells. Furthermore, high performance techniques such as RAMAN, PT/PA, etc., have high potential for use in early detection and evaluation. These methods are highly sensitive, and their specificity is at the single cell level. The destruction of CSCs can be achieved by using chemotherapy, gene therapy, or cancer-targeting therapy, in addition to methods that target the CSCs’ self-renewal pathways. Moreover, highly sensitive lasers photothermal techniques can be used as an alternative method of treatment in combination with nanomaterials (Biris et al., 2009a, b). The nanomaterials to be used for these techniques should be irradiated at specific wavelengths in order to overcome the CSCs’ resistance to hyperthermia. It is expected that CSCs that are resistant to traditional hyperthermia will succumb when they are irradiated in the presence of nanomaterials because of their unique core properties. By combining such approaches, a highly efficient cancer treatment could be achieved. A schematic of this complex, multi-functional approach is highlighted in Figure 1. Targeting the self-renewal pathways through inhibitorbased nanomaterials could result in significant breakthroughs in the treatment of cancer. Due to their surface properties, nanomaterials are capable of carrying multiple drug loads to specific CSCs and discharge these drugs in a time-release fashion. In addition, given that their size (1–100 nm) is similar to those of the various cellular subcomponents, they can easily interface with critical molecular pathways resulting

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Nanomaterials for targeted drug delivery to cancer stem cells

in the destruction of CSCs. Nanomaterials can increase the specific delivery of drugs that have poor adsorption and low solubility (having structural compounds that can help to solubilize drugs; Liu et al., 2011); they also assist with the metabolism and elimination of drugs and increase their bioavailability (LaVan et al., 2003). Given these exceptional properties, the development of suitable nanomaterials could lead to the delivery of drugs to a single cancer cell and thereby reduce the required dose, cost, and undesirable secondary effects. The size, charge, and surface chemistry of nanomaterials have previously been used to increase tissue selectivity (Tiwari et al., 2011). It is important to explore their advantages in order to gain better control over the corresponding pharmacokinetic parameters. Both passive and active targeted delivery of drugs can be achieved using functionalized nanomaterials (Yu et al., 2012). In passive targeting, nanomaterials in the size range of 60–200 nm accumulate in tumors based on permeability and retention effects. It is relatively well-accepted that nonconjugated drugs diffuse non-specifically to all cells, including normal cells. However, conjugated drugs enter tumors via leaky blood vessels and accumulate in the vicinity of the lymphatic drainage (Peer et al., 2007). Active delivery consists of targeting the tumor with specific ligands, such as peptides (Wang et al., 2009), hormones (Patil et al., 2009a, b), antibodies (Shah et al., 2009), folates (Shakeri-Zadeh et al., 2010), and growth factors (Hayashi et al., 2009). The classes of nanomaterials with potential for targeting CSC cells include the following: optically active semiconductor quantum dots, magnetic iron-oxide nanocrystals, carbon nanotubes, gold nanorods, and polymer nanoparticles. Quantum dots can be successfully used in vivo and in vitro for targeting the self-renewal pathways and for imaging the tumor due to their special properties, such as optical brightness and stable light emissions (Alivisatos et al., 2005). For example, images of tumors have been collected in vivo by injecting antibody-conjugated quantum dots into mice (Gao et al., 2004). Carbon nanotubes have attracted attention as highly efficient carriers for the delivery and targeting of cancer cells (Pantarotto et al., 2004; Singh et al., 2005). Due to their strong near infrared (NIR) absorption, gold nanorods have been exploited as agents for in vivo photothermal therapy (Alkilany et al., 2012). A potential application has been provided by the treatment of deep-tissue tumors in mice (Dickerson et al., 2008). Toxicological studies have confirmed that such nanostructural particles are highly biocompatible and are stable in various biological environments (El-Ansary & Al-Daihan, 2009). Moreover, Orza et al. (2011, 2014) have demonstrated that colloidal gold-based nanomaterial substrates induce increased proliferation of mesenchymal stem cells, and improve their differentiation into myocardial and neuronal stem cells. It has also been shown that nanoparticles, once taken up by the cells, do not cluster or agglomerate even at higher concentrations or at various incubation times (Connor et al., 2005; Khan et al., 2007; Tkachenko et al., 2003). The advantages of using colloidal gold in biological applications are related to the easy and rapid methods of preparation and the ability to functionalize their surfaces with chemical and biological molecules. For example, thiol-gold bonds have been intensively used since they have a high-


affinity conjugation superior to most previously reported approaches that have relied on non-specific interactions, i.e. electrostatic adsorption (Alivisatos et al., 1996; Le´vy, 2006; Zanchet et al., 2001). Polymer nanoparticles, synthetic or natural, can also be used to transport various drugs, DNA, proteins, etc., across cell membranes. Their internalization mechanism is partially understood but still under scientific investigation (Zaki & Tirelli, 2011; Zhang & Smith, 2000). Internalization of nanomaterials through macropinocytosis (Devine et al., 1994; Harush-Frenkel et al., 2008), endocytosis, and transduction (Binder & Lindblom, 2003) have been reported. Synthetic cationic polymers generally are capped inside the cell through endocytosis – for example, polymers composed of molecules, such as diethylaminoethyl-dextran, poly-L-lysine, polyamidoamine dendrimers, etc. In the case of some natural polymers, internalization can occur via endocytosis or via receptors (Fischer et al., 2001; Lindgren et al., 2000). Moreover, the nanotechnology systems that were used for CSC research until present are listed below; for example, in an extensive review paper, Vinogradov & Wei (2012), summarized nanosystems developed prior to 2012 (Table 1), focusing on drug delivery, targeting different genes active in CSCs, and finally their destruction. An encapsulated treatment regime developed by GomezCabrero et al. (2013) consisted of the combination of the chemotherapeutic drug doxorubicine and the anti-CSC agent IMD-0354. Using both in vitro and in vivo model systems, they demonstrated that this combined therapy was efficient in targeting the specific tumor of interest resulting in greater accumulation of the drug in the targeted tumor. These results suggested that a similar combined therapy may be useful in the treatment of resistant tumors in humans. Another recent encapsulated therapy reported by Liu et al. (2013) described the utility of gelatinases-stimuli nanoparticles in combination with an anticancer drug with miRNA-200c for the treatment of gastric cancer. This regime using simultaneous delivery of a drug and miRNA targeting specific tumor cell types sensitized these same cells by suppressing growth via inhibition of CSC and non-CSC cancer cells.

Cancer stem cell biology The existence of CSCs has pushed traditional oncological research in a new direction, given that these cells have been identified as a sub-population of tumor cells with a high capacity for initiation, propagation, and growth (Alison et al., 2011). Normal stem cells and CSCs are believed to share similar properties dependent on the cell type (Li & Neaves, 2006; Li et al., 2006). The functional properties of CSCs are similar to those of other stem cells: self-renewal, ability to differentiate into several lineages, and a great capacity for proliferation. The similarities between CSCs and indigenous, normal, somatic stem cells suggest that CSCs may exist because of single gene or nonlethal chromosomal mutations or an heritable epigenetic alteration to normal stem cells (Li & Neaves, 2006; Li et al., 2006). However, they may also form mutations in progenitor cells that regain their selfrenewal properties (Cozzio et al., 2003; Huntly et al., 2004; Jamieson et al., 2004; Krivtsov et al., 2006). Whereas the size of normal stem cells has been shown to have little variation


A. Orza et al.

for different lineages, the dimensions of CSC lineages vary significantly (Jordan, 2009; Taussig et al., 2008). During tumor evolution, the immunophenotype, along with other properties, is not maintained. Some CSCs may be identified by their markers: CD24, CD44, CD133, A2B5, CD166, EpCAM, and integrins (Dg Marhaba et al., 2008; Lee et al., 2008). Many groups have focused on targeting different CSC markers in order to find a way to increase the selectivity and the specificity of various treatment regimens. Recently, CD 133 has been targeted in hepatocellular and gastric cancers using an antibody–drug conjugate – murine antihuman CD133 antibody conjugated with monomethyl auristatin F (Smith et al., 2008). In addition to their unique properties – dormancy, high expression of anti-apoptotic proteins, high expression of ABC pumps, etc. – CSCs have been found to be resistant to conventional chemotherapeutics and to ionizing radiation (Diehn et al., 2009; Eyler & Rich, 2008; Li et al., 2008). The functional properties of CSCs suggest that traditional, standard chemotherapies and radiotherapies no longer represent a solution for treatment given their remarkable ability to repair DNA damage and their multi-drug resistance (Eyler & Rich, 2008). Dekaney et al. (2009) have shown that CSCs withstand chemotherapy because they have the ability to reconstruct the tumor. Another study by Hoeijmakers (2001) demonstrated that CSCs can activate the reconstruction of their DNA in order to survive chemotherapy. However, the mechanism(s) through which CSCs reconstruct their DNA is not fully understood. Bao et al. (2006) have shown that, after radiotherapy, glioblastoma multiform CSCs repair their DNA through the activation of ataxia telangiectasia mutated (ATM) and checkpoint kinase 1. Another difficulty with the treatment of CSCs is that they express high levels of multi-drug resistance pumps (Moitra et al., 2011), which confer upon these cells – acute myeloid leukemia SP (side population; Wulf et al., 2001), neuroblastoma SP (Hirschmann-Jax et al., 2004), and breast cancer cells (Hinrichsen et al., 2006) – the ability to pump out a large range of compounds including amphiphilic compounds, such as taxanes, anthracyclines, and vinca alkaloids as determined by HOECHST dye efflux assay (Moitra et al., 2011). The ability of CSCs to evade therapeutics is based on their self-renewal capacity. In order to maintain their ‘‘proper’’ functionality, during treatment and afterward, many signaling pathways are required. The Hedgehog (Hh), Notch, and Wnt/ b-catenin are considered to be pathways of self-renewal signals that can be deregulated in the case of CSCs. As selfrenewal is one of the most important properties of CSCs, targeting these cells through such pathways by inhibiting or altering their signaling is promising. In addition, using inhibitor-based nanomaterials, more effective treatment could be achieved because nanomaterials can easily interact with the cells and alter their bio-physiological characteristics. Moreover, because their relatively high surface area can be multi-functionalized, they can simultaneously carry many and/or different drug loads and signaling molecules for the detection and targeting of CSCs. A generally desirable property of nanomaterials used in such applications is biocompatibility. Nanomaterials have frequently been found

Drug Metab Rev, 2014; 46(2): 191–206

to be biologically inert; most interestingly, they can be easily manipulated to confer inertness via functionalization with suitable ligands (Calcagno et al., 2010; Ford et al., 2002). These two promising research areas – nanotechnology and understanding the biology of CSCs – must be well-integrated in order to find an efficient solution for cancer treatment that offers new options for the millions of cancer patients worldwide. The biology of self-renewal pathways along with the mechanism of the sub-cellular interaction of nanomaterials must therefore be understood in detail. The Hh pathway has attracted considerable interest in cancer biology due to its inappropriate reactivation in many tumors (Merchant & Matsui, 2010). Mutations in genes of the Hedgehog pathway have a drastic influence on CSCs’ deregulated self-renewal ability. In carcinogenesis, the basic Hedgehog signaling, in addition to a combination of growth factors, increases selfrenewal ability (Bhardwaj et al., 2001; Reya et al., 2001). Also, mutation of the sonic Hh activates the renewal mechanism. Inappropriate reactivation of Notch and WNT/ b-catenin signaling has also been observed in various tumors (Ranganathan et al., 2011; Valkenburg et al., 2011). Such data suggest that targeting these pathways through multiinhibitor-based nanomaterials may affect the deregulated self-renewal of CSCs. It is crucial to find an optimal nanosystem (nanomaterial-inhibition molecule) that has the specificity to target CSCs in order to stop their self-renewal. To achieve this goal, an advanced understanding of cell biology and CSC biology, including Hedgehog, Notch, and WNT/b-catenin signaling, must be achieved along with highly advanced techniques of nanomaterial synthesis, functionalization with different target molecules, and purification.

Hedgehog, Notch, WNT/b-catenin signaling as new cancer therapeutic targets It has been shown that the Hh protein is secreted from Hh-secreting cells (Hausmann et al., 2009). The Hh signalsecreting cells conjugate the surface of the Hh protein with two lipid molecules. Cholesterol is linked at the C-terminal via the activity of an intein domain within Hh itself, and, at the N-terminal, palmitic acid is linked via the Ski-Rasp protein. Cholesterol molecules linked to the Hh surface confer good trafficking, secretion, and receptor interaction. In addition, sonic Hh is released from its secreting cells via dispatched protein and sends signals to its target cells to regulate targeted genes. The signals are received by binding the Hh protein to the trans-membrane protein (Ptch), where a de-repression of the GPCR-released protein Smoothened SMO occurs. Ptch acts as a sterol pump in the absence of the Hh protein and regulates the SMO by removing oxysterols created by 7-dehydrocholesterol reductase. Ptch acts as a protector molecule that pumps out oxysterols from the SMO surroundings. When the Hh protein is linked to the Ptch or a mutation occurs in the Hh or Ptch, the oxysterols accumulate around SMO (Hausmann et al., 2009). Accumulated sterols cause SMO to become and to remain more active. A schematic view of the Hh self-renewal mechanism is presented in Figure 2.

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Nanomaterials for targeted drug delivery to cancer stem cells


Figure 2. The proposed activation of the Hh self-renewal mechanism. With kind permission from reference Hausmann et al. (2009).

Due to the ability of SMO to sense molecules outside the cell and to initiate transduction signals, we may conclude that regulation leads to changes in the expression of genes; thus, the inhibition of SMO or the inhibition of the Ptch catalytic activity must be well-studied in order to discover new therapeutics to treat cancer. More research is needed in order to fully understand the multiple connections of the Hh signaling pathway. Heritable alterations, such as somatic mutation in SMO, Ptch, or downstream effectors play a major role in the development of many cancers. Hahn et al. (1996) and Thompson et al. (2006) have demonstrated that many medulloblastoma patients carry somatic mutations in SMO and Ptch1. In addition, Yang et al. (2008) have suggested that changes to the Hh pathway activation results in uncontrolled cellular proliferation in medulloblastoma. Moreover, DayaGrosjean & Couve´-Privat (2005) indicated that certain basal cell carcinomas have specific Hh mutation patterns. However, Kool et al. (2008) showed that these alterations in PTCH, SMO, and SUFU are usually detected in medulloblastoma group SHH. Thus, the evidence that the Hh pathway is involved in CSCs, although not irrefutable, is very compelling. In addition, the aberrant production of growth factors may be a result of the excessive production of Hh ligands produced by the CSCs. Chen et al. (2002) published their findings concerning a pharmacologically antagonized compound that can inhibit the Hh pathway using the teratogenic steroidal alkaloid cyclopamine. Several other SMO-inhibiting compounds have been reported by Frank-Kamenetsky et al. (2002). Furthermore, inhibition of this pathway has been reported in glioblastoma-SCs (Bar et al., 2007) and pancreatic-SCs (Feldmann et al., 2007). Recently, the first class of oral SMO inhibitor has been tested clinically and has demonstrated good activity by GDC-0449 (Von Hoff et al., 2009). The results are promising but more studies are required. Synthesized kinase inhibitors have a high toxicity profile. Nanomaterials combined with pharmacological molecules could provide an alternative. Given their superior properties, nanomaterials can be considered a new generation of therapies capable of overcoming many of the biological and biomedical barriers that interfere with single inhibitor molecules.

Targeting the Notch signaling pathway Cell differentiation, proliferation, and survival are all affected by the Notch pathway. Abnormal functionality of Notch signaling can result from a variety of mutations and finally lead to human cancer. Notch signaling is composed of four Notch receptors, Notch 1–4. Proteolytic cleavage of the Notch receptors by furin-like convertases in the trans-Golgi network gives rise to two Notch subunits: (1) the extra-cellular ligandbinding domain is composed of epidermal growth factor subunits and three LIN12/Notch sequences; (2) the transmembrane sub-unit includes short extracellular units and one trans-membrane domain, as well as a large intracellular domain that includes a RAM sequence, a C-terminal PEST sequence, two nuclear localization signals (NLS), and seven iterated cdc10/ankyrin-like repeats. Mammalian Notch 1 and 2 have C-terminal transcriptional activation domains (TAD), while Notch 1, 2, and 3 contain cytokine response (NCR) regions (Allenspach et al., 2002). When the Notch ligands, receptor is pairing, conformational changes appear, and later their bond is cleaved. The intracellular Notch domain enters the nucleus where it interacts with co-activators to generate the Notch transcriptional complex. Other oncogenic signaling, such as the NFkB pathway, the hypoxia sensor HIF1a, and the estrogen receptor alpha, communicates with the Notch receptor (Pannuti et al., 2010). Schematically, the Notch signaling is presented in Figure 3(A and B). The influence of the Notch signaling pathway in CSCs has been observed primarily in breast cancer. The Erb-B2 gene is over-expressed in approximately 20% of human breast cancers (Cicalese et al., 2009; Magnifico et al., 2009). In the structure of the gene, Notch binding sequences have been identified. Notch signaling activates in the presence of HER2 overexpression (Korkaya & Wicha, 2009). Moreover, Sansone et al. (2007) have demonstrated that breast tumors acquire an hypoxia-resistant phenotype following Notch 3 induction by IL-6. Thus, the Notch pathway and hypoxia-sensing machinery may cooperate in controlling the CSCs’ proliferation and survival. According to Fan et al. (2010) and Wang et al. (2010), glioblastoma-SCs are characterized by a high Notch activity that causes cells to become radio-resistant. Recently, Fischer et al. (2011) demonstrated the implication of Notch in colon cancer when they inhibited signaling by using DLL4 combined with irinotecan which reduces the KRAS-mutant


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Figure 3. (A,B) Human Notch receptors. Diagrammatic representations of the four known human Notch receptors (hNotch) (A). Ligand-induced Notch signaling pathways (B). With kind permission from reference Allenspach et al. (2002).

(Allegra et al., 2009; 40% of colon cancers have a KRAS mutation).

Targeting the WNT/b-catenin signaling pathway Stem cell self-renewal and proliferation are dependent also upon the WNT pathway. Several types of cancer have been attributed to abnormal activation of WNT signaling. The WNT pathway also plays an important role in leukemic hematopoietic stem cell deregulation (Mikesch, 2007). The canonical signaling of WNT is initiated by binding the WNT ligand to the Frizzled receptor. The signaling is mediated by a key b-catenin molecule. The b-catenin – a cytoplasmatic protein that catalyzes the activity of protein destruction – contains an adenomatous polyposis coli (APC), an axin, and a tumor suppressor gene, as well as CK1 (casein kinase 1) and the serine/threonine kinases GSK3b (glycogen-synthase kinase 3 b; Mu¨ller-Tidow et al., 2004). Upon activation of the Frizzled receptor, the b-catenin complex translocates to the nucleus where it assists in the expression of the various targeted genes involved in proliferation, motility, and stem cell maintenance (Moon et al., 2002). Figure 4 schematically illustrates WNT b-catenin signaling. Inhibition of this pathway may be promising for cancer therapy. You et al. (2006) have demonstrated that WNT signaling is responsible for the initiation of lung metastasis and breast cancer. Moreover, blocking the WNT signaling by either siRNA or the use of specific antibodies has been shown to inhibit tumor growth and induce apoptosis in cancer cells (Verma et al., 2003). The mechanism of targeting the CSCs’ self-renewal pathways using pharmacological inhibitors has been proposed by Maugeri-Sacca` et al. (2011) in a recent review, as shown in Figure 5.

Figure 4. The representation of the canonical Wnt pathway. With kind permission from reference Moon et al. (2002).

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Figure 5. Proposed procedures for the targeting and inhibition of various self-renewing mechanisms in cancer cells. With kind permission from reference Maugeri-Sacca` et al. (2011).

However, specific targeting of all three pathways could pave the way for more selective targeting of CSCs. Given the ineffectiveness of cancer treatments currently in use, targeting the CSCs’ signaling pathways through the delivery of drugs/ biomolecules (inhibitors)-based nanomaterials appears to be a promising route to cancer treatment. Nanomaterials enable inhibitors to reach the tumor with greater efficiency and with less overall toxicity. Currently, anti-cancer drugs have poor specificity and generate high toxicity. However, through the specific targeting of CSCs’ self-renewal pathways, targeted accumulation of the drugs could be achieved and collateral secondary effects avoided. Recently, a few research papers of great interest, proposing new targeted therapeutics based on the combination of drugs and nanomaterials along with a specific targeting of the CSCs pathways, have been published (Burke et al., 2012; Lim et al., 2011). Unfortunately, the number of projects describing these issues is rather small suggesting that, although promising, this is still an early niche domain. Very recently, Lim et al. (2011) have reported targeting malignant brain tumors, medulloblastoma, and glioblastoma cells using polymer nanoparticles encapsulated with curcumin, NanoCurcTM. The targeted mechanism occurs through

the Hh pathway. The group mixed together the pre-distillated polymers: N-isopropylacrylamide, vinylpyrrolidone, and acrylic acid in a molar ratio of 60:20:20. The team then polymerized the mixed monomers under inert atmosphere for 24 h at 30  C using APS and FeSO4 as initiator and activator. The purification was made using dialysis. In the second step, they loaded 15% curcumin on the surface of the already prepared polymer nanoparticle solution. A dry ice/acetone bath was used to ‘‘snap-freeze’’ the resulting solution that was then lyophilized. The synthesized polymer nanoparticles encapsulated with curcumin were cultured with stem-like cells from a malignant brain tumor. The team analyzed the percentage difference in those cells expressing the marker CD133 with and without the curcumin polymer particles. The growth of the brain tumor cells was inhibited by these nanocomposites via G2/M cell cycle arrest and programmed cell death. The MTS assay showed that 3 days of treatment using 5–10–20 mM curcumin caused a dose-dependent decrease in cell growth in stem-like cells of malignant glioma (Figure 6A). Flow cytometric analysis revealed that, following addition of nanocurcumin, there was a sharp decline in the CD133positive population in the JHH-GBM14 within 2 days


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Figure 6. (A) Nanodelivered curcumin inhibit the growth of the brain tumor cells by cell cycle arrest and programmed cell death. MTS assays collected from the brain tumor cell lines JHH-GBM14; (B) Curcumin was found to lower the CD133-positive stem-like fraction in the glioblastoma cells JHH-GBM14. With kind permission from reference Lim et al. (2011). * and ** shows that the administration of 10 mM and 20 mM of nanocurcumin drug is statistically significant compared with the vehicle alone and 5 mM concentration.

(Figure 6; Lim et al., 2011). There was a step-wise decrease of 92% in JHH-GBM14 neurospheres from 7.7–0.6% with increasing doses of curcumin (Figure 6B). The most common primary tumors of the cerebrospinal axis are malignant gliomas (Beauchesne, 2011). Tumors of the primary or recurrent central nervous system (CNS) tumors carry a grim prognosis: the median length of survival for patients with high-grade primary glial tumors ranges from 11 to 33 months upon initial diagnosis, and 7 months following a recurrence (Henke et al., 2009; Snyder & Dowdy, 2004). Temozolomide is an oral alkylating agent used for the treatment of malignant tumors of neuroendocrine origin, including high-grade gliomas and melanomas. This drug has the ability to alkylate or methylate DNA most often at the N-7 or 0–6 positions of guanine residues, thus damaging DNA and triggering apoptosis of the cancer cell (Stupp et al., 2005). Post-operatively, temozolomide concomitant with adjuvant radiation treatment is considered to be the standard of care for patients with high-grade CNS malignant gliomas. The inability to effectively treat malignant gliomas has been attributed to CSCs and their chemoresistant properties, as well as their ability to stimulate neoangiogenesis. New insights have been provided by Lim et al. (2011), who have shown that the proposed system can reduce the growth and proliferation of stem cell glioblastoma line. The new therapy presented in this article could be an alternative for incurable malignant glioma; nevertheless, more research must be conducted in order to draw a clear conclusion, e.g., through in vivo application in preclinical animal models. Other kinase pathways, such as TGFb, NFkB, and others, play a critical role in the progress of malignancies. The inhibition of the proliferation of lung carcinoma cells and melanoma has been induced in vitro with a polymer nanoparticle conjugated PD98059 selective MAPK inhibitor as reported in a study published by Basu et al. (2009). The system not only suppresses the growth of tumors but also enhances the effectiveness of cisplatin chemotherapy.

In general, the kinase inhibitors have been the most intensively studied oncogenic signaling pathways. More than 30 kinase inhibitors have been developed at the level of Phase I clinical trials. Among these, Tarceva, Sprycel, and Gleevec are high-profile drugs; however, kinase inhibitors are generally highly toxic (Cozzio et al., 2003; Jamieson et al., 2004). Moreover, a combined therapy using inhibitor-functionalized nanomaterials and laser ablation could lead to the efficient treatment of cancer. Burke et al. (2012) have demonstrated the advantages of using carbon nanotubes to overcome the resistance of breast-CSCs (BCSCs) to hyperthermic therapy. Non-stem breast cancer cells (NSBCCs) and breast cancer stem cells BCSCs were first exposed to water bath treatments between 43 and 49  C for 10, 15, 30, and 60 min. (The results are presented in Figure 7A–D.) When heated to 47  C, the viability of NSBCCs and BCSCs was reduced to 0.33, 0.23, 0.11, and 0.05 and 0.81, 0.76, 0.49, and 0.28, respectively. Figure 7(E and F) confirms that CSCs are resistant to hyperthermia in all treatment conditions. Moreover, when a mixture of CSCs and NSBCCs was hyperthermally treated, flow cytometry was used to analyze viable cells in order to determine the percentage of CD44high/CD24low cells. It was found that the CSCs’ survival increased by 1.6- to 1.9-fold (p50.001). In order to decrease the BCSCs’ resistance, they were exposed to carbon nanotubes used as thermal agents under exposure to NIR laser irradiation. This combination of carbon nanotubes and laser exposure significantly decreased the viability of both types of cells: BCSCs and NSBCCs. Figure 8 presents the sensitivity of BCSCs to carbon nanotube-mediated thermal ablation.

Conclusions In this review, we have presented some of the significant research highlights in CSC treatment and alternative therapies to cancer treatment with a focus on the destruction of CSCs.

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Figure 7. (A–F) Breast cancer stem cells (BSCS) were shown to have a significant resistance to hyperthermia. With kind permission from reference Burke et al. (2012).

These cells are critical to the failure of existing cancer treatments: through their self-renewal pathways, they are able to maintain tumor progression and evade radiation and drug treatments. Therefore it is essential to better understand their biology, and, most important, given the complexity of the interactions that occur in these cells, it is necessary to find pathways for the specific targeting and destruction of the CSCs. Multifunctional nanosystems could be a solution for the early detection of CSCs and their targeted destruction. A sensitive method of detection could be achieved by using highly specific techniques, such as Raman scattering and photothermal/photoacoustic spectroscopies, that would provide the ability to detect even a single cancer cell. Moreover, the destruction of the cell could be achieved by a number of approaches that include gene therapy or drug delivery along

with targeted therapies or their combination with thermal ablation. The use of nanomaterials for CSC detection and destruction is promising. Understanding the CSCs’ self-renewal properties and the successful inhibition of the pathways responsible for such processes could possibly overcome important limitations that still exist in the treatment of cancer. The non-specific toxicity of the many potent inhibitors has limited their clinical application. In this review, nanotechnology has been proposed as a model system that could be used to target the CSCs’ self-renewal pathways (Hedgehog, Ntch, and Wnt/b-catenin) in order to achieve specific toxicity in addition to the controlled release of various inhibitor molecules. Of all nanomaterials, gold nanoparticles could be one of the most convenient agents to be used in targeting CSCs for


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Figure 8. Breast cancer stem cells (BSCS) were found to have a high sensitivity to carbon nanotube-mediated thermal ablation when exposed to laser irradiation. With kind permission from reference Burke et al. (2012).

a number of reasons: (1) they can be readily synthesized in different shapes having tunable sizes between 1–100 nm with a fairly narrow distribution; (2) they are very stable for long periods of time, even years; (3) they can be easily functionalized covalently through their well-known, strong thiols bonds; (4) they are highly biocompatibility; and (5) they are easily detected by electron microscopy or PT/PA spectroscopy. The latest findings in this exciting research area could represent the foundation of major breakthroughs in cancer biology and treatment by suggesting new opportunities for the detection, targeting, and destruction of CSCs using multifunctional nanomaterials. Nanomaterials could be used to target multiple pathways simultaneously with a combination of inhibitors, including conventional therapeutics and receptors. In conclusion, nanotechnology offers unique biocompatible platforms that must be explored in order to find new, advanced treatments for cancer.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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DOI: 10.3109/03602532.2014.900566

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Nanomaterials for targeted drug delivery to cancer stem cells.

Recent developments in cancer biology have identified the existence of a sub-poplulation of cells - cancer stem cells (CSC) that are resistant to most...
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