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Fluorescent/magnetic micro/nano-spheres based on quantum dots and/or magnetic nanoparticles: preparation, properties, and their applications in cancer studies Cong-Ying Wen,a,b Hai-Yan Xie,a,c Zhi-Ling Zhang,a Ling-Ling Wu,a Jiao Hu,a Man Tang,a Min Wua and Dai-Wen Pang*a The study of cancer is of great significance to human survival and development, due to the fact that cancer has become one of the greatest threats to human health. In recent years, the rapid progress of nanoscience and nanotechnology has brought new and bright opportunities to this field. In particular, the applications of quantum dots (QDs) and magnetic nanoparticles (MNPs) have greatly promoted early diagnosis and effective therapy of cancer. In this review, we focus on fluorescent/magnetic micro/nanospheres based on QDs and/or MNPs (we may call them “nanoparticle-sphere (NP–sphere) composites”) from their preparation to their bio-application in cancer research. Firstly, we outline and compare the main four kinds of methods for fabricating NP–sphere composites, including their design principles, operation processes, and characteristics (merits and limitations). The NP–sphere composites successfully inherit the unique fluorescence or magnetic properties of QDs or MNPs. Moreover, compared with the nanoparticles (NPs) alone, the NP–sphere composites show superior properties, which are also discussed

Received 2nd December 2015, Accepted 18th January 2016 DOI: 10.1039/c5nr08534a www.rsc.org/nanoscale

1.

in this review. Then, we summarize their recent applications in cancer research from three aspects, that is: separation and enrichment of target tumor cells or biomarkers; cancer diagnosis mainly through medical imaging or tumor biomarker detection; and cancer therapy via targeted drug delivery systems. Finally, we provide some perspectives on the future challenges and development trends of the NP–sphere composites.

Introduction

Cancer is one of the most serious threats to human life. According to the World Health Organization (WHO), more than 8 million people die of cancers each year in the world, and the number of deaths increases each year.1,2 Early diagnosis and timely effective therapy are the keys to improving the outcomes for cancer patients. However, current clinical diagnostic strategies suffer from the disadvantages of being timeconsuming, having low sensitivity, requiring laborious operation, and so on;3–5 meanwhile routinely used (chemo-) thera-

a Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan, 430072, P. R. China. E-mail: [email protected]; Fax: +0086-27-68754067; Tel: +0086-27-68756759 b College of Science, China University of Petroleum (East China), Qingdao, 266555, P. R. China c School of Life Science and Technology, Beijing Institute of Technology, Beijing, 100081, P. R. China

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peutic agents for cancers are generally rapidly cleared from the circulation and usually have serious side effects.6,7 Thus, to better ensure the safety of human life and health, developing rapid, sensitive, reliable detection methods and smart target drug delivery systems has been pursued. In recent years, with the rapid progress of nanoscience and nanotechnology, various nanomaterials have shown great superiority and potential in the biomedicine field.8–11 Among them, quantum dots (QDs), magnetic nanoparticles (MNPs), and functional materials based on these two, are those with the greatest application value.12–14 QDs, as fluorescent semiconductor nanocrystals, exhibit good photochemical stability and high photoluminescent quantum yields. They have broad absorption, and a narrow and symmetric photoluminescence (PL) spectra covering a wide range (from UV to near-infrared) which can be tuned by varying the size and chemical composition of the nanocrystals, resulting in simultaneous excitation of differently colored QDs with a single wavelength.15–17 MNPs usually refer to the nanomaterials containing iron (Fe) or cobalt (Co) as well as their alloys and oxides. MNPs become superparamagnetic at room temperature when their size is

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below a critical value, and such individual MNPs have a large constant magnetic moment, which behaves just like a giant paramagnetic atom with a fast magnetic response and negligible remanence (their coercivity almost equals zero).18–20 These features avoid MNPs agglomerating at room temperature, and allow MNPs to be manipulated easily just by a magnet. Based on such excellent properties, QDs and MNPs have shown many exciting potential applications in cancer research, such as tumor biomarker enrichment and detection, tumor cell separation and analyses, labeling and dynamic tracking, fluorescence or magnetic resonance (MR) imaging, drug delivery, and so on.21–24 These may significantly improve our understanding of the occurrence and development of cancers, which can greatly facilitate their early diagnosis and effective therapy. Yet despite their promising potential, considerable challenges still exist in practical operation. For instance, high-quality QDs or MNPs are mainly prepared by thermal decomposition of organometallic compounds in high-boiling organic solvents, and the as-produced NPs are coated by hydrophobic ligands which are only soluble in nonpolar organic solvents.18,25–28 For their biological application, hydrophobic NPs must be made watersoluble, and how to preserve their original optical or magnetic properties during water-solubilization treatment is a great challenge. Besides, surface engineering and biofunctionalization of NPs are also crucial for their participation in biological processes, which may encounter problems of aggregation, nonspecific adsorption, bioactivity decrease, and the difficulty to remove the excess molecules, etc.25 Moreover, subsequent biological applications usually take place in very complex matrices (serum, whole blood, spinal fluid, etc.), which may significantly affect the properties of the NPs. Since QDs and MNPs were successfully synthesized, various methods for their protection and modification have been explored.17,29–32 One of the most important methods is constructing nanoparticle-sphere (NP–sphere) composites, which combine NPs and spheres ( polymer spheres, silica spheres, or similar ones in micro/ nano scale) through certain interactions.33–38 In the NP–sphere

Cong-Ying Wen

Cong-Ying Wen studied at Southwest University for her BS (2008) in chemistry, and received her PhD (2014) in analytical chemistry from Wuhan University under the guidance of Prof. DaiWen Pang. She is now working as a lecturer at China University of Petroleum (East China). Her research interests are focused on fluorescent/magnetic nanospheres based on quantum dots and/or magnetic nanoparticles, including their construction and bioapplications.

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composites, the NPs are confined in closed spaces, which may protect them from the negative influence of the environment, and the spheres have hydrophilic surfaces with rich functional groups, which facilitate their modification and bioconjugation. What’s more, the spheres have a large space for loading not only lots of NPs, but also drugs and other substances, which helps to construct multi-functional materials.39–41 By regulating the type and amount of loaded NPs, encoded spheres with different fluorescence or magnetic signal can be obtained for high-throughput simultaneous analyses.33,42–44 In addition, the NP–sphere composites also have the advantages of convenient manipulation, signal amplification, high stability, good biocompatibility, and so on. Hence, the NP–sphere composites have a very promising prospect in bioapplication, and some of them have already come into the market for scientific research or even for application in practice. During the past decade, our group has been working on the construction and application of fluorescent/magnetic biotargeting nanospheres based on QDs and/or MNPs. We have made a series of achievements and accumulated some experiences and perspectives.34,45–60 Herein, we mainly review the four currently used methods for preparing QD/MNP-based fluorescent/magnetic micro/nano-spheres, and then summarize the characteristics of the achieved NP–sphere composites. Furthermore, we discuss their recent applications in cancer research in detail, ranging from separation, diagnosis, to therapy. Finally, we conclude with an outlook for the challenges and future directions of the NP–sphere composites in reaching clinical applications.

2. Construction of the fluorescent/ magnetic micro/nano-spheres Based on nanoparticles (NPs, including QDs and MNPs), fluorescent/magnetic micro/nano-spheres are constructed mainly through four methods (Scheme 1): (I) embedding of NPs into micro/nano-spheres; (II) incorporation of NPs during the

Hai-Yan Xie

Hai-Yan Xie received a PhD in chemistry in 2004 from Wuhan University in China. Then she joined Beijing Institute of Technology and was promoted to full professor in 2010. She was awarded the Program of National Natural Science Foundation Outstanding Youth Foundation in 2014 and the Program of New Century Excellent Talents of the Ministry of Education of China in 2008. Her research interests focus on biolabeling and bionanotechnology.

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Scheme 1 Methods for the construction of fluorescent/magnetic micro/nano-spheres based on QDs and/or MNPs: (I) embedding of NPs into micro/nano-spheres; (II) incorporation of NPs during the micro/nano-sphere formation process; (III) assembly of NPs onto the surfaces of micro/ nano-spheres; (IV) in situ synthesis of NPs in micro/nano-spheres.

micro/nano-sphere formation process; (III) assembly of NPs onto the surfaces of micro/nano-spheres; (IV) in situ synthesis of NPs within the pores of micro/nano-spheres. In techniques (I) and (III), micro/nano-spheres and NPs are pre-prepared and then combined together. In the other two techniques, combination occurs during the formation process of micro/nanospheres (II) or NPs (IV). The following provides a brief overview of the principles and characteristics of the four methods. 2.1.

Embedding NPs into the micro/nano-spheres

In this method, NPs are embedded into micro/nano-spheres through the interactions (including hydrophobic interaction,33–35 electrostatic interaction,61,62 and so on) between NPs and the pores of the spheres (Scheme 1(I)). Nie’s group33 first embedded hydrophobic QDs into polymer spheres for optical coding (Fig. 1A), in which a solvent mixture containing chloroform and propanol or butanol (5 : 95 by

Zhi-Ling Zhang

Dr Zhi-Ling Zhang received his BS (1997) in chemistry from Jilin University. He obtained his PhD (2002) in analytical chemistry from Wuhan University and finished his postdoctoral research at Ecole Normale Supérieure de Paris during 2003–2004. He is currently a professor in the College of Chemistry and Molecular Sciences of Wuhan University. His research interests are focused on microfluidics, bioelectrochemistry, nanotechnology and their application in biology and medicine.

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volume) was used to swell the hydrophobic pores of the microspheres to facilitate the transport of the QDs into the microsphere interior by hydrophobic interactions. Then the achieved QD-embedded microspheres were dispersed in a polar solvent and the pores shrank, allowing the QDs to be retained. Based on similar principles, our group,34,45,46 for the first time, simultaneously incorporated QDs and iron oxide nanocrystals into much smaller polymer nanospheres (Fig. 1B, diameter: ca. 200 nm). With subsequent biofunctionalization, we obtained fluorescent-magnetic-biotargeting trifunctional nanospheres. Not only had the nanospheres attained the integration of multiple functionalities, but also their nanoscale gave them higher reaction flexibility and faster binding kinetics in biological applications. We applied for a patent on this method in 2003.63 Afterwards, Nie’s group35 also embedded QDs and MNPs into mesoporous silica microspheres to fabricate dual-functional carriers for optical encoding and

Dai-Wen Pang received his BS (1982) and PhD (1992) in chemistry from Wuhan University (WHU), and completed his postdoctoral research in virology at WHU in 1994. Then he joined WHU and was promoted to full professor in 1996. He was the Dean of the College of Chemistry and Molecular Sciences (2001–2005), and has been the Director of the Key Laboratory of Analytical Chemistry for Biology Dai-Wen Pang and Medicine (MOE) from 2008 and a member of the National Steering Committee for Nanotechnology (2007-present). His interests focus on quantum dots (QDs), including live-cell synthesis and quasi-bio-synthesis of QDs, and QD-based real-time tracking of single viruses.

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Fig. 1 (A) Schematic illustration and fluorescence microscope image of CdSe/ZnS QD-tagged beads prepared by embedding method. Reproduced with permission from ref. 33. Copyright 2001 Rights Managed by Nature Publishing Group. (B) Schematic illustration and TEM image of the magnetic fluorescent biotargeting nanospheres. Reproduced with permission from ref. 45. Copyright 2007 American Chemical Society. (C) Schematic diagram illustrating the preparation and the internal structure (strong interactions between hydrophobic surface ligands on the nanoparticles and long carbon chain (C-18) alkyl molecules on the silica pore walls) of the dual-functional optical and magnetic mesoporous beads. Reproduced with permission from ref. 35. Copyright 2006 American Chemical Society.

magnetic separation (Fig. 1C). The embedding method is one of the most convenient methods for the fabrication of fluorescent/magnetic micro/nano-spheres. What’s more, highquality oil NPs are directly incorporated into the hydrophobic pores of the spheres, and the organic ligands on the NP surface are hardly damaged at all, allowing the NPs to maintain their optical or magnetic properties to the greatest extent.29 However, the embedding process has a certain randomness, and the distribution of NPs through the obtained fluorescent/magnetic sphere interior is not always uniform.64,65 The NPs are mainly located in the outer zones of the spheres,33 which limits their loading capacity. Another disadvantage is that the NPs may leak out of the sphere pores in nonpolar suspending media. 2.2. Incorporating NPs during the micro/nano-sphere formation process Scheme 1(II) briefly shows this fabrication process: NPs are incorporated into the micro/nano-sphere interior as the monomers are polymerized into spheres, mainly by suspension,65–67 dispersion,68,69 emulsion,70–72 or condensation polymerization.73,74 Zhang et al.75 (Fig. 2A) utilized polymerizable surfactants to transfer aqueous CdTe nanocrystals into a solution of styrene monomer, and through subsequent radical polymerization, they got CdTe-PS composites. Meanwhile oil QDs could be directly encapsulated into polystyrene spheres induced by a miniemulsion polymerization approach (Fig. 2B),76 and further a method for kinetically entrapping QDs by crosslinking the polymer was developed, which helped to maintain a uniform dispersion (Fig. 2C).65 Magnetic spheres can also be

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constructed in similar ways. Li et al.73 (Fig. 2D) prepared magnetic microspheres through the polymerization of urea and formaldehyde, which induced Fe3O4 nanoparticles to aggregate in urea-formaldehyde (UF) resin, followed by silanization and calcination. The obtained magnetic microspheres had a high saturation magnetization (61.38 emu g−1), which was attributed to the complete removal of UF resin by calcination to achieve high magnetic nanoparticle content. Recently, microfluidics have been applied to the fabrication of NP-polymer composites using droplet-assisted polymerization, which have shown great advantages of precise control, convenient manipulation, and fast reaction kinetics (Fig. 2E).77–81 In these polymerization methods, NPs extend throughout the sphere interior during sphere formation, which improves the NP distribution inhomogeneity problem to a certain extent, and efficiently avoids NP leakage. But the reaction conditions usually need to be carefully controlled, and the NPs may aggregate during polymerization, which may influence their fluorescence or magnetic properties.65,82,83 Besides, this method also faces the limitation of NP load capacity and the difficulty to control precisely the number of loaded NPs, which is not very suitable for multiple encodings. 2.3. Assembling NPs onto the surfaces of the micro/ nano-spheres With layer-by-layer assembly methods (Scheme 1(III)), NPs can be decorated onto the surfaces of micro/nano-spheres through the interactions between the NPs and the moieties on the spheres, such as electrostatic interaction,84–86 coordination

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Fig. 2 (A) Preparation procedures for the fabrication of fluorescent composites based on aqueous CdTe nanocrystals through radical polymerization. Reproduced with permission from ref. 75. Copyright 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Strategy for the formation of carboxyl-functionalized fluorescent nanospheres consisting of hydrophobic QDs and polystyrene by an emulsion polymerization method. Reproduced with permission from ref. 76. Copyright 2013 Springer Science+Business Media Dordrecht. (C) Schematic diagram for kinetic entrapment of QDs by cross-linking the polymer chains during polymerization to maintain a uniform nanoparticle dispersion. Reproduced with permission from ref. 65. Copyright 2015 American Chemical Society. (D) Schematic representation for the preparation procedure of the magnetic colloidal nanoparticle cluster/silica (CNC/silica) microspheres. Reproduced from ref. 73 with permission from the Royal Society of Chemistry. (E) Schematic for one-step synthesis of monodisperse functional polymeric microspheres (fluorescent, magnetic, or NIR adsorption) with droplet microfluidics. Reproduced with permission from ref. 80. Copyright 2015 American Chemical Society.

interaction,38 bioaffinity,87,88 disulfide linkage,89 and so on. Compared with the first two methods, assembly of NPs on a sphere surface doesn’t need to consider the NP size or shape. The assembly usually happens in a quasi-homogeneous system, and the reaction conditions are very mild, usually gentle shaking at room temperature. Wilson et al.84 (Fig. 3A) successfully attached negatively charged CdSe/ZnS QDs on the positively charged surfaces of magnetic microspheres which were previously coated with a foundation layer of poly(allylamine). QD deposition made the ξ-potential of the spheres more negative, and then through further assembly of another positive polymer ( poly(ethyleneimine), PEI), they could attach a second layer of QDs, followed by coating three and a half bilayers of PEI + poly(sodium 4-styrenesulfonate) (PSS). By repeating the coating procedures (steps 2 and 3 in Fig. 3A), multiple layers of QDs could be located in a densely packed dark shell surrounding the microspheres. Even after assembling 15 layers of QDs, the microspheres still had well-defined core–shell structures, suggesting that additional layers could be assembled without disruption. The multilayer assembly technique facilitated the high NP load capacity of this method. What’s more, the photoluminescence intensity increased uniformly in proportion to the number of QDs assembled, which demonstrated that the assembly imposed a high degree of control. Thus, it’s conceivable that by tuning the coating amount and the type of NPs in each layer as well as changing

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the assembly layers, encoding can be achieved precisely and the code number can be greatly expanded. Wilson et al.90 then improved their method, and directly deposited hydrophobic QDs on PEI coated microspheres through forming covalent bonds between PEI and the QDs. Compared with electrostatic or covalent interaction, biological self-assembly has now becomes more promising and attractive owing to its high and specific affinity. Rauf et al.87 (Fig. 3B) produced QD barcodes by the layer-by-layer assembly of streptavidin- and biotinfunctionalized QDs. The streptavidin–biotin interaction was sufficiently strong to stabilize the assembled codes, and they provided a reagentless method to bring modular components together. Meanwhile, the surface-bound streptavidin on the resultant spheres enabled them to conjugate with biological molecules without further functionalization, and also made them minimally non-specific. However, the assembly strategies mentioned above have usually been applied to microspheres rather than nanospheres. While spheres on the nanoscale have minor steric hindrance and higher flexibility in bioapplications, their fabrication is very important. Therefore, our group38 expanded the assembly method to nanospheres (Fig. 3C) in which not only hydrophobic QDs but also hydrophobic MNPs could be straightforwardly assembled on the surface of nanospheres through coordination between the primary amines of PEI and metallic atoms from NPs. Hence, with this method, fluorescent encoded, magnetic encoded,

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Fig. 3 (A) Preparation for QD-encoded microspheres with a layer-by-layer assembly method using electrostatic interaction, and their biological functionalization: (1) attachment of polyamine foundation layer to microspheres; (2) assembly of QD/polyamine bilayers; (3) assembly of polyamine/ polysulfonate bilayers; (4) attachment of dextran immunosorbent. Reproduced from ref. 84 with permission from the Royal Society of Chemistry. (B) Barcode fabrication using biological self-assembly of QD-biotin and QD-streptavidin conjugates. Reproduced with permission from ref. 87. Copyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Schematic diagram for the fabrication of fluorescent-magnetic nanospheres based on hydrophobic QDs and MNPs (upper), and fluorescence spectra and magnetic hysteresis loops of the as-synthesized fluorescent-magnetic dualencoded nanospheres (lower). Reproduced with permission from ref. 38. Copyright 2012 Institute of Physics.

and fluorescent-magnetic dual-encoded nanospheres were all precisely constructed. We further calculated its huge encoding potential, which would surely increase with the number of coating layers. From the above review, it can be concluded that the assembly method gains the advantages of high load capacity, high controllability, good reproducibility, mild conditions, and can utilize various kinds of interactions to combine NPs and spheres without consideration of the NP size or shape. Nevertheless, it also can be seen that the assembly process is very tedious and time-consuming. Some assembly methods even undergo a transfer from water into the oil phase, then from the oil into the water phase, over and over again. Besides, another outer shell is usually needed to cap the obtained fluorescent/magnetic spheres for protection and conjugation.53,84,90 2.4.

Synthesizing NPs in the micro/nano-spheres

When the porous microspheres are saturated in a solution containing precursors for synthesizing QDs or MNPs, by controlling certain conditions, the precursors can directly react to form NPs within the pores of microspheres, thereby providing the microspheres with fluorescence or magnetic functionality (Scheme 1(IV)). As early as the 1980s, Ugelstad et al.91,92 used this method to pioneer studies on the fabrication of magnetic polymer microspheres (Fig. 4A). The porous polymer microspheres were first impregnated in solutions of Fe(II) and Fe(III)

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salts, then treated with a base to synthesize MNPs, finally, polymerization was carried out on the surface of the magnetic microspheres to fix the iron oxides and supply functional groups. Ugelstad et al. applied for several patents, and successfully commercialized the magnetic microspheres, which were widely used by researchers, under the name “Dynabead®”.93 Afterwards, in situ synthesis of QDs into porous microspheres was also developed by Yang et al.94 As Fig. 4B shows, the polymer microspheres were first swollen in chloroform containing Cd, Zn, Se, and S precursors which diffused into the microspheres subsequently. Then, with thermal decomposition, QDs were synthesized into microspheres, and the polymer spheres were de-swelled gradually as the chloroform evaporated. By changing the precursor ratios, they obtained fluorescent microspheres with a wide range of emission wavelengths (Fig. 4C). Directly synthesizing NPs within the pores results in a very uniform distribution of the nanocrystals. The mesopores on the sphere surface are sealed after preparation, which causes the NPs to be fixed into the microspheres and efficiently avoids NP leakage. But this method was mainly applied to micro-scale spheres, and it is difficult to fabricate a variety of barcodes or fluorescent-magnetic bifunctional spheres, since only one kind of NP can be fabricated under certain conditions. Above we have given a general review of the four methods for fabricating NP–sphere composites, mainly from their

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Fig. 4 (A) Scheme of the fabrication of magnetic microspheres developed by Ugelstad et al. Reproduced with permission from ref. 92. Copyright 2010 Institute of Physics. (B) Illustration of the facile single step for in situ preparation of highly luminescent Cd1−xZnxSe1−ySy QD-encoded poly (styrene-co-ethylene glycol dimethacrylate-co-methacrylic acid) beads (PSEMBs).94 (C) Fluorescence microscope images (left) and corresponding photoluminescence spectra (right) of QD barcodes prepared as in B (The scale bar is 20 μm). (B, C) Reproduced from ref. 94 with permission from the Royal Society of Chemistry.

Table 1

Summary comparison of the four construction methods

Item Operation process Operation condition Operation period NP distribution NP aggregation Load capacity Encoding type Controllability Stability Composite size

(I) Embedding of NPs into spheres

(II) Incorporation of NPs during sphere formation

(III) Assembly of NPs on sphere surface

(IV) In situ synthesis of NPs into spheres

Very convenient Non-mild (such as ultrasonication) About 1 h Non-uniform Some Relatively low Rich Relatively random Stable in polar solvent Micro/nano scale

Convenient Non-mild (such as vigorously stirring) Several hours Uniform Some Medium Medium Relatively controllable Stable Micro/nano scale

Very tedious Very mild (such as gentle shaking) Several days Uniform Little Very high Very rich Very controllable Stable Micro/nano scale

Convenient Non-mild (such as high temperature) Several hours Uniform Very little High Poor Controllable Stable Micro scale

design principles, operation processes, and their characteristics. Each method has its own advantages and limitations, which are summarized in Table 1. Researchers, on the one hand, have always been trying to improve these methods, and some disadvantages even have been overcome under certain conditions. On the other hand, researchers can select an appropriate method according to their application demands

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and the experimental conditions available. They can even couple two or more methods to achieve better effects. For example, the combination of embedding and assembly can maximize space utilization, which may help to construct much smaller spheres with high brightness or a fast magnetic response, thus efficiently solving the contradiction between the size and signal intensity.

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3. Properties of the fluorescent/ magnetic micro/nano-spheres First of all, the fluorescent/magnetic micro/nano-spheres successfully inherit the unique fluorescence or magnetic properties of the QDs or MNPs. Meanwhile, compared with the NPs alone, the fluorescent/magnetic micro/nano-spheres show additional advantages in biological applications, which are discussed in detail below. (1) Fluorescent/magnetic micro/nano-spheres have much higher stability, and the optical and magnetic properties of NPs can be maintained very well even in harsh conditions. For one thing, during the incorporation process, the ligands on the NP surface are hardly damaged, allowing the NPs to maintain their characteristics to a great extent. For another thing, after incorporation, the NPs are confined in enclosed spaces, which may protect them from the negative influence of the environment. Nie’s group33 reported that, unlike free QDs in aqueous buffer, the embedded QDs were stable under temperature cycling conditions, and Yang et al.94 also reported that the fluorescence intensity of their QD barcodes could be maintained effectively for at least a month. Meanwhile, our group had done some experiments to monitor the stability of the NP–sphere composites. The fluorescent nanospheres (FNs) fabricated by our embedding method34,45–47 were dispersed into pure fetal bovine serum, and their fluorescence intensity changed little during 30 min incubation (Fig. 5A). Besides, our previous studies53 had shown that even in whole blood the magnetic nanospheres (MNs) made by our developed assembly method could remain monodisperse (Fig. 5B) and be

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re-collected at nearly 100% with only a commercial magnetic scaffold. Furthermore, we also monitored the stability of six batches of FNs and MNs with storage time, which were simply dispersed in pure water and stored at 4 °C, noting their fluorescence and magnetic properties, dispersibility, and usability. As shown in Fig. 5C and D, the fluorescence intensities of the six batches of FNs were essentially unchanged with increasing storage time (mean relative standard deviation (RSD): 10.0%), and the fluorescence spectra of the FNs after 12 month storage remained almost the same with the newly prepared FNs. The magnetic properties also exhibited high stability. In 12 months, the saturation magnetizations of the six batches of MNs hardly changed (mean RSD: 5.1%), and the MNs retained superparamagnetic properties at room temperature (Fig. 5E and F). Fig. 6 showed that the hydrodynamic sizes of FNs (Fig. 6A) and MNs (Fig. 6C) had no obvious increase trend with the storage time, and their polydispersity index (PDI) values remained at about 0.1 (Fig. 6B and D), which confirmed that the FNs and MNs didn’t aggregate and retained good monodispersibility for at least 12 months. What’s more, after one year storage, the FNs and MNs were modified with the antiepithelial-cell-adhesion-molecule (anti-EpCAM) antibody to fabricate immunofluorescent nanospheres (IFNs) and immunomagnetic nanospheres (IMNs), which were used, respectively, to label and capture breast cancer cells. (The related experimental methods are in our previous work.51,53) From Fig. 7, it can be seen that the anti-EpCAM IFNs successfully labeled SK-BR-3 cells with red fluorescence, and the antiEpCAM IMNs efficiently captured more than 95% of MCF-7 cells, while the FNs and MNs showed low nonspecific adsorption. All of the above long-term monitoring convincingly

Fig. 5 (A) Fluorescence intensities of FNs in pure fetal bovine serum at different incubation times. (B) Hydrodynamic sizes and polydispersity index (PDI) values of the MNs before (left) and after incubation (right) in whole blood. Reproduced with permission from ref. 53. Copyright 2014 American Chemical Society. (C) Fluorescence intensity of the FNs (one color indicates one batch) at different storage times. Error bars = ±SD (n = 3). (D) Fluorescence spectra of the newly-prepared FNs (black) and the FNs after 12 month storage (red). (E) Saturation magnetization values of the MNs (one color indicates one batch) at different storage times. (F) Magnetic hysteresis loops of the newly-prepared MNs (black) and the MNs after 12 month storage (red) measured at room temperature.

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Fig. 6 (A) Hydrodynamic diameters of the FNs at different storage times. (B) PDI values of the FNs at different storage times. (C) Hydrodynamic diameters of the MNs at different storage times. (D) PDI values of the MNs at different storage times. One color indicates one batch. Error bars = ±SD (n = 3).

Fig. 7 (A) Bright field (top row) and fluorescence (bottom row) microscopic images of SK-BR-3 cells, respectively, labeled with six batches of antiEpCAM IFNs. (B) Bright field (top row) and fluorescence (bottom row) microscopic images of SK-BR-3 cells, respectively, treated with six batches of FNs. (C) Capture efficiencies of anti-EpCAM IMNs to MCF-7 cells ( positive) and MNs to MCF-7 cells (negative). Error bars = ±SD (n = 3).

demonstrates that the fluorescent/magnetic spheres have high stability, which makes them excellent fluorescence probes and magnetic separation tools. Another merit of protection of NPs into micro/nano-spheres can be exhibited by their modification. Modification, especially the covalent conjugation and coordination conjugation, usually leads to NP aggregation and reduction of brightness and stability of the resultant conjugates,25 which can be almost completely avoided in sphere modification. (2) Micro/nano-spheres have a large space for loading. Firstly, a great number of NPs can be encapsulated into a single sphere, which can provide a highly amplified signal and improve the sensitivity in bioassay. As Nie’s group33 reported,

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a single 1.2 μm microsphere was able to be incorporated with thousands of QDs. Our group also calculated that about 1800 QDs were attached on one layer of a 250 nm nanosphere by the assembly method.54 As we know, MNPs usually show a slow magnetic response, and need to be captured under a highgradient magnetic field, which limits their application. For instance, the magnetic activated cell sorting technology developed by Miltenyi Biotech Corp.,95 known as MACS-technology, utilizes 50 nm MNPs to capture target cells with the help of a high-gradient magnetic separation-column that aren’t available generally. The collection of MNPs into a single sphere can facilitate a much more rapid magnetic response and cause separation by an ordinary magnetic scaffold to be achieved

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Fig. 8 (A) Capture efficiencies of magnetic microspheres (∼3 μm, obtained from Bangs Laboratories) at different attraction times with a commercial magnetic scaffold. Reproduced with permission from ref. 49. Copyright 2010 Elsevier Ltd. All rights reserved. (B) Capture efficiencies of magnetic nanospheres (∼250 nm, prepared by our group through a layer-by-layer method) at different attraction times with a commercial magnetic scaffold. Reproduced with permission from ref. 53. Copyright 2014 American Chemical Society.

within only seconds to minutes (Fig. 8A and B).49,53,96 Thus, compared with the monodisperse MNP colloids, magnetic spheres show better isolation performance, which extends the magnetic capture to common laboratories, and even to on-site application. Secondly, the micro/nano-spheres can simultaneously load QDs, MNPs, drugs, and so on, to fabricate multi-functional materials with fluorescence tracking, magnetic separation, diagnosis, therapy, and other functionalities.25,97–99 Multi-functional materials have great potential applications in cancer study, which will be discussed in part 4. Thirdly, as we mentioned repeatedly in part 2, by regulating the kinds and amounts of NPs loaded, we can obtain encoded devices with different fluorescence or magnetic signals (Fig. 1A, 3C and 4C), which have become an important barcoding technology to supply a platform for high-throughput simultaneous analyses.33,38,94 (3) Micro/nano-spheres supply large surfaces that can be utilized, and the ones with hydrophilic surfaces are usually chosen in order to be useful in biological applications. For the widely used high-quality QDs and MNPs, which are mostly produced by organic phase synthesis, incorporation with hydrophilic spheres is an efficient method for water solubilization.

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What’s more, the micro/nano-spheres have rich groups on their surfaces25,32 which greatly facilitate subsequent biofunctionalization and enable the spheres to be coupled with many more biomolecules, greatly improving the binding efficiency in the bio-recognition. As we have calculated, the number of the active affinity sites on each antibody-modified nanosphere (∼380 nm) was about 100,53 and the active streptavidin number on each streptavidin-conjugated nanosphere (∼250 nm) could reach 200 (unpublished data). On the other hand, these groups also can be further modified to obtain other reactive groups (such as –COOH, –NH2, –SH, –COCl, etc.), which can meet various experimental requirements, or they can be conjugated with certain functional molecules to improve their biocompatibility or reduce their non-specific adsorption. For example, many researchers have already introduced PEG to the sphere surface to reduce steric hindrance and prevent non-specific binding.29,51,100,101 (4) Compared with NPs, the micro/nano-spheres can be more conveniently manipulated due to their larger size. In the modification and bio-functionalization of QDs, ultrafiltration, chromatography, gel electrophoresis, or a similar separation technology is usually used to remove the excess molecules, which makes the modification process tedious and timeconsuming.102 Nonetheless, these manipulations still cannot achieve efficient and complete removal, and the residual free molecules may influence the bio-recognition process. Relatively speaking, the modification of micro/nano-spheres is much more convenient and time-saving, usually by common centrifugation or magnetic separation.45,54 Of course, the fluorescent/magnetic micro/nano-spheres also have some disadvantages, and the greatest one is that their reaction kinetics and flexibility become slower as their size increases. Fabrication of high bright fluorescent spheres or quick-response magnetic spheres with a much smaller size is one of the goals that researchers have always pursued. However, despite their defects, fluorescent/magnetic micro/ nano-spheres have been proved to have promising applications in biological research.

4. Fluorescent/magnetic micro/ nano-spheres for cancer study This section summarizes the biological applications of fluorescent/magnetic micro/nano-spheres, mainly in the field of cancer research (Fig. 9). 4.1.

Separation and enrichment

In bioassays, as targets usually exist within complex biological matrices, their highly efficient isolation and enrichment are crucial and necessary steps for accurate analyses. As mentioned above, magnetic spheres have excellent superparamagnetic properties at room temperature, which enables them to be conveniently manipulated just by an external magnet. Besides, they have a high surface-to-volume ratio and fast kinetics in solution, and their bio-modification is easy. Therefore,

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Fig. 9

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Recent trends in cancer studies using fluorescent/magnetic micro/nano-spheres based on QDs and/or MNPs.

the magnetic sphere-based separation technology has excellent isolation performance and has been widely used in bioassays. The isolated objects can be from ions,103,104 small molecules105,106 or biomacromolecules,49,54,107,108 to viruses,52,56–58 bacteria51,59,109 or cells,110–112 and so on. In cancer study, magnetic spheres are mainly applied to the isolation of tumor cells, tumor biomarkers, and other substances relative to the occurrence, development, diagnosis, and treatment of cancer. Tumor cell isolation is one of the earliest applications of the magnetic spheres, and our group has done a series of work in this field. As early as 2005, we had successfully used folic acid modified fluorescent-magnetic nanospheres to capture

Hela and MCF-7 cancer cells.34 Then we further constructed wheat germ agglutinin-conjugated fluorescent-magnetic trifunctional nanospheres (WGA-TFNS) to recognize human prostate carcinoma DU-145 cells with little cytotoxicity, and by only 0.33 mg of WGA-TFNS, more than 1.0 × 105 DU-145 cells were able to be captured.45 The experimental manipulation is very convenient. Just as Fig. 10A showed, bio-targeting nanospheres were first added to the matrix, followed by gentle incubation, and then a magnet was used to capture the cells bound with the nanobioprobes. In our subsequent work,50 by embedding QDs of different colors red fluorescent magnetic nanospheres and green fluorescent magnetic nanospheres were fabricated,

Fig. 10 (A) General experimental operation procedure for capture of target cells with magnetic spheres. Reproduced with permission from ref. 50. Copyright 2011 American Chemical Society. (B) Depiction of capture and release of cancer cells through a biotin-triggered decomposable immunomagnetic system. Reproduced with permission from ref. 126. Copyright 2015 American Chemical Society. (C) CTC enrichment with IMNs directly followed by immunocytochemistry (ICC) identification, culture, and the reverse transcription-polymerase chain reaction (RT-PCR). Reproduced with permission from ref. 53. Copyright 2014 American Chemical Society.

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and they were then respectively modified with two kinds of antibodies to recognize and isolate multiple types of tumor cells with high efficiency and selectivity. What’s notable in this work is that rapid separation of a small number of spiked tumor cells in a large population of cultured normal cells (about 0.01% were tumor cells) was achieved simply and inexpensively without any pretreatment before cell analysis. It can be seen that magnetic spheres have the ability of highly efficient isolation and enrichment, and therefore they have recently been applied to the research of circulating tumor cells (CTCs).110,112–114 CTCs are tumor cells which are shed from tumors into the bloodstream, and their detection and investigation is of great significance to early diagnosis of tumors, treatment monitoring, prognosis, and metastasis diagnosis.115–118 However, CTCs are extremely rare in the extremely complex matrix (only up to hundreds of CTCs out of >109 hematological cells in 1 mL of blood), which makes their investigation extremely difficult.119–121 Magnetic separation technology facilitates the efficient purification and enrichment of CTCs and greatly promotes CTC study. An automated immunomagnetic enrichment technology for CTC detection has been approved by the US Food and Drug Administration (FDA) and comes into the market, known as CellSearch, which shows high accuracy and sensitivity with good reproducibility.122–124 In the CellSearch system,125 IMNs (120–200 nm) modified with anti-EpCAM antibody and biotin analogue were first used to capture CTCs, and then streptavidin is added to bind the biotin analogue, followed by the treatment of excess IMNs, which can bind to the bound streptavidin to increase the number of IMNs combined with CTCs, hence achieving a fast magnetic response. After magnetic separation, biotin is added to bind competitively streptavidin to release excess IMNs. Based on a similar principle, Lu et al.126 developed a biotintriggered decomposable immunomagnetic system for the capture and release of CTCs. As shown in Fig. 10B, the immunomagnetic beads, which were modified with antibodies through the interaction between Strep-Tactin and Strep-tag II, were first used to recognize and capture tumor cells, and then D-biotin was added to compete effectively with Strep-tag II for its higher affinity with Strep-Tactin. As a result, the Strep-tag II-tagged antibody was detached from the immunomagnetic beads, and the captured tumor cells were easily released. Quantitative experiments showed that 70% of the captured cells could be released, and 85% of the released cells remained viable. However, these methods introduced more steps before tumor cell analyses, which not only made the operation procedure more complicated, but also increased cell loss and influenced cell viability. Thus, we53 used a layer-by-layer assembly method to construct quick-response MNs, nearly all of which could be captured by 1 min attraction with a commercial magnetic scaffold. In addition, their nanometer scale provided them them fast kinetics and good biocompatibility. After modification with the anti-EpCAM antibody, the obtained IMNs were able to successfully capture tumor cells in whole blood with an efficiency of more than 94% via only 5 min incubation. Moreover, the IMN binding had little influence on the

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isolated cells, and the cells remained viable at more than 90.5%, which could be directly used for culture, reverse transcription polymerase chain reaction (RT-PCR), and immunocytochemistry (ICC) identification without disassociating IMNs (Fig. 10C). We further successfully applied the IMNs to the detection of CTCs in cancer patient peripheral blood samples, showing great potential in CTC studies. In clinical cancer diagnosis, compared with tumor cells, biomolecule biomarkers such as proteins, genes, and so on, are much more widely used.4,127,128 In their detection, magnetic separation is also a preferred choice for pre-concentration. The target biomarkers can be isolated from the complex matrix into a relatively pure environment with a highly increased concentration, which can significantly improve the anti-interference ability and the sensitivity of the detection method. Moreover, magnetic separation can be conveniently coupled with various identification techniques, such as fluorescence observation, electrochemical detection, polymerase chain reaction (PCR), culture, and so on.43,129–132 The sandwich-type detection method is a typical design, in which bio-modified magnetic spheres are used to capture the targets, followed with the addition of bio-modified signal probes to form sandwich complexes. Through monitoring their signal, qualitative detection or quantitative analysis can be achieved. Li et al.131 developed an immune sandwich assay for carcinoembryonic antigen (CEA) detection by coupling upconversion phosphors (UCPs) and magnetic beads (MBs). As shown in Fig. 11A, UCPs conjugated with the anti-CEA antibody were used as reporter probes, and magnetic beads modified with another biotin-tagged anti-CEA antibody were employed as separation tools. With the assistance of a magnet, the asformed immune sandwich could be readily isolated from the assay matrix for sensitive detection. Gu’s group133 reported a phage-mediated method to count cancer-biomarker miRNA molecules at attomolar concentrations just by the naked eye. In this method (Fig. 11B), miRNA-capturing magnetic microparticles were used to capture target miRNA which was simultaneously combined with the phage-gold nanoparticle couple (in a one-in-one manner) modified by another capturing oligonucleotide. After magnetic separation, the phage was released from the resultant sandwich complex containing equimolar phage and miRNA, and developed into one macroscopic fluorescent plaque in a Petri dish. By counting the plaques with the naked eye, they achieved the quantification of miRNAs with ultrasensitivity. In these methods, without the help of MNs, high sensitivity and strong anti-interference ability would not have been attained. Recently, magnetic spherebased separation technology has been integrated with microfluidics to avoid the drawbacks involved in conventional magnetic separation methods which are performed in Eppendorf tubes with significant reagent consumption and a tedious washing process.57,134,135 Our group5 used a nickel pattern to generate high magnetic field gradients for the formation of controllable superparamagnetic bead (SPMB) patterns in microfluidic channels. CEA and alpha-fetal protein (AFP) could be simultaneously captured respectively in two channels,

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Fig. 11 (A) Schematic illustration of the principle of CEA detection based on UCPs and magnetic beads. Reproduced from ref. 131 with permission from the Royal Society of Chemistry. (B) Schematic representation of the phage-mediated counting strategy. Reproduced with permission from ref. 133. Copyright 2015 Rights Managed by Nature Publishing Group.

and then with high luminescent QDs as fluorescence indicators, sensitive and rapid detection of dual cancer biomarkers was achieved directly in serum (Fig. 12). With the development of magnetic separation techniques, they are no longer limited to scientific research, but have been extended to practical applications. Corporations, such as Invitrogen, Bangs, Ademtech, and so on, have fabricated a variety of magnetic spheres with different functionalities to meet the needs of researchers and technical staff. For example, Dynabeads of various sizes can be modified with different ligands (such as antibody, protein, antigen, DNA/RNA, etc.), and are available for many applications.136 4.2.

Cancer diagnosis

On the 2013 World Cancer Day, the UICC (Union for International Cancer Control) indicated that, advances in understanding risk and prevention, early detection and treatment have revolutionised the management of cancer leading to improved outcomes for patients, and in addition, investing in prevention and early detection of cancer is cheaper than dealing with the consequences.137 Thus, early diagnosis of tumors has great medical significance. Recently, cancer is diagnosed mainly through medical imaging and tumor biomarker monitoring, in which QDs, MNPs and the materials based on them show great application advantages due to their unique optical and magnetic properties.12,138–141 During the past few decades, scientific breakthroughs from physics, chemistry, engineering, and medicine have led to the rapid development of biomedical imaging techniques, such as magnetic resonance imaging (MRI), computer tomography (CT), positron emission tomography (PET), optical

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Fig. 12 On-chip dual detection of cancer biomarkers based on selfassembled magnetic bead patterns and quantum dots. (A) Schematic diagram of an integrated magnetic field controllable chip for simultaneous detection of AFP and CEA. The region enclosed by a dashed line was the capture zones of the anti-AFP-SPMBs and anti-CEA-SPMBs. (B) Schematic diagram of the principle for simultaneous detection of AFP and CEA. (C) Optical (left) and fluorescence (right) images for the detection of AFP and CEA with these patterns. Reproduced with permission from ref. 5. Copyright 2012 Elsevier B.V. All rights reserved.

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fluorescence imaging, single-photon emission computed tomography (SPECT), photo-acoustic (PA) imaging, ultrasound (US) imaging, and so on.142 Among them, MRI and optical fluorescence imaging, which are noninvasive and avoid using harmful radiation, show the most value in medical applications.143–145 QDs, compared with traditional fluorescent dyes, are much brighter and have improved photostability, which enable long-term observation and imaging. Moreover, QDs have large Stokes shifts and broad excitation spectra, facilitating multiplexed in vivo cell detection and tracking.15 Nie’s group12,25 compared the imaging sensitivity of QDs and green fluorescent protein (GFP). Just as Fig. 13A (a–c) shows, although the QD-tagged cells (Fig. 13A (b)) and the GFP-transfected cells (Fig. 13A (c)) were similarly bright in cell cultures, only the QD signal was observed in vivo. Further, with a single light source, they explored multicolor imaging with QDencoded microbeads (Fig. 13A (d)). It is worth mentioning that micro/nano-composites based on near-infrared (NIR) QDs have recently attracted more-and-more attention in the in vivo imaging field, owing to the advantage of NIR fluorescence in terms of its large penetration depth while the tissues (or cells) emit low auto-fluorescence in this region; moreover the NIR QDs can avoid the use of Cd, Pb, or similar toxic precursors,

Review

which are more suitable for in vivo imaging.146,147 Our group had successfully prepared Ag2S and Ag2Se QDs for NIR fluorescence imaging in vivo.148–150 While compared with optical imaging and other imaging techniques, MRI usually has much higher spatial resolution. MRI has now become an essential part of modern clinical imaging, in which magnetic nanocomposites have been developed as a novel excellent MRI contrast agents.138,143 Magnetic nanocomposites have high magnetic signal strength, greater contrast enhancement and relatively low cytotoxicity. What’s more, their properties such as magnetism, size, and facile modification can be tuned conveniently to meet different imaging demands.138,142,144 Xie et al.151 prepared 4-methylcatechol coated MNPs, which could be directly conjugated with a peptide, c(RGDyK), via the Mannich reaction. When administrated intravenously, these MNPs accumulated in tumor cells, which were readily tracked by MRI. As shown in Fig. 13B, the MR signal intensity of tumor changed significantly after the injection of MNPs. However, MRI also has its limitations, such as its sensitivity still cannot compare with that of PET which can reach up to the femtomolar level of the biological targets of interest.138,142 Thus, multimodal imaging, which can integrate the complementary merits of different imaging modalities to enhance both the sensitivity

Fig. 13 (A) Sensitivity and multicolor capability of QD imaging in live animals: (a) in vivo imaging of implanted QD-tagged and GFP-transfected tumor cells. (b) Fluorescence images of the QD-tagged cancer cells. (c) Fluorescence images of the GFP-labeled cancer cells. (d) Simultaneous in vivo multicolor imaging with QD-encoded microbeads. Reproduced with permission from ref. 12. Copyright 2004 Rights Managed by Nature Publishing Group. (B) MRI of the cross section of the U87MG tumors implanted in mice without MNPs (a) and with the injection of MNPs (b). Reproduced with permission from ref. 151. Copyright 2008 American Chemical Society. (C) Schematic diagram for multifunctional nanocomposites consisting of multiple kinds of nanoparticles, targeting agents, and other functional molecules. Reproduced from ref. 143 with permission from the Royal Society of Chemistry. (D) Versatility of MNPs as a platform material for various imaging modalities. (a) The magnetic parameters and surface functionalities of the MNPs are tuned via their size, composition, and surface chemistry. (b) MNPs combined with a secondary imaging component (e.g. fluorescent tag or radioisotope) for multi-modal imaging. (c) MNP-based non-traditional multi-modal imaging only with MNPs as tracers. Reproduced from ref. 142 with permission from the Royal Society of Chemistry.

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and accuracy of clinical imaging diagnostics, is a very important development trend.145,152,153 For example, the combination of MRI and PET can achieve the high resolution of MRI and the high sensitivity of PET, which provides more detailed and accurate imaging information than using each alone.154 Magnetic nanocomposites can carry a wide range of other imaging moieties (fluorescent molecules, QDs, and radioisotopes etc.) either inside the composites or on their surfaces (Fig. 13C),143 which makes them an important platform for multi-modal imaging applications. Shin et al.142 summarized various multi-modal imaging techniques in great detail, as shown in Fig. 13D, including T1–T2 dual mode MRI,155 MRIoptical dual mode,156,157 MRI-PET/SPECT dual mode,158 MRI and US imaging,159 MRI and photoacoustic (PA) imaging,160,161 and so on. Both Park et al.162 and Shibu et al.163 successfully fabricated MNP-QD hybrid nanocomposites to obtain a bimodal contrast agent for combined MRI and fluorescence imaging. The in vivo MR and fluorescence images showed magnetic and fluorescence contrast enhancements, which confirmed the advantages of the combination of MRI (for the determination of full anatomical distribution in vivo) and optical imaging (for microscopic resolution and in vivo fluorescence imaging). Apart from QDs, NIR-to-visible upconversion nanoparticles (UCNPs) are also utilized as MRoptical imaging probes, due to their narrow emission peak, high photostability, deeper penetration depth, and the use of NIR light as an excitation source.164 Besides, fluorescent molecules, radioisotopes, gold nanoparticles, and other kinds of imaging agents could also be coupled with MNPs to achieve multimodal imaging.142,165,166 In summary, a detailed explanation of the features of the bioimaging techniques with QD/ MNP-based nanocomposites is supplied in Table 2. From all the above, it can be seen that QD/MNP-based nanocomposites, as the new generation of biomedical imaging agents, will greatly benefit accurate cancer detection. As for tumor biomarker detection, micro/nano-composites based on QDs or MNPs can be directly employed as reporter probes for qualitative or quantitative analysis of targets.139,141 Since hundreds of NPs can be encapsulated into a single sphere, which can provide a highly amplified and stable signal,51,189 a higher sensitivity is usually achieved. Zhou et al.76 used QD-based fluorescent nanospheres to perform fluorescent lateral flow immunoassay (LFIA) strips for highly sensitive and rapid detection of AFP, and the detection limit could reach 0.1 ng mL−1, a sensitivity 200 times higher than that of commercial colloidal gold-labeled LFIA strips. Our group51 also utilized fluorescent nanospheres coupled with magnetic nanospheres to develop a convenient one-step strategy for detecting bacteria or cancer cells, which showed a lower loss and higher sensitivity than the traditional two-step method (as low as 10 cells per mL can be efficiently captured and identified). Attributed to the high stability of the nanocomposites, this strategy had a strong anti-interference ability, which can be directly applied to serum samples, or even whole blood samples. More notably, high throughput multiplexed detection could be achieved with QD-encoded

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spheres. The basic principle is shown in Fig. 14A, and the target of interest is identified by the barcode signal and quantified by the label signal.190 Early in 2001, Nie’s group33 had successfully fabricated QD-tagged microbeads for multiplexed detection of DNAs (Fig. 14B) using spectral analysis, and up to now, biomarker proteins, cancer cells, etc. all have been simultaneously identified, indicative of their great potential in clinical applications for cancer detection.50,191–194 Also, other researchers distinguished several fluorophores by their life time for multiplexed measurements, which can help in the event of too much spectral overlap.195,196 Apart from utilizing fluorescence signals, magnetic composites can also be excellent reporter probes, which usually lead to ultrasensitive detection, mainly because most biological samples exhibit virtually no magnetic background. Tan’s group141 successfully used aptamer-conjugated magnetic nanoparticle (ACMNP)-based nanosensors for pattern recognition of cancer cells by magnetic relaxation measurements. As shown in Fig. 14C (a), when multiple magnetic nanosensors bound to their target cells, they tended to aggregate to form clusters, inducing coupling of the magnetic spin moment. This generated strong local magnetic fields, leading to inhomogeneities that accelerated the spin-dephasing of the adjacent water protons and resulted in a decreased spin–spin relaxation time (T2). With this method, the magnetic nanosensors were able to detect as few as 10 cancer cells in 250 μL of sample with high selectivity and sensitivity. Furthermore, as the number of receptors increased on the cells, ΔT2 became larger (Fig. 14C (b)), based on which cancer cell types with different expression levels of membrane receptors could be successfully differentiated. Besides, some researchers also developed a detection system utilizing the giant magnetoresistance (GMR) of magnetic nanocomposites, which can reach zeptomole or even single-molecule sensitivity.197–199 4.3.

Cancer therapy

For cancer patients, timely and effective treatment is another key to improve their survival. However, routinely used (chemo-) therapeutic agents usually suffer from some serious disadvantages. For instance, their low molecular weight generally causes them to be cleared rapidly from the circulation. Their small size and/or their high hydrophobicity make them present with a large volume of distribution. Consequently they don’t accumulate well at the pathological site, and what is more serious is that their accumulation in healthy tissues may cause inadvertent side effects.7,200,201 To solve these problems, various kinds of drug delivery systems have been designed to: (1) maintain the drug concentration at safe levels; (2) achieve appropriate target site accumulation; and (3) engineer a long circulation to achieve longer half-life. The drug delivery system can perfectly balance the efficacy and the toxicity of anticancer drugs, which can greatly improve therapeutic efficacy. In recent years, the progresses in bio-nanotechnology and nanomedicine have brought new opportunities to drug delivery systems for cancer therapy.6,11,202 Just as described in Part 3,

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Summary of the features of the bioimaging techniques with QD/MNP-based nanocomposites

Signal measured

Modality

Labels

Fluorescence imaging

QDs

Visible to infrared light

MRI

MNPs

Radio frequency waves

Magnetic particle imaging (MPI)

MNPs

Radio frequency waves

T1–T2 dualmode MRI

T1–T2 dual-mode contrast agents (e.g. combination of Gd- or Mn-based chelates (T1 elements) and metal ferrite MNPs (T2 elements))

Radio frequency waves

(Magnetic particle) MP-MR dualmode imaging MR-optical dualmode imaging

MNPs

Radio frequency waves

MNPs combined with fluorophores (e.g. fluorescent dyes, QDs, UCNPs) MNPs combined with radioisotopes (e.g. 124I, 64Cu, 111In, 99m Tc)

Radio frequency waves and light Radio frequency waves and γ-rays

MR-US dualmode imaging

Microbubbles loaded with MNPs

Radio frequency waves and high frequency sound waves

MR-PA dualmode imaging

MNPs combined with probes that absorb light and create sound signals (e.g. gold nanostructures and NIRabsorbing dyes)

Radio frequency waves and high frequency sound waves

MR-PET/SPECT dual-mode imaging

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Typical references

Imaging features Fluorescence imaging has the advantages of high sensitivity, low cost, and quick tracking, enabling real-time application and multicolor imaging. However, it has low spatial resolution and poor tissue penetration, and suffers from relatively severe background interference from absorption, scattering, or autofluorescence of samples. Furthermore, application of QDs containing Cd may cause biotoxicity. MRI now has become one of the most important medical imaging techniques with high spatial resolution, excellent soft tissue contrast, and low cytotoxicity, without tissue penetrating limitation or radiation damage. But it has some disadvantages such as long imaging time, low sensitivity, high cost, and interference from artifact signals. MPI directly determines the spatial distribution of MNPs by exploiting their non-linear magnetization curve. It is a quantitative imaging modality with high sensitivity and fast image acquisition allowing for real-time applications. It has good biosafety without background interference or penetration depth limitation. But its spatial resolution is relatively low. Compared with single-mode MRI, T1–T2 dual-mode MRI can provide complementary T1-weighted and T2-weighted MR images enabling self-confirmation of the signals, which minimizes the artifact signals in MRI to obtain more accurate diagnostic images. Compared with other multi-mode imaging, T1–T2 dual-mode MRI is achieved by a single instrument, without the problems of discrepancies in the penetration depth or image mismatch occasionally happens when moving a sample between different instruments. However, other drawbacks of MRI still exist, such as low sensitivity and long imaging time. The MPI-MRI dual-mode technique utilizes only MNPs as tracers without the need of other additional imaging moieties. It can be used to obtain sensitive and quantitative information on the NP location, and achieve high resolution anatomical imaging at the same time. Simultaneously performing fluorescence optical imaging and MRI can combine the high sensitivity of optical imaging and the high spatial resolution of MRI.

12, 25, 146, 147, 167

PET and SPET are known for their very high sensitivity, but limited by their low spatial resolution. Thus, the combination of MRI with PET/SPECT can provide tomographic images with much high spatial resolution and much high sensitivity to achieve more detailed and accurate information, especially in deep tissues (all three techniques have no tissue penetrating limitation). However this MR-PET/SPECT dual-mode imaging is expensive and undergoes radiation damages. US imaging is real-time, cost effective, portable, non-ionizing, and widely available. It can image structure and function simultaneously free of geometric distortion, but it has poor tissue discrimination ability and poor tissue penetration. US imaging and MRI are complementary in many clinical applications, and their combination can simultaneously enhance both US and MR imaging, providing adequate and comprehensive imaging information. PAI is a noninvasive imaging modality with high sensitivity and high spatial resolution, but with relatively poor penetration depth, and PAI also suffers from ambiguities arising from photoacoustic background signals of the endogenous photoabsorbers within the tissues. MRI-PAI dual-mode technique displays strong PA signal enhancement and significant contrast enhancement for MRI, which can achieve precise tumor localization and boundary identification, and realize “selfconfirming for fault-free diagnosis”.

154, 158, 177–181

23, 138, 143, 151, 168

169–172

142, 155, 173, 174

142

152, 162, 163, 175, 176

159, 182–185

160, 161, 186–188

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Fig. 14 (A) Schematic illustration for the basic principle of a typical suspension array platform for simultaneous analyses of multiple targets. Reproduced from ref. 190 with permission from the Royal Society of Chemistry. (B) Schematic illustration for multiplexed detection of DNAs with QDtagged beads. Probe oligos (no. 1–4) were conjugated to the encoded beads to hybridize with the target oligos (no. 1–4), which were then detected with a blue fluorescent dye. Reproduced with permission from ref. 33. Copyright 2001 Rights Managed by Nature Publishing Group. (C) Schematic illustration for cancer cell detection and pattern recognition with the magnetic nanosensors. Without target cells, the magnetic particles were well dispersed, resulting in a high T2 of surrounding water protons. The addition of target cells led to the aggregation of magnetic particles, decreasing the T2 of adjacent water protons (a), and the value of ΔT2 reduced with the decrease of receptor expression level on various cell lines (b). Reproduced with permission from ref. 141. Copyright 2012 American Chemical Society.

micro/nano-composites have a large space for loading QDs, MNPs, drugs, and so on, which enables them to be an excellent platform for engineering multifunctional devices. Among them, the magnetic targeted drug delivery systems have drawn special attention due to the unique magnetic properties of MNPs. For instance, through magnetic guidance, composites with drugs and MNPs can be delivered to lesion sites via applying an external magnetic field, and then release drugs under some stimulus ( pH, field, heat, etc.), which can greatly reduce toxic side effects.203–206 Thomas et al.207 incorporated zinc-doped iron oxide nanocrystals (ZnNCs) into mesoporous silica nanoparticles. Then the base of the molecular machine was attached to the nanoparticle surface, followed by drug loading and capping (Fig. 15A). When the drug delivery system was set to an alternating current (AC) magnetic field, the nanocrystal generated local internal heating to cause the molecular machines disassemble and allow the drugs to be released. Thomas et al. then used the delivery system to treat breast cancer cells, and 37% of the cells were killed, suggesting that this system would be a promising tool for target cancer therapy. Now, magnetic targeted drug delivery systems have been applied to in vivo research, and have also

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achieved good therapeutic efficacy. Li et al.208 developed a magnetic mesoporous silica nanoparticle-based PEI and fusogenic peptide-functionalized siRNA delivery system (denoted as M-MSN_siRNA@PEI-KALA), which is shown in Fig. 15B (a). These delivery vehicles possessed a notable siRNA protective effect and little cytotoxicity. They could be internalized easily into cells with an excellent endosomal escape capability, thereby successfully releasing the loaded siRNA into the cytoplasm to mediate remarkable interference effect on the target gene of the tumor cells. In the in vivo experiments, these vehicles significantly inhibited the tumor growth (Fig. 15B (b)), showing their potential application in cancer treatment. MNPs and QDs, on the other hand, are excellent imaging reagents, and their coupling with drug delivery contributes to the combination of cancer diagnosis and therapy. There are several significant advantages for this combination:200 (1) imaging-guided chemotherapy helps monitor and quantify drug release. (2) The biodistribution and the target site accumulation of the therapeutic agents can be non-invasively assessed in real time. (3) Relying on the first two advantages, researchers can regulate and optimize the therapeutic inter-

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Fig. 15 (A) Sketch for the fabrication of drug delivery systems and their release of drugs under an AC magnetic field. Reproduced with permission from ref. 207. Copyright 2010 American Chemical Society. (B) (a) Flowchart illustrating the preparation of siRNA delivery vectors based on magnetic mesoporous silica nanoparticles (1–3), and their application to the in vivo cancer treatment (4–5). (b) Growth curves of tumors treated with different M-MSN-based delivery systems (the positive group (M-MSN_VEGF siRNA@PEI-KALA) showed significant inhibition to the tumor growth). Reproduced with permission from ref. 208. Copyright 2012 Published by Elsevier Ltd. All rights reserved.

ventions in a timely manner. (4) Imaging can also help to predict therapeutic responses, and evaluate the drug efficacy longitudinally. Therefore, imaging-guided drug delivery, facilitating the integration of diagnosis and treatment, can not only improve disease diagnosis and therapy, but also greatly promote the study of medical efficacy and toxicity, which would help us to better understand the process of drug delivery. Reddy et al.209 gave a schematic diagram (Fig. 16A) to show the general structure of the multifunctional device with magnetism, fluorescence, drug loading and bio-targeting, which can be used for simultaneous imaging, therapy, and cell

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sorting. Yu et al.24 reported anti-biofouling polymer-coated, thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPIONs) loaded with doxorubicin (Dox; an anticancer drug) for combined cancer imaging and therapy in vivo (Fig. 16B and C). These Dox@TCL-SPIONs (Fig. 16B (a)) were intravenously injected into tumor-bearing mice, and then MR imaging was performed at scheduled time points to examine the localization and accumulation of the nanoparticles. At 4.5 h postinjection, noticeable darkening appeared in the tumor area, indicating a large accumulation of the nanoparticles within the tumor (Fig. 16B (b)), and in 24 h, most of the nanoparticles were removed from the tumor. The authors further compared the biodistribution of Dox in mice by fluorescence imaging for several major organs after intravenous injection of both Dox@TCL-SPIONs and free Dox (Fig. 16B (c and d)), which suggested that the Dox@TCL-SPIONs more readily accumulated in the tumor with much lower organ toxicity. Further in vivo experiments validated that the Dox@TCLSPIONs showed remarkable inhibition of tumor growth of approximately 63%, which was even much higher than that of free Dox at an 8-fold higher dose (Fig. 16C (a)). Moreover, from the monitoring of mice body weight (Fig. 16C (b)) and the white blood cell number, a high dose of Dox exhibited severe toxicity, while the Dox@TCL-SPIONs was hardly toxic. Apart from combination with drugs, MNPs themselves are a kind of theranostic agent due to the fact that they can provide hyperthermia under an alternating magnetic field (AMF).206,210,211 Compared with healthy cells, tumor cells are more sensitive to a temperature increase, and hence MNPs can be used to increase the temperature of tumor tissue in vivo and destroy pathological cells, which has fewer side effects than chemotherapy and radiotherapy. What’s more, hyperthermia coupled with MRI can cause cancer treatment to proceed under monitoring in real time and in situ. In addition to direct tumor-cell killing, hyperthermia can also make tumor cells more susceptible to concomitant radio- or chemotherapy.212–215 Thus combination of multiple therapies may achieve much better treatment efficacy. van der Zee et al.216 compared radiotherapy alone and the radiotherapy plus hyperthermia in locally advanced pelvic tumors. The complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia, and 3-year overall survival was 27% in the radiotherapy group and 51% in the radiotherapy plus hyperthermia group, which suggested that hyperthermia coupled with standard radiotherapy might be more useful in the treatment of locally advanced cervical tumors. Kim et al.,217 Li et al.218 and Quinto et al.219 also found that the double effects of heat and drug were more effective than either chemotherapy or hyperthermia treatment alone. Now, combined therapy has become one of the most important development directions for cancer research, which has a great potential to improve the cure and survival rates of cancer patients, and in this field, nanocomposite-based drug delivery exhibits great application value, due to its easy manipulation, great versatility, good biocompatibility, and so on.

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Fig. 16 (A) Schematic diagram for the general structure of a multifunctional device with magnetism, fluorescence, drug loading and bio-targeting, which can be used for simultaneous imaging, therapy, and cell sorting. Reproduced with permission from ref. 209. Copyright 2012 American Chemical Society. (B, C) Dox@TCL-SPIONs for combined cancer imaging and therapy in vivo. Reproduced with permission from ref. 24. Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) (a) Schematic diagram for the formation of Dox@TCL-SPIONs. (b) T2-weighted MR images of the tumor-bearing mice performed at 0 h and 4.5 h after injection of Dox@TCL-SPIONs. (c, d) Fluorescence images of major organs and allograft tumors after intravenous injection of Dox@TCL-SPIONs (c) and free Dox (d) into tumor-bearing mice: 1 liver; 2 lung; 3 spleen; 4 tumor; 5 heart; 6 kidney. (C) Antitumor efficacy and toxicity analyses of Dox@TCL-SPIONs in tumor-bearing mice: (a) excised tumors from mice euthanized after the 19th day of treatment with: 1 control; 2 TCL-SPION; 3 Dox (0.64 mg kg−1); 4 Dox (5 mg kg−1); 5 Dox@TCL-SPION (0.64 mg Dox kg−1). (b) Evolution of body weight of each group during the treatment. Arrows indicate the day of drug injection.

5. Conclusions and outlook This review mainly outlined the preparation and the properties of the QD/MNP-based fluorescent/magnetic micro/nanospheres, and further discussed their recent applications in cancer research in detail. Based on QDs and/or MNPs, fluorescent/magnetic micro/nano-spheres are constructed mainly through embedding the NPs into spheres, incorporating the NPs during the sphere formation process, assembling the NPs onto the surfaces of the spheres, or in situ synthesis of the NPs within the pores of the spheres. Each method has its own advantages and limitations, and researchers can select the appropriate one according to their demands and the available experimental conditions. The obtained NP–sphere composites not only inherit the unique fluorescence or magnetic properties of QDs or MNPs, but also show superiority over the NPs alone, for example, their high stability, strong signal, great versatility, good biocompatibility, convenient manipulation, and so on. Hence, the fluorescent/magnetic micro/nanospheres exhibit great application value in cancer study: they

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can be used to isolate and enrich tumor cells or biomarkers from complex biofluids which greatly facilitates subsequent analyses; they can be utilized as imaging agents or reporter probes for cancer diagnosis; and they have now become an important platform for target drug delivery which may significantly improve the cure and survival rates of cancer patients. Although much progress has been made with QD/MNPbased fluorescent/magnetic micro/nano-spheres, numerous challenges and issues remain to be resolved, and there is still a long way to go to substantiate their application in practice.220–223 In terms of fabrication, novel synthetic methods still need to be explored to improve the problems with the current methods. To meet various application demands, NP–sphere composites with different morphology, different sizes (from nanometer to micrometer range), and different amounts of NPs have been pursued. Meanwhile, more convenient operation procedures and mass production are other important development directions. For the modification of spheres, orientation conjugation of functional molecules and precise control of their number are the main

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challenges. In addition, suitable surface coatings have been employed to improve the biocompatibility, specificity, and selectivity of the NP–sphere composites. As for their practical application, on the one hand, it’s critical to develop a sound understanding of the thermodynamics and kinetics of the binding reaction at the sphere/solution interface, which will provide a theoretical foundation to guide their scientific application, such as better control of the formation of the sphere– biomolecule conjugates, easier optimizing of the operating conditions in targeted biological applications, and so on. On the other hand, to ensure the smooth transition from bench to the bedside, many issues must be addressed before the NP– sphere composites can be used in humans, including their biocompatibility, in vivo targeting efficacy, pharmacokinetics, biodistribution, toxicity, etc. Many researchers have been devoting themselves to these studies, and some have even made great progresses which, although are far from being ideal, show a very bright prospect for application.

Acknowledgements This work was supported by the National Natural Science Foundation of China (no. 21535005, 21505157), the National Basic Research Program of China (863 Program, no. 2013AA032204), the 111 Project (111-2-10), Collaborative Innovation Center for Chemistry and Molecular Medicine, the Fund for Young Scientists of Shandong Province (no. BS2015SF001), and the Fundamental Research Funds for the Central Universities (no. 15CX02070A).

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or magnetic nanoparticles: preparation, properties, and their applications in cancer studies.

The study of cancer is of great significance to human survival and development, due to the fact that cancer has become one of the greatest threats to ...
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