Magnetically engineered semiconductor quantum dots as multimodal imaging probes.

www.advmat.de www.MaterialsViews.com

REVIEW

Magnetically Engineered Semiconductor Quantum Dots as Multimodal Imaging Probes Lihong Jing, Ke Ding, Stephen V. Kershaw, Ivan M. Kempson, Andrey L. Rogach,* and Mingyuan Gao* information, thus improving the efficacy and sensitivity of clinical imaging diagnosLight-emitting semiconductor quantum dots (QDs) combined with magnetic tics. To date, the combinations of imaging resonance imaging contrast agents within a single nanoparticle platform are techniques such as positron emission considered to perform as multimodal imaging probes in biomedical research tomography (PET)/computer tomoand related clinical applications. The principles of their rational design are graphy (CT) and PET/magnetic resonance imaging (MRI) have already developed outlined and contemporary synthetic strategies are reviewed (heterocrystalinto commercial imaging instruments line growth; co-encapsulation or assembly of preformed QDs and magnetic that are being adopted clinically. Furnanoparticles; conjugation of magnetic chelates onto QDs; and doping of thermore, optical imaging (OI) techQDs with transition metal ions), identifying the strengths and weaknesses niques have shown superior potential in of different approaches. Some of the opportunities and benefits that arise extracting detailed biomedical information through in vivo imaging using these dual-mode probes are highlighted where with high imaging sensitivity and with low cost imaging facilities in comparison to tumor location and delineation is demonstrated in both MRI and fluorescence clinically used MRI, CT and PET methods. modality. Work on the toxicological assessments of QD/magnetic nanopartiFluorescent inorganic nanocrystals cles is also reviewed, along with progress in reducing their toxicological side having optical properties that are governed effects for eventual clinical use. The review concludes with an outlook for by their composition, size, and surface future biomedical imaging and the identification of key challenges in reaching chemistry offer specific advantages for optical imaging. Semiconductor quantum clinical applications. dots (QDs),[8–24] carbon dots,[25–28] graphene[29,30] and silicon dots,[31–34] noble metal clusters,[35–39] and lanthanide-doped up-conversion 1. Introduction nanocrystals[40–42] have all shown potential in extracting detailed biological information at subcellular levels in vitro with high Multimodal imaging using nanostructures synergistically inteimaging sensitivity. However, due to the poor spatial resolugrated with multiple functional entities has ignited intense tion and optical penetration in tissue, the complementarity of research interest worldwide, offering revolutionary imaging these probes with magnetic resonance imaging (MRI), which tools for biomedical applications.[1–7] Integrating the compliis one of most important clinical tools nowadays for visualizing mentary merits of different imaging modalities is an effecinternal anatomical structures with extremely high spatial resotive approach to extract accurate and reliable biomedical lution, is strongly desirable. In this context, the combination of optical imaging techniques and MRI offers a powerful combination of imaging modalities for more accurate biomedical Dr. L. H. Jing, K. Ding, Dr. I. M. Kempson, Prof. M. Y. Gao detection.[43,44] Institute of Chemistry, Chinese Academy of Sciences Bei Yi Jie 2 Development of multimodal optical + MRI imaging probes Zhong Guan Cun, Beijing 100190, China obviously relies on the design and subsequent fabrication of E-mail: [email protected] nanostructures offering both modalities within a single platDr. S. V. Kershaw, Prof. A. L. Rogach form. Nanometer-sized semiconductor QDs are well known Department of Physics and Materials Science as powerful fluorescent probes because of their outstanding & Centre for Functional Photonics optical properties governed by the quantum confinement effect. City University of Hong Kong Tat Chee Avenue, Kowloon, Hong Kong S.A.R Their emission window covers a broad spectral range from the E-mail: [email protected] visible into the near-infrared, enabling us to optimize detecDr. I. M. Kempson tion/imaging performance. They are easily functionalized by Ian Wark Research Institute a variety of surface modifications thereby: facilitating targeted University of South Australia delivery; prolonging systemic circulation (which is imporMawson Lakes, S.A. 5095, Australia tant for biocompatibility) and exploiting the enhanced permeability and retention (EPR) effect in tumors; allowing for the DOI: 10.1002/adma.201402296

Adv. Mater. 2014, DOI: 10.1002/adma.201402296

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

wileyonlinelibrary.com

1

www.advmat.de

REVIEW

www.MaterialsViews.com

incorporation of therapeutic ligands, and developing multifunctional nanoparticles. Furthermore, QD-based nanostructures imparted with magnetic properties offer the opportunity for multifunctional bioimaging and biomedical applications. To date, magnetically engineered QDs are commonly synthesized by one of the following four approaches: heterocrystalline growth; co-encapsulation/assembly of separately preformed QDs and magnetic particles; conjugation of magnetic chelates onto QDs; and doping of QDs with paramagnetic transition metal ions. Herein, we review these contemporary approaches towards engineering QD-based nanomaterials for fluorescence/ magnetic-resonance multimodal imaging. We first introduce the optical and magnetic properties of the respective building blocks, and then discuss the synthesis methods, highlighting in particular the core@shell structure design and paying special attention to the criteria useful for properly balancing the useful physical properties of the resulting multimodal probes. Subsequently, we present a selection of proof-of-concept examples with regard to in vivo tumor imaging of these probes, and discuss the related toxicity concerns. We conclude with an outlook on their future perspectives towards clinical applications.

2. Properties of Quantum Dots and MRI Contrast Agents 2.1. Optical Properties of Semiconductor Quantum Dots Semiconductor nanocrystals, or colloidal QDs exhibit strong size-dependent optical properties when their radii are smaller than their bulk exciton Bohr radii.[8–10,20] Due to quantum confinement, decreasing the crystal size gives rise to an increasing bandgap.[9] This results in strongly size-dependent QD absorption and emission spectra, with the band edge features of both shifting to higher energies with decreasing particle sizes. The optical properties of QDs exhibit a very useful set of features favorable for biomedical applications, such as narrow and symmetrical emission profiles, beneficial for color purity and precise tunability of emission; broad excitation range combined with high molar absorption coefficients, which enables the simultaneous excitation of different-sized QDs with a single excitation source and high-throughput detection. They exhibit high photoluminescence (PL) quantum yield (QY) and robustness against photo-bleaching which allows long-term visualizing and tracking of biological processes and they have relatively long PL lifetimes which enables exclusion of interference from biological background noise (i.e., auto-fluorescence).[12,45,46] Up to now, different kinds of QDs such as II–VI Zn(S,Se)[47] and Cd(S,Se,Te),[14,19,48–51] II–V Cd3(P,As)2,[52,53] III–V In(P,As),[54,55] IV–VI Pb(S,Se),[56,57] I–VI Ag2(S,Se)[58,59] I– III–VI CuIn(S,Se)2[60–70] and AgIn(S,Se)2,[58,65,67] and IV (C, Si, Ge)[25,71,72] materials have been successfully applied as fluorophores in biomedical fields. Owing to the strong dependence of both QD stability and their fluorescence on the surface quality, appropriate surface engineering of QDs is often required. Their small size gives rise to a large surface-to-volume ratio, and consequently a potential large fraction of dangling or unsaturated bonds on the surface, which may detrimentally provide non-radiative dissipation

2


Dr. Lihong Jing is an assistant professor in the Institute of Chemistry, Chinese Academy of Sciences. She received her Ph.D. in Physical Chemistry (2011) under the supervision of Prof. Mingyuan Gao in that institute. She worked as a Research Assistant and Research Associate at Prof. Andrey L. Rogach’s group at City University of Hong Kong in 2011 and 2013, respectively. Her major research focuses on the synthesis and biomedical applications of semiconductor quantum dots and associated multifunctional nanomaterials. Prof. Andrey L. Rogach is a Chair Professor of Photonics Materials and the Director of the Centre for Functional Photonics at City University of Hong Kong. He received his Diploma in Chemistry (1991, with honors) and Ph.D. in Physical Chemistry (1995) from the Belarusian State University in Minsk, and worked as a staff scientist at the Institute of Physical Chemistry at the University of Hamburg, Germany, from 1995 to 2002. During 2002– 2009, he held a tenured position of lead staff scientist at the Department of Physics of the Ludwig-MaximiliansUniversität in Munich, where he completed his habilitation in Experimental Physics. His research focuses on the synthesis, assembly and optical spectroscopy of colloidal semiconductor and metal nanocrystals and their hybrid structures, and their use for photovoltaic, photocatalytic, and imaging applications. Prof. Mingyuan Gao is a Full Professor in Institute of Chemistry, Chinese Academy of Sciences. He received his B.Sc. (1989) and Ph.D. (1995) in Polymer Chemistry and Physics at Jilin University. He worked as research assistant and associate in Germany from 1996 to 2002 and was an A. v. Humboldt fellow between 1996 and 1998. He took his current position upon a “Hundred-talent Program” of CAS in 2001. He received the “National Science Fund for Distinguished Young Scholars” from NSFC in 2002. His research focuses on the synthesis as well as biological and biomedical applications of functional nanomaterials.





REVIEW

channels for photogenerated charge carriers. Efficient passivation of such surface trap states is therefore particularly important to maintain and further improve PL QYs and the stability of QDs against photobleaching. In this respect, core@shell nanostructures with a wide bandgap semiconductor shell grown on a narrower bandgap semiconductor core are a particularly efficient solution for surface passivation. Of prime consideration here is the lattice mismatch between the core and shell materials which can induce lattice strain thus degrading the desirable optical properties. Small lattice mismatch and suitable shell thickness allowing for nanoparticle epitaxial growth are important to avoid these issues. To date, epitaxial growth of II–VI CdSe QDs (Eg,bulk ≈ 1.74 eV) with ZnS shell (Eg,bulk ≈ 3.61 eV) or CdS shell (Eg,bulk ≈ 2.49 eV) has been most frequently used, based on the organic phase thermal decomposition of suitable precursors.[73–76] The resulting core@shell structures with optimized shell thicknesses can routinely achieve PL QYs above 50%. Very recently, by controlling the growth kinetics of a CdS shell at a slow growth rate, CdSe@ CdS QDs with a PL QY of 97% have been reported.[77] Synthesis of epitaxial-type core@shell QDs using the aqueous phase synthetic routes is more challenging in comparison with the organic phase based approach. Since water is a strong polar solvent, it can not only coordinate with cadmium ions in different forms depending on the pH of the system, but also readily induces complicated dynamics for surface capping molecules.[19] By choosing a mercapto acid (e.g., thioglycolic acid, mercaptopropionic acid, or glutathione) as a surface stabilizing agent,[78] on the basis of pioneering investigations of Henglein,[79] and Rogach and Weller,[80,81] an important breakthrough towards strongly fluorescent aqueous CdTe QDs (Eg,bulk ≈ 1.43 eV) was achieved by Gao et al.[19,78,82] The growth kinetics of the shell materials on these QDs can be controlled via either an illumination-assisted process[83] or an ammonia incubation process:[84] in both cases mercapto-acid molecules slowly release sulfide which deposits on the surface of the CdTe QDs in combination with Cd2+ ions, forming a CdTe@CdS core@shell structure.[14,19,21,85] This can greatly enhance the PL QYs up to values of 85%. Apart from the most studied II–VI CdSe and CdTe QDs, core@shell nanostructures also enhance the PL QY of I–III– VI QD cores such as CuInS2 and CuInSe2 QDs. These two kinds of QDs exhibit direct band gaps of ca. 1.53 eV and ca. 1.05 eV, respectively, and therefore offer emission windows ranging from the visible to the NIR. Importantly, they do not contain toxic heavy metals, and thus offer the opportunity to fulfill the potential of QDs without the toxicity limitations encountered by Cd-based II–VI QDs. After ZnS shell coating, the PL of the resulting ternary core@shell QDs which are commonly synthesized with organic phase based approaches can be greatly improved. Their PL QYs generally exceed 50%[61,70] and in some cases reach up to 80%.[64,86] The intrinsic lattice mismatch (2–3%) between the CuInS2 core and the ZnS shell is low enough to allow epitaxial shell growth. However, shell overgrowth on CuInS2 QDs typically induces a significant hypsochromic shift of the emission wavelengths, indicating some changes in composition or size of the underlying fluorescent cores. It has been proposed that due to the small difference between the ionic radius of Zn2+ and Cu+, Zn2+ ions readily

diffuse into the CuInS2 core lattice which exhibits a chalcopyrite structure. The indiffusion results in a slightly modified form of zinc blende lattice in which Cu+ and In3+ ions occupy the positions of the displaced Zn2+ ions, eventually leading to an interfacial gradient in composition.[63,66] Alternatively, the hypsochromic shift may also result from a surface reconstruction[61] or etching of the cores.[64] The exact mechanisms are yet to be verified, and will likely lead to better-defined ZnS shell structures on CuInS2 core QDs in the future. The colloidal stability of core-only or core@shell QDs in complex biological environments may be an obstacle to extending their use in bioapplications. With this in mind, encapsulation of the QDs within inert materials such as silica[84,87–90] or polymers[91–95] can both improve their colloidal and chemical stabilities preventing oxidation by ambient oxygen, and impede the leaching of heavy metal ions. A drawback is the related large increase of the overall size of the resulting nanoparticles.

2.2. Magnetic Properties of MRI Contrast Agents MRI is a powerful non-invasive imaging technique in both fundamental studies and disease diagnosis, which has triggered intense exploitation to visualize the anatomical structure of the body and extract physiological information with high spatial resolution and soft tissue contrast.[43,96] The principle of MRI is based on the computer-assisted imaging of relaxation signals of water proton spins excited by radio frequency pulses in an external magnetic field. Differences in the local environments of water in different biological tissues bring about changes in their relaxation rates, thereby providing contrast. The relaxation of proton spins to their equilibrium states involves two principal processes, namely longitudinal (or spin-lattice) relaxation characterized by a relaxation time T1, and transverse (or spinspin) relaxation characterized by a relaxation time T2. MRI contrast agents principally work by shortening the T1 or T2 relaxation times of surrounding water protons,[97,98] and can generally be divided into two categories, i.e., T1 and T2 contrast agents, yielding signal brightening or darkening in the images, respectively. The efficiency of the contrast agents to shorten longitudinal (T1) and transverse (T2) relaxation times of water protons are quantified by the concentration-independent relaxivities r1 and r2, respectively. Higher values of r1 or r2 (which correspond to stronger reduction in T1 or T2) result in enhanced detection sensitivity, which favors the minimization of a contrast agent’s dose. Positive contrast agents are most frequently chosen from paramagnetic metal chelates consisting of metal ions with a number of unpaired electron spins such as Gd3+, Mn2+, and Fe3+.[99–102] In particular, paramagnetic Gd3+-based (e.g., GdDTPA, DTPA = diethylenetriaminepentaacetic acid) and Mn2+based (e.g., Mn-DPDP, DPDP = dipyridoxal diphosphate) small molecular chelates have been developed as efficient type T1 contrast agents, benefiting from a large number of unpaired electrons with parallel spin and a spin-relaxation time matchable with the Larmor precession frequency of protons within a suitable magnetic field.[100] However, due to the potential toxicity of Gd3+ and Mn2+ ions, chelates with low dissociation rates and high excretion rates are required in order to reduce



3

www.advmat.de

REVIEW


physiological side effects. Conversely, their intrinsically low molecular weight results in short blood circulation times because of the rapid excretion through the urine, hampering high-resolution imaging that requires extended scan times. In addition, they can not be easily functionalized, thus hampering specific targeting. Slowing the rotational rates of paramagnetic chelates could facilitate the interactions between the paramagnetic ions and nearby water to enhance relaxometric performance. A reliable way to slow tumbling rates (by strengthening their overall molecular rigidity) is to incorporate paramagnetic ions into a high molecular weight polymer or protein.[99–101] More recently the introduction of paramagnetic ions into nanoparticle platforms, such as manganese oxides (e.g., MnO, Mn3O4, etc.)[97,102–104] and gadolinium-containing nanoparticles (e.g., Gd2O3, NaGdF4, etc.) [105–108] as T1 MRI contrast agents and molecular imaging probes have started to receive increasing attention. Negative contrast agents most commonly utilize superparamagnetic iron oxide nanoparticles (SPIONs) due to high biocompatibility and long circulation time with appropriate surface modification, i.e., magnetite (Fe3O4) and maghemite (Fe2O3).[98,109–116] Such nanoparticles become super-paramagnetic when their size is below a critical scale where they behave as individual magnetic domains, and therefore they are predominantly used as T2 contrast agents.[98] Owing to continuing efforts over the past decade, the preparation of highly monodisperse magnetic iron oxide nanoparticles with a high degree of crystallinity and controllable particle size has been realized.[97,109,110,112,113,115–123] Precise size control allows indepth investigation of relaxometric properties associated with the nanoparticle size.[124–126] In principle, SPIONs also shorten the longitudinal relaxation time, but their innately high magnetic moments prevented them from being utilized as T1 contrast agents. Recent investigations show that magnetic iron oxide nanoparticles below 5 nm are potentially useful as T1 contrast agents,[127–132] due to the domination of paramagnetic behavior arising from the increased degree of spin disorder on the surface of the particles.[133] Anchoring groups of PEGylated ligands have further been shown to tailor relaxometric behavior with 3.6 nm nanoparticles exhibiting excellent T1/T2 contrast enhancement.[114] Such optimization of the relaxometric properties paves a strategy from the fundamental chemistry point of view to design versatile MRI contrast agents.

3. Synthetic Strategies towards Multimodal Nanoparticles As outlined above, the optical and magnetic properties of semiconductor QDs and MRI contrast agents are defined by factors such as size, composition, structure and/or surface chemistry. Rational integration of these two components into multifunctional nanoplatforms should enable versatile fluorescence/MR probes to be obtained. The key aspect in their design is that these two modalities are robustly combined without the loss or compromise of either optical or magnetic performance. Essential considerations include optical and relaxometric properties; the toxicity of the constituent elements; colloidal dispersibility;

4


and desirable surface properties. Current strategies to integrate fluorescent QDs with MRI contrast agents generally include four distinct approaches: heterocrystalline growth; co-encapsulation or assembly of preformed QDs and magnetic nanoparticles; conjugation of magnetic chelates onto QDs; and doping of QDs with transition metal ions.

3.1. Heterocrystalline Growth Heterocrystals typically combine two distinct materials in either core@shell or asymmetric heterodimer structures (Figure 1). Deposition of a semiconductor material on the preformed super-paramagnetic nanocrystals via high temperature decomposition of the respective precursors results in the formation of two distinct functional domains, as has been demonstrated for core@shell structures such as Co@CdSe,[134] FePt@ Cd(S,Se,Te) (Figure 1a)[135,136] and FePt@Pb(S,Se)[137]; and heterodimer structures such as FePt-(Cd,Zn,Pb)S (Figure 1b),[138,139] FePt-Pb(S,Se),[137] γ-Fe2O3-(Zn,Cd,Hg)S,[140] γ-Fe2O3-CdSe[141] and Fe3O4-Cd(S,Se) (Figure 1c and 1d).[142,143] The resulting structural arrangement strongly depends on the lattice mismatch between the QD and the magnetic component, but also on the synthesis parameters such as reaction temperature, surface capping molecules, and the addition sequence of the precursors.[134,135,137,138] For example, FePt@Cd(S,Se) core@shell nanoparticles were produced from Cd(S,Se) and FePt constituents at the reaction temperature of ca. 260 °C (FePt@CdS in Figure 1a), whilst a higher reaction temperature (e.g., 280–300 °C) promoted the formation of heterodimers through the partial coalescence of domains (FePt-CdS in Figure 1b).[135,138,144] This was likely due to intrinsic lattice mismatch and differences in phase transition temperatures affecting the surface wetting at the interface between the two nanoparticle types. The stabilizing ligands of the magnetic seeds can also determine the structure, i.e., ligands containing primary amines (e.g., oleylamine and hexadecylamine) on FePt cores favored core@shell FePt@PbS[137] and FePt@CdS,[136] while oleic acid favored heterodimers.[137] Heterodimers in particular possess separate domains that offer ample opportunities for further design of multifunctional probes, based on two distinct surfaces. Targeting agents, drug molecules or other moieties can be selectively attached to those surfaces on demand. The dual performance of these nanoparticles, however, may be compromised due to the undesirable interface interactions between the fluorescent and the magnetic domains. To maintain or balance the physical properties of each component still remains a challenging task. In particular, the PL QYs of the resulting nanoparticles are often low (below 10%) due to the quenching effect of the magnetic domains, which can be related to the formation of interface states caused by lattice mismatch inducing crystal strain, interface reconstruction around the junction, interfacial doping, and electron transfer/interactions across the interface which may all interfere with the band edge recombination processes of the fluorescent core.[134,145] The super-paramagnetic properties of the magnetic domain are easier to maintain, but interfacial spin disorder can result from interfacial doping, or instabilities between the two crystal lattices.[145] For more details on the




synthesis, physical properties and formation mechanisms of these structures, we direct the readers to several recent comprehensive reviews.[146–149]

3.2. Co-encapsulation/Assembly of Preformed QD and Magnetic Nanocrystals Co-encapsulation typically involves the inclusion of discrete preformed QDs and magnetic nanocrystals into silica or polymers beads, micelles or liposomes. Maintaining spatial separation between the fluorescent QDs and magnetic nanoparticles helps to avoid the emission quenching of the former which is often encountered in the heterocrystals considered above. Silica encapsulation of QDs can be performed either by the Stöber process[150–154] or by the reverse (water-inoil) microemulsion method.[84,87–89,155–157] Co-encapsulation of II–VI QDs (e.g., CdSe, CdTe, CdSe@ZnS, CdSe@CdZnS) and magnetic nanocrystals (e.g., Fe3O4, γ-Fe2O3) are particularly successful examples.[155,158–162] As an alternative to encapsulation, the nanoparticles can be loaded into mesoporous silica microspheres (e.g., 3–5 µm in diameter with 30 nm pores). This has been demonstrated for CdSe@ZnS QDs and Fe3O4 nanoparticles, driven by hydrophobic interactions between the stabilizing ligands of the nanoparticles and hydrophobic octadecyl chain modified pores.[163] Surface attachment of nanoparticles on silica spheres through covalent bonding has also




REVIEW

Figure 1. Core@shell and heterodimer structures of QDs and magnetic nanoparticles formed by heterocrystalline growth. TEM images of: a) core@shell FePt@CdS. Reproduced with permission.[135] Copyright 2007, American Chemical Society; b) FePt-CdS heterodimers. Reproduced with permission.[138] Copyright 2004, American Chemical Society. c,d) HRTEM images of Fe3O4-CdSe heterodimers (c) with the corresponding SAED analysis (d). Reproduced with permission.[142] Copyright 2008, American Chemical Society.

been demonstrated,[164] but the close proximity of the QDs and magnetic nanoparticles in such cases can still decrease the PL QY of the resulting architectures. Better spatial separation can be achieved by concentric layering of films containing QDs onto silica spheres containing magnetic particles.[159,161] Rather than silica, polymer or organic materials are also often used as a carrier matrix for the encapsulation of QDs and magnetic nanoparticles. This is commonly achieved by the following two strategies: i) geometric confinement of nanocrystals into porous polymer materials such as microbeads via hydrophobic interactions,[165] amphiphilic micelles via hydrophobic interactions,[166–169] polyelectrolyte multilayers via electrostatic[170–173] or covalent interactions;[174] or ii) polymerizing radical monomers in the presence of nanocrystals.[175,176] As an example of the first strategy, water-soluble CdTe QDs stabilized by thioglycolic acid and Fe3O4 nanoparticles stabilized by citric acid were simultaneously loaded into ca. 10 nm diameter pore channels of 5.6 µm diameter porous polymer microcapsules;[171,173] fluorescence quenching was minimized by separation of the Fe3O4 and CdTe nanoparticles with intermediate polymer layers. Detrimentally, diffusion of oxygen and water into the porous matrix materials may result in partial degradation of the QDs. Therefore, hydrophobic matrices possessing a compact structure are more suitable for achieving chemically robust structures, and these can be produced by radical polymerization of hydrophobic monomer droplets containing organic-soluble nanocrystals. Avoiding the aggregation of inorganic nanoparticles caused by their incompatibility with the polymerizable component is still a challenge for this approach. In addition, maintaining the high PL QY of the QDs may be challenging as well since a lot of radicals efficiently quench their emission. We have previously demonstrated that using a polymerizable surfactant to transfer the aqueous CdTe QDs to the styrene phase is an effective solution to the aggregation problem in polystyrene (PS).[91,92,95] This modified mini-emulsion polymerization method is based on the simultaneous transfer of CdTe and Fe3O4 nanoparticles from an aqueous medium into the styrene phase using polymerizable DVMAC (didecylp-vinylbenzylmethylammonium chloride) surfactant as a phase transfer agent and polymerizable OVDAC (octadecyl-p-vinylbenzyldimethylammonium chloride) surfactant as an emulsifier.[175] The resulting bifunctional polymeric beads (as shown in Figure 2) covalently incorporate both kinds of inorganic nanoparticles via vinyl groups. In addition, pre-coating of the Fe3O4 nanoparticles with a silica shell regulated the internal structure of the composite beads, and minimized re-absorption of the fluorescence emission of the QDs by Fe3O4. On the downside, the resulting structures became relatively large, typically exceeding 50 nm in diameter. Encapsulation-based techniques often utilize biocompatible materials, or can improve the biocompatibility of the resulting composite structures through proper surface modification, as the surface chemistry of silica and polymer microbeads is already well developed. Further advantages of this approach include the possibility of high payloads of multiple nanocrystal types, easy manipulation of the desired properties by varying the ratio between different kinds of nanoparticles, and the possibility of optical encoding by the use of different QDs. A high loading with magnetite results in much stronger magnetic

5

www.advmat.de

REVIEW


forces. As an example, in the absence of any linker molecules, positively charged polyethylenimine capped CdSe@ZnS QDs can efficiently assemble onto negatively charged citric acid capped Fe3O4 nanorings through electrostatic interactions,[177] while amphiphilic poly(4-vinylpyrollidone) capped Fe3O4 nanoparticles can overcoat hydrophobic 1-dodecanethiol capped CuInS2@ZnS QDs through hydrophobic–hydrophobic interactions.[178] Alternatively, upon crosslinking via linker molecules, CdSe@ZnS QDs could bind onto the surface of γ-Fe2O3 nanocrystals capped with thiol-containing polymers providing terminal functional thiol groups as chemical linkers,[179] while streptavidin capped CdSe@ZnS QDs can be successfully assembled on Fe3O4 capped with biotin-derived ligands.[71] Also for these nanostructures, reabsorption of incident and/or emitted light by Fe3O4 or γ-Fe2O3 components, and possible non-radiative energy or charge transfer processes between QDs and magnetic nanoparticles can reduce the PL QY.[169,177–179] In addition, these structures may suffer from the disassembling of their components under certain environmental conditions.

3.3. Conjugation of Paramagnetic Chelates onto QDs

Figure 2. Co-encapsulation of preformed CdTe QDs and magnetic Fe3O4 nanocrystals inside polymer microbeads. a) TEM image of polystyrene beads simultaneously incorporated with red CdTe QDs and Fe3O4@SiO2 particles (the scale bar corresponds to 100 nm). b–d) Three confocal fluorescence microscopy images acquired by a successive scan along the z axis of the presented composite bead. The bottom photographs show aqueous dispersions of the bifunctional beads incorporated with red and green CdTe dots, respectively, in combination with Fe3O4@SiO2 particles. The photographs were taken in ultraviolet light before and after a permanent magnet (0.5 T) was fixed in between the vials. Reproduced with permission.[175] Copyright 2008, IOP Publishing.

moments than is possible with individual Fe3O4 nanoparticles, improving both magnetic guidance (direction of administered magnetic particles via an externally applied magnetic field) and magnetic separation. The relatively large size (>50 nm) of these carriers poses a limitation on their applicability to extravascular targeting, but enhances their suitability for targeting the receptors of endothelial cells of blood vessels. Yet another approach towards integration of preformed QDs and magnetic nanoparticles is through interparticle interaction guided self-assembly. These interactions may include electrostatic,[177] hydrophobic,[178] coordinating,[179] and covalent conjugating,[180,181] or biomolecule-assisted (such as the barnase-barstar or (strept)avidin-biotin systems)[182,183]

6


Among the paramagnetic metal chelates, Gd chelates are most commonly used to directly coat onto QDs. The resulting conjugates are expected to possess enhanced relaxometric properties, amplifying MRI signals due to slow tumbling rates, and allow for high-performance T1-weighted MR imaging. Gd chelates (e.g., Gd-DTPA, Gd-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), etc.) and their derivatives are generally introduced onto QD surfaces by either non-covalent or covalent bonding. Non-covalent bonding is often provided by hydrophobic interaction guided self-assembly (Figure 3a)[2,184–189] or molecular coupling techniques such as the biotin-streptavidin interaction (Figure 3b).[190–192] Covalent bonding makes use of reactive functional groups such as silane-, thiol-, carboxyl- or amine- moities to connect Gd chelates with capping ligands on the QD surface. Pioneering work by Mulder and co-workers reported the coating of CdSe@ZnS QDs with paramagnetic chelating lipids.[185,188,193] Gd-DTPA was covalently bound to a lipid consisting of hydrophobic distearyl amide (DSA) chains to produce a paramagnetic chelating lipid (Gd-DTPA-DSA), which was simultaneously assembled together with PEGylated lipid onto hydrophobic CdSe@ ZnS QDs via hydrophobic interactions with surface ligands (Figure 3a). The resulting PEGylated water-soluble paramagnetic QD-based micelles can remain relatively small (diameters < 10 nm) despite achieving high payloads, each carrying up to 150 Gd-DTPA-DSA lipids. Importantly, an ionic relaxivity r1,Gd of 12.4 mM−1 s−1 at 37 °C (1.5 T) could be achieved, three times greater than that of free Gd-DTPA under the same field strength. This was attributed to the lower tumbling rate of the Gd-DTPA-DSA lipids when embedded into the QD micelle. The high particle relaxivity r1,QD of 2000 mM−1 s−1 of these nanostructures renders them attractive candidates for T1-weighted imaging. Apart from the direct coating of QDs, Gd-DTPA-DSA together with PEGylated lipids can be physically adsorbed




onto the surface of hydrophobically modified silica particles incorporated with CdSe-based QDs.[186,187] The resulting structures were ca. 35 nm in size, and carried an increased payload of up to 3200 Gd-DTPA-DSA units per QD particle. They exhibited a high ionic relaxivity of 14.4 mM−1 s−1 and a QD particle relaxivity of 46000 mM−1 s−1 (1.5 T), combined with a high QD PL QY of 35%.[187] In yet another approach, Bakalova et al. first stabilized the hydrophobic QDs with short-chain detergent micelles in order to transfer them into an aqueous phase.[194,195] The micellar QD surface was then coated with silica by using


REVIEW

Figure 3. QDs conjugated with paramagnetic chelates. a) Schematic representation of a nanoparticulate contrast agent consisting of a QD core covered by a micellar shell composed of PEGylated phospholipids and paramagnetic (Gd-based) lipids. Pentapeptidic peptides with an RGDsequence in a cyclic confirmation were also conjugated to the nanoparticle to provide specificity for ανβ3-integrin, an angiogenesis-specific endothelial cell surface receptor. Reproduced with permission.[185] Copyright 2006, American Chemical Society. b) Schematic representation of a QD containing approximately 1 AnxA5 and 10 streptavidin molecules, with surface conjugation to biotinylated Gd-wedges, containing eight Gd-DTPA complexes each (AnxA5-QD-Gd-wedge). Green: QD; yellow: streptavidin; red dot: Gd-DTPA; red star: lysine-wedge; blue: AnxA5. Reproduced with permission.[192] Copyright 2007, American Chemical Society. c) Bidentate thiol-containing Gd-chelating ligands directly coordinating with the surface cations of InP@ZnS QDs. Reproduced with permission.[202] Copyright 2011, American Chemical Society.

n-octyltriethoxysilane, possessing long hydrophobic chains to render them vitreophilic and they were then reacted with triethoxyvinylsilane as a silica shell precursor. Hydrophobic Gd chelating ligands were introduced into the micellar layer between the QD and the silica shell. The resulting 18 nm nanostructures retained the very high PL QYs of the constituent QDs (in the range of 35–50%), however their relaxivities were not reported. Covalent bonding of Gd chelating ligands to a QD surface, or its surface capping ligands, is particularly useful to avoid detachment under certain environmental conditions. A pioneering example of this design was reported by Holloway and co-workers.[196] CdS:Mn@ZnS QDs (3 nm) were first encapsulated within a silica shell of ca. 4–7 nm thickness, which was subsequently terminated by both positively charged amine groups and negatively charged phosphonate groups. To introduce paramagnetic properties, a Gd-chelating silane coupling agent, rather than DTPA or DOTA, was covalently bound to the silica surface. The resulting particles showed strong (PL QY ≈ 28%) emission from the Mn dopant, and were photostable. Their ionic relaxivities r1,Gd and r2,Gd were determined to be 20.5 and 151 mM−1 s−1 (4.7 T), respectively. In subsequent work, maleimide-activated Gd-DOTA were covalently bound to thiol groups terminating thin silica shells (ca. 2–3 nm) of CdSe@ZnS QDs.[197] The resulting 8 nm sized QD conjugates carrying ca. 45 Gd ions per particle showed ionic/QD particle relaxivities of 23/1019 mM−1s−1 and 54/2438 mM−1s−1 at 1.4 T for r1 and r2, respectively. These values were 6 and 14 times higher than for free Gd-DOTA, ascribed to the lower tumbling rate of the Gd-chelates attached to a hydrophilic silica surface. In the absence of silica coating, Gd ions can be attached at the surface of QDs by either an amidation coupling reaction between Gd-chelating ligands and the surface capping ligands of QDs such as CdSeTe@CdS,[198] CdTe@ ZnS,[199] CdS,[200] and CuInS2@ZnS,[201] or utilizing mono-, di- or multi-dentate thiol-containing Gd-chelating ligands directly coordinating with the surface cations of QDs as demonstrated for InP@ZnS (Figure 3c)[202,203] and CdSe@ZnS[204] QDs. Nevertheless, the high binding affinity of the chelating ligand may heavily etch the QDs before it coordinates with the paramagnetic metal ions for forming the magnetic metal chelates on the QD surface. The conjugation of magnetic chelates onto QDs strongly depends on the coordination reaction, providing flexibility for tailoring the composition in terms of paramagnetic payloads. Importantly, the longitudinal relaxometric performance of the resulting conjugates, originating from unpaired electron spin-proton dipolar interactions, is strongly and inversely correlated with the metal ion-proton distance. With Gd3+ ions located at the surface of the hybrid particles and therefore close to surrounding water molecules, strong longitudinal relaxation between the metal and local protons is favored, promoting higher ionic and QD particle relaxivities. However, there are safety concerns over the dissociation of Gd3+ ions from the surface, and the chelated metal ions can suffer from leaching in vivo due to the trans-chelation induced by proteins. Moreover, detachment of the Gd-chelating ligands from the QD surface may lead to inaccurate (and unstable) imaging information.



7

www.advmat.de

REVIEW


3.4. Doping of QDs with Paramagnetic Transition Metal Ions Doping of the crystalline lattice of semiconductor QDs with paramagnetic transition metal ions is yet another attractive approach toward fluorescent/paramagnetic dual-modal probes.[205–209] The resulting nanostructures combine the advantages of the very small size (e.g., 50%) for Mn dopant emission from doped ZnSe[218,243] and doped CdS@ZnS QDs,[216] accompanied with strong quenching of the QD bandgap excitonic emission. For more details we further refer the readers to several excellent

Figure 4. PL spectra of Mn-doped ZnSe QDs for different types of doping processes. Introduction of the dopant (small yellow dots) to the reaction system: a) alongside the host precursors for ZnSe QDs, b) before nucleation of the ZnSe host, and c) in the shell of a core/shell structured CdS@ZnS QD. All spectra were recorded with an excitation wavelength of 350 nm. Reproduced with permission.[245] Copyright 2011, American Chemical Society.

8






REVIEW

reviews covering chemical strategies and theoretical aspects of the doping chemistry of QDs.[206,221,244–248] The dopant location and doping level (i.e., concentration of the dopants per QD) strongly influences the photoluminescence properties of QDs. In general, in un-doped QDs, the photoexcited electron–hole pair can recombine radiatively to give rise to excitonic emission, but one or both of the carriers can also be trapped and result in non-radiative recombination. Such non-radiative relaxation channels include either internal crystal lattice structural defects or surface defect states. In doped QDs, the strength of exchange interactions between dopant and charge carriers strongly determines the photophysical process.[249] This can either induce energy transfer from the host nanocrystal to the dopant, or generate new defects as additional trapping states for charge carriers, leading to the quenching of excitonic emission. Consequently, photophysical processes characteristic of the doped QDs mainly include exciton radiative recombination, exciton non-radiative trapping, and excitonMn2+ ion energy transfer. As a consequence of strong exciton-Mn2+ energy transfer, highly efficient Mn2+ dopant impurity emission (Figure 4) can be realized for the majority of Mn2+ doped Zn(S,Se) and Cd(S,Se) QDs. The Mn2+ states residing within the bandgap of the host QDs give rise to a characteristic orange Mn2+ dopant emission center at around 585 nm (ca. 2.1 eV), as determined by the radiative transition from the first excited state, 4T1, to the ground state 6A1.[216,217,237,238,250,251] The dopant emission is typically very stable with a large Stokes shift, and emission wavelength almost independent of the QD host size and composition (subject to the Mn2+ excited state being bracketed by the QD bandgap).[227,245] The emission intensity strongly relies on efficient energy transfer from the excitonic states of the host QD to the Mn dopant ions.[252,253] In the context of dual-modal probes, doping Mn2+ ions into a QD host lattice can favor the enhancement of dopant emission, but reduces the bandedge PL of the QD host. Therefore, crystal structure design is required to properly balance optical and magnetic properties while maintaining the small dimensions of the resulting dual probes, which we consider below for the most widely used core-shell architecture. As reviewed in Section 2.1, the core@shell QDs possess both strong photoluminescence originating from radiative recombination in the core, and improved stability against photobleaching. Doping of the Mn ions into the core coated by a shell of the wide-bandgap semiconductor has been done for CdS:Mn@ZnS QDs.[242,254,255] Doping Mn ions into the shell has also been reported, such as for CdS@ZnS:Mn,[256,257]CdSxSe1-x@ZnS:Mn,[258] and ZnSe@ ZnS:Mn[259,260] QDs, which can conveniently be achieved by deposition of a Mn-doped ZnS shell on the preformed undoped cores. In the case of wide bandgap QDs such as ZnS, ZnSe, and CdS the lowest level of the Mn2+ ligand-field excited states falls within the gap between the lowest conduction and highest valence states of the host QD and the dopant therefore introduces a gap state that can readily be populated by excited carriers (electrons) in the QD that would otherwise have relaxed radiatively from the bandedge. Recombination therefore takes place between the new dopant (Mn2+) level and the ground state. Doping therefore results in quenched QD excitonic photoluminescence whilst Mn2+ dopant emission is efficiently

Figure 5. Two possible relaxation mechanisms realized in the Mn2+doped semiconductor QDs with a wide (a) and a narrow (b) bandgap. a) In the wide-bandgap material, efficient energy transfer from the QD host to Mn2+ quenches their excitonic emission and sensitizes the Mn2+ 4 T1→6A1 emission. b) In the narrow-bandgap material, Mn2+ excited states are located outside the bandgap and above the lowest conduction level so that the nanocrystals show the excitonic emission of the host. Reproduced with permission.[261] Copyright 2008, American Chemical Society.

sensitized by the host, as shown in Figure 5a.[221,261] Since the energy of the excitonic transitions in QDs strongly depends on their size, while the energy of the Mn2+ ligand-field transition does not, a decrease of the bandgap energy of the host QDs can prevent energy transfer from the QD host to the Mn dopant, so that the original QD emission remains unchanged (Figure 5b).[261] Specifically for CdSe QDs, there was no Mn2+ dopant emission for the sizes >3.3 nm, as above this diameter the lowest conduction level of the QD host fell below the Mn2+ excited states. As a consequence of the blocked energy transfer from CdSe QD host to Mn2+, the strong CdSe QD excitonic emission was maintained. However, even with appropriately aligned energy levels, strong PL emission is often challenging to achieve since the inclusion of dopant impurity atoms in the structure can give rise to additional non-radiative recombination channels for the QD excitons. The inclusion of even small numbers of dopant ions per QD can introduce structural defects (and significant lattice strain) if the dopant ionic radius does not fit easily within the host lattice. The solution to this class of problem can be found, for example, by introducing a spacer between the emitting QD core and the dopant atoms, or by otherwise tailoring the radial-position of the dopant’s location (particularly in the case of heterostructures).[66,213,252,257,262] This can be achieved, for example, by coating the host QD with a shell of a semiconducting material doped with Mn2+ ions. To date, Mn-doped ZnS shells on organic solution-grown CdSe (Figure 6a)[213,252] and on aqueous-grown CdTe QD cores (Figure 6b)[262] maintaining strong excitonic emission with QYs up to 20% and 45%, respectively, have been demonstrated. The ZnS shell both provided a suitable matrix for manganese doping (compatible lattice) and maintained the high PL QYs and improved the chemical stability of the QD cores. Of critical issue is the eventual release of heavy elements such as Cd2+ which causes such QDs[263,264] to be cytotoxic. The cytotoxicity of Cd2+ ions is currently an unavoidable problem in



9

www.advmat.de

REVIEW


reported Mn-doped CuInS2 QDs with a Zn gradient in the CuInS2 core and a ZnS outer shell, i.e., CuInS2@ZnS:Mn, where Mn ions were mainly located in the ZnS shell.[66] The ZnS shell enhanced the fluorescence of the underlying CuInS2 core, and prevented heavy fluorescence quenching caused by Mn-doping. For semiconductor shells doped with paramagnetic ions to be utilized as T1 contrast agents, it is crucially important to determine the dopant’s location, as it strongly influences their relaxometric properties. Electron spin resonance (ESR) spectroscopy is a powerful tool for assessing the successful inclusion of paramagnetic ions into semiconductor lattices, and for characterizing the dopant's local chemical environment. It can discriminate between dopants incorporated into the crystalline lattice, or simply attached to the surface of QDs. For Mn ions, the ground state 6A1 of Mn2+ splits into six Zeeman splitting components (mS = ±1/2, ±3/2, ±5/2) under an applied magnetic field. One resonance results in a six-line hyperfine splitting spectrum possessing a signature of the electron-nuclear hyperfine coupling of Mn2+ (electron spin S = 5/2, nuclear spin I = 5/2), which can be sensitively Figure 6. Core-shell QDs doped with Mn ions in the shell. a) TEM images of 4.7 nm Mn-doped probed using ESR spectroscopy. The covacore@shell CdSe@Zn1−xMnxS QDs synthesized by an organic phase-based high temperature lent nature of the different Mn2+ sites can thermal decomposition approach, together with absorption and PL spectra for the composi- be revealed via hyperfine splitting, allowing tion x = 5%, with core sizes changing from top to bottom as 8.0, 4.6, 3.8, and 3.5 nm. Repro- Mn2+ ions located within the nanocrystal latduced with permission.[213] Copyright 2007, American Chemical Society. b) 4.3 nm Mn-doped tice (on substitutional positions) to be distincore@shell CdTe@ZnS:Mn QDs synthesized by an aqueous-phase-based approach (scale bar guished from Mn2+ coordinated within other in the inset corresponds to 2 nm), together with temporal evolution of the absorption and PL [221,270] [ 262 ] spectra for different growth times. Reproduced with permission. Copyright 2013, American compounds or at other types of site. Chemical Society. Accordingly, Mn2+ ions at surface ionic sites or sites with significant lattice distortion should show much larger hyperfine splitting than Mn2+ ions transferring these imaging probes to clinical application. Zinc chalcogenide QDs are less toxic,[218,243] but the smaller exciton on internal sites within ordered lattices.[221,270,271] Mn2+ ions Bohr radius (and wide bandgap) of these materials requires the substituted for Zn2+ and Cd2+ on covalently bound tetrahedral excitation photons to have much higher energy. Apart from prosites in cubic bulk ZnS and CdTe lattices typically show hypervoking optical damage to tissue, the reduced tissue penetration fine splitting constants of 64 × 10−4 cm−1 and 57 × 10−4 cm−1 depth of this excitation light is a limiting factor in their bioimrespectively. Much larger values of around 90 × 10−4 cm−1, conaging applications. Recent attention has therefore been strongly sistent with a predominantly octahedral environment, have shifted towards I–III–VI QDs, such as CuIn(S,Se)2 as promising been identified with either interstitial or surface lattice bound Mn2+ locations.[272] For Mn-doped CdSe QDs,[239] and InP Cd-free candidates for in vivo applications.[60–64,66,70,86,265–269] Such QDs can be excited by incident light with wavelengths QDs,[271] hyperfine splitting constants of 83 × 10−4 cm−1 and of up to 600 nm, and their emission covers a wide range from 82.5–87.6 × 10−4 cm−1 respectively have been observed, though the visible to the near-infrared (NIR). PL QYs of up to 60% it has also been shown that more complex core@shell strucwhen coated by a ZnS shell can be achieved. In addition, their tures such as CdSe@ZnS:Mn, CdTe@ZnS:Mn can substanlonger PL lifetimes (in the range of several hundreds of nanotially influence the splitting constant values.[213] In terms of seconds, as compared to several tens of nanoseconds for II–VI deciding upon the best doping structure, it is helpful to know QDs) make them particularly appealing for visualizing cellular that Mn2+ ions have high binding energies at the zinc blende processes through time-gated elimination of interfering back(001) facets of II–VI nanocrystals.[205] Furthermore, since Mn2+ ground auto-fluorescence and scattering of (pulsed) excitation ions are a better match to Zn2+ rather than Cd2+ in terms of light. Therefore, magnetically engineered CuIn(S,Se)2-based ionic radii (Mn2+ (0.80 Å), Zn2+ (0.74 Å), Cd2+ (0.97 Å)), then QDs hold great potential as dual-modal imaging probes with it is preferable to dope Mn2+ ions into a ZnS shell rather than lower toxicity and suitable optical properties. We recently a Cd-based core. As for thinner shells (e.g., 1 or 1.5 monolayer

10






REVIEW

or even less), the splitting constant (close to 90 × 10−4 cm−1) is similar to that observed for isolated Mn2+ on the QD surface lattice.[213,262] This can be attributed to isolated Mn2+ ions having a different binding environment at the surface of a thin ZnS shell, acting as a crystallographically disordered doping matrix, rather than those in a bulk lattice.[213,217,262,273] It has been previously shown for shell-doped CdSe@ZnS:Mn QDs that the splitting value strongly depends on the thickness of the ZnS shell, and that the decreasing hyperfine splitting indicates that a thicker shell provides a more ordered matrix for Mn2+.[213] To summarize, while ESR can not accurately determine the Mn2+ radial location (numerically), it acts as an effective guide characterizing the binding nature of the Mn2+ ions which varies based on the spatial environment, i.e., it can distinguish between ions within lattices, at interfaces or on surfaces. The relaxometric properties of Mn-doped QDs still need to be thoroughly investigated. Several studies revealed that Mn-doped core@shell QDs can exhibit higher longitudinal relaxivity r1,Mn (ion relaxivity): e.g., 10–13.1 mM−1 s−1 (7 T) for 4.7 nm CdSe@ZnS:Mn,[213] 5.4–10.7 mM−1 s−1 (3 T) for 4.3 nm CdTe@ZnS:Mn,[262] and 4.5–6.3 mM−1 s−1 (1.5 T) for 3.6 nm CuInS2@ZnS:Mn.[66] The longitudinal ionic relaxivity r1,Mn of Mn2+ strongly depends on the tumbling time of the paramagnetic Mn2+ centers and their distance with water proton as well. Either slowing the tumbling of paramagnetic ions or shrinking paramagnetic ion-proton distance can favor higher r1 relaxivity. Thus, the above high r1 values can be attributed to the slowed global tumbling time of Mn2+ ions localized in the surface shell lattice of above shell-doped QD. This is in line with the observations that the relaxivities of paramagnetic Gd chelates can be increased after conjugation onto QD surfaces as we discussed in Section 3.3. Ionic relaxivity r1,Mn for either CdTe@ZnS:Mn[262] or CuInS2@ZnS:Mn[66] QDs is inversely correlated with Mndoping levels, and shows a monotonic decrease with increasing Mn-doping level. This ionic relaxivity dependence is suggested to be caused by enhanced spin-spin interactions between neighboring Mn2+ ions with increasing Mn2+ dopant concentration. This detracts from the relaxometric properties of ‘isolated’ ions which are the largest contributor to the relaxivity enhancement. Interestingly and in contrast to the ionic relaxivity (r1,Mn) behavior, the QD particle relaxivity (r1,QD) values increased with rising dopant levels.[262] The QD particle relaxivity r1,QD values of 4.3 nm diameter CdTe@ZnS:Mn QDs increased from 574.92 to 727.10 mM−1s−1 upon increasing the Mn dopant concentration.[262] Paramagnetic ions embedded into the ZnS shell of QD are major contributors to the relaxivity enhancement due to highly efficient dipolar interactions between the electron spins of paramagnetic ions and nearby water protons. Consequently, increased Mn-doping levels can lead to increased QD particle relaxivity, until a surface density is reached where Mn–Mn coupling occurs. It is quite clear that surface shell lattice doped Mn2+ ions with slow tumbling rates and favoured spin-proton dipolar interactions with surrounding water molecules promote high performance MR contrast enhancement, but there are still gaps in the detailed mechanistic understanding of how factors such as particle surface coating structure, QD size and shell thickness contribute to the overall doping level-/location-dependent

relaxometric properties. In addition, by making use of the sensitive ESR technique, in particular by coupling the hyperfine splitting data with relaxometric measurements, a more complete picture of the relationship between spatial locations of paramagnetic centres and relaxometric properties may be derived for the doped QDs community. While this section has placed the emphasis on Mn2+ doping, rare-earth elements bearing the unique magnetic and optical properties associated with f-electron energy levels (e.g., Gd3+, Dy3+, Ho2+, Yb3+, Eu3+, etc) may also similarly provide relevant optical and magnetic properties for dual- or multimodal probes and have been considered in a number of original papers and reviews.[40,274–277]

4. Application of Fluorescent/Magnetic Probes for In Vivo Imaging of Tumors As reviewed thus far, significant progress over the past ten years has been achieved in constructing QD-based multimodal nanomaterials. Major motivations behind these numerous activities are for in vitro and in vivo biomedical applications, including hyperthermia therapies, magnetic separation, and targeted and non-targeted biomedical imaging. In respect to potential in vivo applications, a pioneering study by Santra et al.[212] addressed trans-activator of transcription (TAT) mediated transport of doped QDs across the blood-brain barrier. CdS:Mn@ZnS nanoparticles of 3.1 nm diameter were covalently conjugated with cell-penetrating TAT peptide, and the conjugates were used for ex vivo fluorescence imaging of brain tissues. While MRI was not actively utilized in that study, it demonstrated the potential for the delivery of diagnostic and therapeutic agents for brain diseases. As another example, phospholipid-co-encapsulated γ-Fe2O3 and CdSe@ZnS nanoparticles with final sizes ranging from hundreds of nanometers to several micrometers,[278] were investigated as agents for in vivo and ex vivo imaging with regard to their biodistribution in the liver, spleen, lung, and heart. The images were particularly striking due to the near absence of any background auto-fluorescence.[278] Importantly, these multimodal probes successfully retained their optical and magnetic properties within a complex biological environment. Current research anticipates that magnetically engineered QDs will be applied to cancer diagnosis by MR imaging and intra-operative surgical guidance by optically demarcating tumor tissue from healthy tissue, and for the visualization of tumor metastases. Furthermore, the nanoparticles can be functionalized for specific targeted delivery. The following section specifically considers their delivery to tumors in conjunction with the concerns over toxicity inherent to clinical implementation.

4.1. Passive Delivery to Tumor with Enhanced Permeation and Retention Owing to the poorly structured and leaky blood vessels characteristic of tumors, nanoparticles can be passively extravasated via the enhanced permeability and retention (EPR) effect.[279–282] The EPR effect can result in more than 25 times



11

www.advmat.de

REVIEW


greater accumulation in tumors compared to healthy muscle tissue.[283] Poly(lactide)-tocopheryl polyethylene glycol succinate (PLATPGS) copolymer co-encapsulated with Fe3O4 and commercial QDs with a resulting overall hydrodynamic size of 325 nm were employed for tumor imaging.[167] For in vivo MRI studies, these nanocomposites allowed the detection and non-invasive MR imaging of mouse subcutaneous MCF-7 tumor Xenografts in vivo. The findings were further confirmed by ex vivo fluorescence imaging of the organs. The copolymer encapsulation of the particles reduced the toxicity, improved biocompatibility, and obscured detection by the human immune system, thus increasing their half-life in circulation. Sustained circulation promoted greater tumor accumulation and improved imaging. However, in this study, accumulation in the skin also significantly increased the background for in vivo fluorescence imaging and limited accurate presentation of the organs. Following our previous studies on imaging tumors in vivo with Fe3O4[109,112,114,116] and NaGdF4,[284] or magnetic/up-conversion fluorescent NaGdF4:Yb,Er nanoparticles,[285] we developed a biocompatible molecular probe based on 3.6 nm PEGylated CuInS2@ZnS:Mn QDs with an extremely low cytotoxicity.[66] The IC50 (50% inhibitory concentration) value was about 167.9 ± 9.9 µmol/L, in large contrast to 0.023 ± 0.002 µmol/L for thioglycolic acid stabilized CdTe QDs. Fluorescence images acquired for the pre- and post-injection of these particles at different time points to achieve in vivo imaging of subcutaneous LS180 tumor xenografts[66] are presented in Figure 7. The lower frame of Figure 7 shows that a significant fluorescence signal appears 10 min post-injection from the tumor region and increases to a maximum at around 6 h. Considering that the intraperitoneal tumor model can better reflect the nature of cancers as it can be taken as a metastatic model, we further studied PEGylated CuInS2@ZnS:Mn QD uptake in intraperitoneally inoculated tumors in mice which can mimic the metastasis of colorectal cancers. Figure 8 shows T1-weighted MR images acquired before and after intravenous nanoparticle delivery. The T1 value in the tumor region decreased and reached a minimum at 8 h post-injection. A strong correlation with the kidney indicates renal clearance, typical for small particle sizes.[214] To further show the biodistribution of the injected particles, the main organs such as lung, heart, liver, spleen, part of the stomach, kidney, tumor, and part of the intestine were excised for fluorescence imaging 24 h post-injection (lower right panel of Figure 8). Liver tissue presented the strongest signal, followed by stomach, kidney, tumor, and spleen, but no optical signal was observed from the heart and lung. The reticuloendothelial system, including the liver and spleen, accumulates nanoparticles during clearance. The strong signals from the kidney further suggest that some of the injected particles are excreted through the renal clearance pathway. Although the tumor T1 contrast had become very weak 24 h post-injection, the fluorescence imaging showed that there remained a detectable optical signal from the harvested tumor. With respect to the fluorescence signal from the stomach, careful observation revealed that it was due to the contents of the stomach rather than accumulation of nanoparticles within the organ tissue itself. In addition, the above dualmodal probes are still progressing towards to their application

12


in orthotopic tumor model, which represents a more advanced and realistic scenario and is deep seated and possess metastatic potential, better than subcutaneous or intraperitoneal tumor xenograft models. While the EPR effect can lead to significant delivery of nanoparticles, it varies from tumor to tumor, and also strongly depends on the particle size, shape, and surface coating.[279] In addition, the EPR effect is not commonly observed in some types of cancers such as gastric and pancreatic cancers.[286] With this in mind, targeted delivery can offer greater specificity compared to passive delivery relying on the EPR of tumors.

4.2. Active Targeting of Tumors Active targeting to enhance specific and efficient delivery of probes can be achieved by covalently conjugating QDs with tumor-specific targeting moieties. Functional groups include small molecules (e.g., folic acid and hyaluronic acid), peptides (e.g., cyclic arginine-glycine-aspartic acid (RGD), cyclic asparagine-glycine-arginine (NGR), HIV-1 TAT, proteins (e.g., antibodies, antibody fragments, transferrin, etc.), and aptamers.[287] A major motivation for active targeting is to detect tumor and metastases as small as possible for early detection. Absolute uptake of nanoparticles by small tumors is obviously low due to their physical size, but also because of minimal and immature vasculature.[288] In this context, active targeting is highly relevant for imaging and early detection. Shi and co-workers investigated ex vivo tumors using assemblies of CdSeTe@ZnS and Fe3O4 nanoparticles (ca. 150 nm overall size).[180] The nanocarrier was capped with biodegradable poly(lactic-co-glycolic acid) (PLGA) and anti-prostate specific membrane antigen (anti-PSMA) for tumor targeting. The PLGA enabled loading of a chemotherapeutic drug, paclitaxel. Both in vitro and in vivo targeting investigations demonstrated that the constructed PSMA-specific probes can effectively target LNCaP prostate cancer cells and tumors expressing PSMA. This study confirmed preferential association with tumor tissue by ex vivo fluorescence imaging, but unfortunately it was not extended to MRI. Ostendorp et al. conducted in vivo MR imaging with QDbased particles targeting CD13, a protein overexpressed by angiogenic blood vessels.[190] Biotinylated Gd-DTPA dendrimeric wedge and CD13-specific cNGR peptide were simultaneously assembled onto the surface of streptavidin coated CdSe@ZnS QDs by the streptavidin-biotin interaction. The resulting cNGRlabelled paramagnetic particles (overall size of ca. 29 nm) were applied as a targeting probe, and successful molecular imaging was achieved of tumor angiogenesis and infarcted hearts with in vivo MRI. These findings were further validated using ex vivo two-photon laser scanning microscopy, which showed that the cNGR-labelled QDs accurately co-localized with vascular endothelial cells in the tumor rim. Mulder and co-workers designed paramagnetic CdSebased probes conjugated with ανβ3-specific RGD peptide for angiogenic targeting.[2,185,186,188] Gd-DTPA chelating lipid and PEGylated lipid were simultaneously assembled onto the hydrophobic QDs, in order to achieve MRI contrast and biocompatibility, respectively. Effective targeting of tumor angiogenesis




REVIEW

4.3. Toxicity Concerns

Figure 7. In vivo fluorescence imaging of a tumor using PEGylated CuInS2@ZnS:Mn QDs. Upper frame: in vivo fluorescence imaging of a nude mouse bearing a subcutaneous tumor, as indicated by the red dashed line circle, recorded pre- and post-injection of the PEGylated CuInS2@ZnS:Mn QDs. Lower frame: temporal evolution of the integrated fluorescence signals recorded from the tumor region. Reproduced with permission.[66] Copyright 2014, Elsevier.

over-expressing integrin ανβ3 was demonstrated for in vivo fluorescence/MR imaging.[188] Furthermore, replacement of the PEGylated lipid and RGD peptide with macrophage-specific high-density lipoprotein (HDL) apolipoprotein A-I (apoAI), resulted in the construction of a QD core/HDL-mimicking multimodality probe.[184] This was demonstrated to enable fluorescence/MR imaging of atherosclerosis in vivo. More recently, Cd-free InP@ZnS QDs capped with PEGylated phospholipid micelles and Gd-DOTA ligands, were conjugated with anti-caludin-4 antibody or transferrin via amidation coupling chemistry, designed for recognition of a pancreatic cancer cell line. In vivo and ex vivo fluorescence imaging further demonstrated that anti-caludin-4 antibody conjugated paramagnetic probes can target and label the Panl-1 tumor in vivo with high contrast.[189]


One of the major concerns with magnetically engineered QDs is their potential toxicity. The toxicity of nanomaterials depends on multiple factors[289] including chemical composition, size, shape, surface physicochemical properties, concentration, and chemical as well as colloidal stabilities. There is still a distinct lack of systematic investigations on toxicology and pharmacokinetics. A full understanding of degradation, excretion, persistence and immune response is needed. Here, we introduce some of these studies with regard to individual QD and magnetic components. Both acute[290–292] and chronic toxicities[264,293] of QDs have been reported. Primary mechanisms of QD toxicity typically include leaching of toxic heavy metal ions [264,291] and the generation of reactive oxygen species and radicals during irradiation by light.[292,294–296] A number of studies showed that surface modification can reduce QD toxicity by constructing core@ shell or core@shell@shell structures, encapsulation with low toxicity or nontoxic inorganic or organic polymers, or by altering surface chemistry (i.e., capping ligands, surface charge, etc).[214,297] Choi et al. found that the excretion of CdSe@ZnS QDs from mice was mainly governed by their hydrodynamic size.[214] CdSe@ZnS QDs with hydrodynamic size below 5.5 nm resulted in rapid and efficient renal clearance and the elimination of QDs from the body. QDs with hydrodynamic size greater than 15 nm prevented renal excretion. Ye et al. reported a pilot study in which rhesus macaques were intravenously injected with phospholipid micelle capped CdSe@CdS@ZnS QDs (ca. 25 mg/kg).[297] No toxicity was evident; blood and biochemical markers remained within normal ranges after treatment, and the histology of major organs after 90 days presented no abnormalities, indicating no detectable acute toxicity. However, chemical analysis revealed the persistence of elevated cadmium and selenium levels in organs (liver, spleen, and kidney) after 90 days. This slow clearance of QDs suggests that longer-term studies are required to determine the long-term biodistribution and morbidities arising due to their presence. To date, it is still debatable whether the long-term accumulation of Cd-based QDs will cause toxicity to the body. Further studies are needed to verify this issue in combination with investigations on the complex biodistribution and clearance of QDs. In addition, development of alternative QDs such as InP, CuIn(S,Se)2, and Ag2S nanocrystals will expand in vivo biomedical opportunities. As for magnetic entities, according to standard toxicological and pharmacological tests of several iron oxide nanoparticle based contrast agents, these hold a bright future in the clinic due to their satisfactory biosafety profiles. This, at least partially, is expected to result from iron being highly regulated within the body, primarily being stored in the ferritin protein.[98] With respect to the paramagnetic ions such as Gd3+ and Mn2+, free Gd3+ ions pose the risk of inducing nephrogenic system fibrosis in patients with impaired kidney function.[127,298] In addition, the release of Gd3+ ions and Mn2+ ions may cause toxicity by following Ca2+ pathways, altering physiological processes.[102,299,300] For example, the Mn2+ ion is an analog of Ca2+ which can lead to intracellular transport and accumulation



13

www.advmat.de

REVIEW


5. Conclusions and Outlook

Figure 8. In vivo MR and ex vivo fluorescence imaging of a tumor using PEGylated CuInS2@ZnS:Mn QDs. Upper panel: T1-weighted MR images acquired pre- and post intravenous injection of the PEGylated CuInS2@ ZnS:Mn QDs into the mouse bearing intraperitoneally transplanted tumors. The tumor and kidney are color-coded to better show the contrast enhancing effects. Left frame of the lower panel: temporal T1 values of tumor and kidney sites. Right frame of the lower panel: ex vivo fluorescence images of main organs harvested 24 h post injection: 1, lung; 2, heart; 3, liver; 4, spleen; 5, part of stomach; 6, kidney (left); 7, kidney (right); 8, tumor; 9, part of intestine. Reproduced with permission.[66] Copyright 2014, Elsevier.

leading to hepatic failure, cardiac toxicity and even induce neurotoxicity.[102,301] Nevertheless, it has been demonstrated that association with a chelating ligand, or specific nanoparticle architectures can act to decrease toxicity.[66] In addition, elimination pathways of the nanoparticles can be balanced by particle size and surface chemistry. Consideration of such design parameters may enable paramagnetic ions to be applied to in vivo applications. The toxicity of QD-based multimodal nanoparticles is determined by intricate mechanisms and is unique to each specific kind of QD. Additionally, toxicity has variable presentation depending on tissue type and variable meaning depending on the specific biological consequence. Further assessment of all platforms currently under consideration is required. Accurate and predictive screening for acute, chronic and long term effects is a field of research particularly challenging to all aspects of nanotechnology. Developments in this area will be critical in the transfer of these technologies from the lab to clinical in vivo application.

14


The motivation for research into multimodal imaging probes is primarily to provide a highly efficient platform to assist in fundamental biomedical research, imaging and clinical applications. An ideal scenario for in vivo imaging would see their clinical application for highly specific contrast enhancement in diagnostic applications of MRI for a myriad of diseases and morbidities. The fluorescent properties would subsequently guide and align surgery with high accuracy. The economic feasibility of such an approach for population screening would not currently be realistic, however, more selectively applied diagnostics, prognostics and therapeutic decision making have much to gain. As an example, metastatic lesions (generally associated with the poorest prognosis in cancer) would be labelled for highly effective identification in MR imaging. This information would provide decision making on therapeutic or palliative courses of action. Confidence in surgical options for excision would be facilitated by visual identification of cancerous tissue, clearly delineated from healthy tissue. With such purposes in mind, design and control over nanoparticle parameters are fundamental to applications. The past decade has seen rapid advances in the successful coupling of the optical properties of QDs with the magnetic properties of MRI contrast agents, offering steady improvements in synthesis techniques to optimize magnetic properties while maintaining the PL QYs of the QDs. Importantly, improvements for biocompatibility, versatile functionalization and substantial reduction in toxic effects are also being achieved. With respect to synthesis, a number of general approaches have been developed and are progressing towards the reproducible and ‘robust’ integration of building blocks with required compositions, sizes, shapes, and surface functionalization. The particle sizes are expected and required to be as small as possible which typically compromises optical properties due to the intimate proximity between magnetic and optical moieties. The related quenching effects of the QD component must be addressed and will likely dictate the lowest practical size limits. The exact mechanisms of the relaxometric enhancement by paramagnetic ions on the QD surfaces are not yet definitively proven, however they appear to facilitate the spin-proton dipolar interaction which is strongly inversely correlated to the metal ion-proton distance (i.e., the proximity of the magnetic metal ions with surrounding water molecules). Considering this, core@shell QD nanostructures with paramagnetic ions doped into the shells represent an important approach owing to their potential in preservation of the two signal entities independently under complex physiological environments. Their structural design (e.g., enlarging the spatial distance between fluorescence center and magnetic ion(s)) together with in-depth investigations on the PL quenching effect are still required to further reduce undesirable interference of the magnetic entities with QDs. Optimization of the optical properties of QDs will see improvements in tunable emission to cover the visible to NIR widow with high PL QYs. At present, many multimodal probes are still limited to UV-blue incident excitation which can cause tissue damage, while the visible light has rather shallow tissue penetration depth. Therefore, the emission window of magnetic QDs needs to be extended to the first (NIR-I, 650–950 nm) and




Acknowledgements The authors acknowledge financial support from the National Basic Research Program of China (2011CB935800), the National Nature Science Foundation of China (21203210, 81090271, 21203211), the project on the Integration of Industry, Education and Research of Guangdong Province (2012B091100476), and the related CityU project 9680062, ICCAS (CMS-PY-201321, CMS-PY-201309), and a CAS visiting fellowship (2013Y2JA0003). Received: May 22, 2014 Revised: June 25, 2014 Published online:

[1] J. Cheon, J.-H. Lee, Acc. Chem. Res. 2008, 41, 1630. [2] W. J. M. Mulder, G. J. Strijkers, G. A. F. Van Tilborg, D. P. Cormode, Z. A. Fayad, K. Nicolay, Acc. Chem. Res. 2009, 42, 904. [3] A. Y. Louie, Chem. Rev. 2010, 110, 3146. [4] J. Kim, Y. Piao, T. Hyeon, Chem. Soc. Rev. 2009, 38, 372.


REVIEW

second near-infrared windows (NIR-II, 1000–1400 nm).[58,302,303] Such materials will provide low absorption and scattering in living tissues, low auto-fluorescence, low signal loss and thus greater signal/background ratio. Furthermore, reducing the emission full width at half maximum (FWHM) in these spectral windows will offer further improvements. Cd-free I–III–VI CuIn(S,Se)2 QDs, for example, are promising for both visible and NIR-I-emission, but emit with a FWHM of ca. 100–150 nm, compared with ca. 20–50 nm for II–VI Cd(Se,Te) QDs. Such broad emission profiles currently limit their applications where multiple targets are to be labelled simultaneously. Further improvements should focus on narrowing the FWHM and enhancing their PL QYs in the NIR. Relaxometric properties of magnetic materials are generally well understood for the separate entities, but still lack in-depth studies for the cases when they become incorporated with QDs. Taking paramagnetic ion doped QDs as an example, there is a continuing need to carefully disclose the relationship between relaxometric behavior and the dopant's location, distribution and doping levels. Furthermore, considering that T1 and T2 contrast agents have different imaging abilities for different organs, QD particles integrated with dual T1 and T2 functionalities may provide further opportunities. Reliable surface modification strategies will undergo continuous advancements for both imaging and theranostics with the smallest probe sizes achievable. Suitable surface coatings will promote longer blood circulation time, improve active targeting, conjugation and in general improve the probes’ specificity and selectivity. In the context of “smart” QD-based multimodal probes, other functionalities will also be increasingly introduced, such as sensitive responses to pH, hypoxia, protease, and metal ions, relevant to the tumor microenvironment. Last but not least, employment of low toxicity QDs will cast them in favorable light for clinical in vivo applications. This is arguably the most important, yet challenging, attribute necessary to achieve. There remain many challenging requirements and yet also many opportunities for further rationally balancing the optical and magnetic properties for high performance multimodal imaging probes.

[5] H. Kobayashi, M. R. Longmire, M. Ogawa, P. L. Choyke, Chem. Soc. Rev. 2011, 40, 4626. [6] D. E. Lee, H. Koo, I. C. Sun, J. H. Ryu, K. Kim, I. C. Kwon, Chem. Soc. Rev. 2012, 41, 2656. [7] R. Koole, W. J. M. Mulder, M. M. van Schooneveld, G. J. Strijkers, A. Meijerink, K. Nicolay, Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2009, 1, 475. [8] W. C. W. Chan, S. M. Nie, Science 1998, 281, 2016. [9] A. P. Alivisatos, Science 1996, 271, 933. [10] M. Bruchez, M. Moronne, P. Gin, S. Weiss, A. P. Alivisatos, Science 1998, 281, 2013. [11] B. N. G. Giepmans, S. R. Adams, M. H. Ellisman, R. Y. Tsien, Science 2006, 312, 217. [12] E. Cassette, M. Helle, L. Bezdetnaya, F. Marchal, B. Dubertret, T. Pons, Adv. Drug Delivery Rev. 2013, 65, 719. [13] I. L. Medintz, H. T. Uyeda, E. R. Goldman, H. Mattoussi, Nat. Mater. 2005, 4, 435. [14] A. L. Rogach, T. Franzl, T. A. Klar, J. Feldmann, N. Gaponik, V. Lesnyak, A. Shavel, A. Eychmüller, Y. P. Rakovich, J. F. Donegan, J. Phys. Chem. C 2007, 111, 14628. [15] X. Michalet, F. F. Pinaud, L. A. Bentolila, J. M. Tsay, S. Doose, J. J. Li, G. Sundaresan, A. M. Wu, S. S. Gambhir, S. Weiss, Science 2005, 307, 538. [16] E. H. Sargent, Adv. Mater. 2005, 17, 515. [17] P. Zrazhevskiy, M. Sena, X. H. Gao, Chem. Soc. Rev. 2010, 39, 4326. [18] A. L. Rogach, A. Eychmüller, S. G. Hickey, S. V. Kershaw, Small 2007, 3, 536. [19] Y. L. Li, L. H. Jing, R. R. Qiao, M. Y. Gao, Chem. Commun. 2011, 47, 9293. [20] T. Erdem, H. V. Demir, Nat. Photonics 2011, 5, 126. [21] V. Lesnyak, N. Gaponik, A. Eychmüller, Chem. Soc. Rev. 2013, 42, 2905. [22] S. V. Kershaw, A. S. Susha, A. L. Rogach, Chem. Soc. Rev. 2013, 42, 3033. [23] C. E. Probst, P. Zrazhevskiy, V. Bagalkot, X. H. Gao, Adv. Drug Delivery Rev. 2013, 65, 703. [24] B. Hotzer, I. L. Medintz, N. Hildebrandt, Small 2012, 8, 2297. [25] C. Q. Ding, A. W. Zhu, Y. Tian, Acc. Chem. Res. 2013, 47, 20. [26] S. J. Zhu, Q. N. Meng, L. Wang, J. H. Zhang, Y. B. Song, H. Jin, K. Zhang, H. C. Sun, H. Y. Wang, B. Yang, Angew. Chem. 2013, 125, 4045; Angew. Chem. Int. Ed. 2013, 52, 3953. [27] X. Y. Zhang, Y. Zhang, Y. Wang, S. Kalytchuk, S. V. Kershaw, Y. H. Wang, P. Wang, T. Q. Zhang, Y. Zhao, H. Z. Zhang, T. Cui, Y. D. Wang, J. Zhao, W. W. Yu, A. L. Rogach, ACS Nano 2013, 7, 11234. [28] Y. Wang, S. Kalytchuk, Y. Zhang, H. Shi, S. V. Kershaw, A. L. Rogach, J. Phys. Chem. Lett. 2014, 5, 1412. [29] X. Yan, B. S. Li, L. S. Li, Acc. Chem. Res. 2013, 46, 2254. [30] J. H. Shen, Y. H. Zhu, X. L. Yang, C. Z. Li, Chem. Commun. 2012, 48, 3686. [31] F. Erogbogbo, K. T. Yong, I. Roy, G. X. Xu, P. N. Prasad, M. T. Swihart, ACS Nano 2008, 2, 873. [32] Y. He, Y. L. Zhong, F. Peng, X. P. Wei, Y. Y. Su, Y. M. Lu, S. Su, W. Gu, L. S. Liao, S. T. Lee, J. Am. Chem. Soc. 2011, 133, 14192. [33] M. L. Mastronardi, E. J. Henderson, D. P. Puzzo, G. A. Ozin, Adv. Mater. 2012, 24, 5890. [34] S. Chinnathambi, S. Chen, S. Ganesan, N. Hanagata, Adv. Healthcare Mater. 2014, 3, 10. [35] S. Choi, R. M. Dickson, J. H. Yu, Chem. Soc. Rev. 2012, 41, 1867. [36] Y. Z. Lu, W. Chen, Chem. Soc. Rev. 2012, 41, 3594. [37] H. F. Qian, M. Z. Zhu, Z. K. Wu, R. C. Jin, Acc. Chem. Res. 2012, 45, 1470.



15

www.advmat.de

REVIEW

www.MaterialsViews.com [38] L. Shang, S. J. Dong, G. U. Nienhaus, Nano Today 2011, 6, 401. [39] J. Zheng, P. R. Nicovich, R. M. Dickson, Annu. Rev. Phys. Chem. 2007, 58, 409. [40] F. Wang, X. G. Liu, Chem. Soc. Rev. 2009, 38, 976. [41] G. Y. Chen, H. L. Qiu, P. N. Prasad, X. Y. Chen, Chem. Rev. 2014, 114, 5161. [42] F. Wang, X. Liu, Acc. Chem. Res. 2014, 47, 1378. [43] R. Weissleder, M. J. Pittet, Nature 2008, 452, 580. [44] T. Pellegrino, S. Kudera, T. Liedl, A. M. Javier, L. Manna, W. J. Parak, Small 2005, 1, 48. [45] A. P. Alivisatos, Nat. Biotechnol. 2004, 22, 47. [46] U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot, R. Nitschke, T. Nann, Nat. Methods 2008, 5, 763. [47] M. A. Hines, P. Guyot-Sionnest, J. Phys. Chem. B 1998, 102, 3655. [48] C. B. Murray, D. J. Norris, M. G. Bawendi, J. Am. Chem. Soc. 1993, 115, 8706. [49] X. G. Peng, Acc. Chem. Res. 2010, 43, 1387. [50] N. Gaponik, D. V. Talapin, A. L. Rogach, K. Hoppe, E. V. Shevchenko, A. Kornowski, A. Eychmüller, H. Weller, J. Phys. Chem. B 2002, 106, 7177. [51] N. Gaponik, S. G. Hickey, D. Dorfs, A. L. Rogach, A. Eychmüller, Small 2010, 6, 1364. [52] S. D. Miao, S. G. Hickey, B. Rellinghaus, C. Waurisch, A. Eychmüller, J. Am. Chem. Soc. 2010, 132, 5613. [53] D. K. Harris, P. M. Allen, H. S. Han, B. J. Walker, J. M. Lee, M. G. Bawendi, J. Am. Chem. Soc. 2011, 133, 4676. [54] R. Xie, D. Battaglia, X. Peng, J. Am. Chem. Soc. 2007, 129, 15432. [55] A. Aharoni, T. Mokari, I. Popov, U. Banin, J. Am. Chem. Soc. 2006, 128, 257. [56] I. Moreels, Y. Justo, B. De Geyter, K. Haustraete, J. C. Martins, Z. Hens, ACS Nano 2011, 5, 2004. [57] Q. Q. Dai, Y. N. Wang, X. B. Li, Y. Zhang, D. J. Pellegrino, M. X. Zhao, B. Zou, J. Seo, Y. D. Wang, W. W. Yu, ACS Nano 2009, 3, 1518. [58] S. L. Shen, Q. B. Wang, Chem. Mater. 2013, 25, 1166. [59] Y.-P. Gu, R. Cui, Z.-L. Zhang, Z.-X. Xie, D.-W. Pang, J. Am. Chem. Soc. 2011, 134, 79. [60] W. Han, L. X. Yi, N. Zhao, A. W. Tang, M. Y. Gao, Z. Y. Tang, J. Am. Chem. Soc. 2008, 130, 13152. [61] L. Li, T. J. Daou, I. Texier, T. T. Kim Chi, N. Q. Liem, P. Reiss, Chem. Mater. 2009, 21, 2422. [62] R. G. Xie, M. Rutherford, X. G. Peng, J. Am. Chem. Soc. 2009, 131, 5691. [63] T. Pons, E. Pic, N. Lequeux, E. Cassette, L. Bezdetnaya, F. Guillemin, F. Marchal, B. Dubertret, ACS Nano 2010, 4, 2531. [64] L. Li, A. Pandey, D. J. Werder, B. P. Khanal, J. M. Pietryga, V. I. Klimov, J. Am. Chem. Soc. 2011, 133, 1176. [65] H. Z. Zhong, Z. L. Bai, B. S. Zou, J. Phys. Chem. Lett. 2012, 3, 3167. [66] K. Ding, L. H. Jing, C. Y. Liu, Y. Hou, M. Y. Gao, Biomaterials 2014, 35, 1608. [67] P. M. Allen, M. G. Bawendi, J. Am. Chem. Soc. 2008, 130, 9240. [68] E. Cassette, T. Pons, C. Bouet, M. Helle, L. Bezdetnaya, F. Marchal, B. Dubertret, Chem. Mater. 2010, 22, 6117. [69] K. Nose, T. Omata, S. Otsuka-Yao-Matsuo, J. Phys. Chem. C 2009, 113, 3455. [70] H. Z. Zhong, Y. Zhou, M. F. Ye, Y. J. He, J. P. Ye, C. He, C. H. Yang, Y. F. Li, Chem. Mater. 2008, 20, 6434. [71] F. Peng, Y. Su, Y. Zhong, C. Fan, S.-T. Lee, Y. He, Acc. Chem. Res. 2014, 47, 612. [72] D. D. Vaughn, R. E. Schaak, Chem. Soc. Rev. 2013, 42, 2861. [73] B. O. Dabbousi, V. Rodriguez, J. R. Heine, H. Mattoussi, R. Ober, K. F. Jensen, M. G. Bawendi, J. Phys. Chem. B 1997, 101, 9463. [74] P. Reiss, M. Protière, L. Li, Small 2009, 5, 154. [75] M. A. Hines, P. Guyot-Sionnest, J. Phys. Chem. 1996, 100, 468.

16


[76] X. G. Peng, M. C. Schlamp, A. V. Kadavanich, A. P. Alivisatos, J. Am. Chem. Soc. 1997, 119, 7019. [77] O. Chen, J. Zhao, V. P. Chauhan, J. Cui, C. Wong, D. K. Harris, H. Wei, H. S. Han, D. Fukumura, R. K. Jain, M. G. Bawendi, Nat. Mater. 2013, 12, 445. [78] M. Y. Gao, S. Kirstein, H. Möhwald, A. L. Rogach, A. Kornowski, A. Eychmüller, H. Weller, J. Phys. Chem. B 1998, 102, 8360. [79] U. Resch, H. Weller, A. Henglein, Langmuir 1989, 5, 1015. [80] A. L. Rogach, L. Katsikas, A. Kornowski, D. Su, A. Eychmüller, H. Weller, Ber. Bunsen-Ges. Phys. Chem. 1997, 101, 1668. [81] A. L. Rogach, L. Katsikas, A. Kornowski, D. S. Su, A. Eychmüller, H. Weller, Ber. Bunsen-Ges. Phys. Chem. 1996, 100, 1772. [82] H. Zhang, Z. Zhou, B. Yang, M. Y. Gao, J. Phys. Chem. B 2003, 107, 8. [83] H. B. Bao, Y. J. Gong, Z. Li, M. Y. Gao, Chem. Mater. 2004, 16, 3853. [84] L. H. Jing, C. H. Yang, R. R. Qiao, M. Niu, M. H. Du, D. Y. Wang, M. Y. Gao, Chem. Mater. 2010, 22, 420. [85] A. Shavel, N. Gaponik, A. Eychmüller, J. Phys. Chem. B 2006, 110, 19280. [86] D. Deng, Y. Chen, J. Cao, J. Tian, Z. Qian, S. Achilefu, Y. Gu, Chem. Mater. 2012, 24, 3029. [87] Y. H. Yang, M. Y. Gao, Adv. Mater. 2005, 17, 2354. [88] Y. H. Yang, L. H. Jing, X. L. Yu, D. D. Yan, M. Y. Gao, Chem. Mater. 2007, 19, 4123. [89] L. H. Jing, Y. L. Li, K. Ding, R. R. Qiao, A. L. Rogach, M. Y. Gao, Nanotechnology 2011, 22, 505104. [90] A. Guerrero-Martinez, J. Perez-Juste, L. M. Liz-Marzán, Adv. Mater. 2010, 22, 1182. [91] H. Zhang, Z. C. Cui, Y. Wang, K. Zhang, X. L. Ji, C. L. Lu, B. Yang, M. Y. Gao, Adv. Mater. 2003, 15, 777. [92] Y. H. Yang, Z. K. Wen, Y. P. Dong, M. Y. Gao, Small 2006, 2, 898. [93] M. Kuang, D. Y. Wang, H. B. Bao, M. Y. Gao, H. Möhwald, M. Jiang, Adv. Mater. 2005, 17, 267. [94] Y. J. Gong, M. Y. Gao, D. Y. Wang, H. Möhwald, Chem. Mater. 2005, 17, 2648. [95] Y. H. Yang, C. F. Tu, M. Y. Gao, J. Mater. Chem. 2007, 17, 2930. [96] R. Weissleder, M. Nahrendorf, M. J. Pittet, Nat. Mater. 2014, 13, 125. [97] J. H. Lee, Y. M. Huh, Y. Jun, J. Seo, J. Jang, H. T. Song, S. Kim, E. J. Cho, H. G. Yoon, J. S. Suh, J. Cheon, Nat. Med. 2007, 13, 95. [98] R. R. Qiao, C. H. Yang, M. Y. Gao, J. Mater. Chem. 2009, 19, 6274. [99] R. B. Lauffer, Chem. Rev. 1987, 87, 901. [100] P. Caravan, J. J. Ellison, T. J. McMurry, R. B. Lauffer, Chem. Rev. 1999, 99, 2293. [101] P. Caravan, Acc. Chem. Res. 2009, 42, 851. [102] M. Kueny-Stotz, A. Garofalo, D. Felder-Flesch, Eur. J. Inorg. Chem. 2012, 1987. [103] H. B. Na, J. H. Lee, K. J. An, Y. I. Park, M. Park, I. S. Lee, D. H. Nam, S. T. Kim, S. H. Kim, S. W. Kim, K. H. Lim, K. S. Kim, S. O. Kim, T. Hyeon, Angew. Chem. 2007, 119, 5493; Angew. Chem. Int. Ed. 2007, 46, 5397. [104] H. W. Zhang, L. H. Jing, J. F. Zeng, Y. Hou, Z. Li, M. Y. Gao, Nanoscale 2014, 6, 5918. [105] J. L. Bridot, A. C. Faure, S. Laurent, C. Riviere, C. Billotey, B. Hiba, M. Janier, V. Josserand, J. L. Coll, L. Vander Elst, R. Muller, S. Roux, P. Perriat, O. Tillement, J. Am. Chem. Soc. 2007, 129, 5076. [106] M. A. Fortin, R. M. Petoral, F. Soderlind, A. Klasson, M. Engstrom, T. Veres, P. O. Kall, K. Uvdal, Nanotechnology 2007, 18, 395501. [107] N. J. J. Johnson, W. Oakden, G. J. Stanisz, R. S. Prosser, F. C. J. M. van Veggel, Chem. Mater. 2011, 23, 3714. [108] C. Y. Liu, Y. Hou, M. Y. Gao, Adv. Mater. 2014, DOI: 10.1002/ adma.201305535. [109] Z. Li, L. Wei, M. Y. Gao, H. Lei, Adv. Mater. 2005, 17, 1001.





REVIEW

[110] Z. Li, Q. Sun, M. Y. Gao, Angew. Chem. 2004, 117, 125; Angew. Chem. Int. Ed. 2005, 44, 123. [111] F. Q. Hu, Y. S. Zhao, Nanoscale 2012, 4, 6235. [112] F. Q. Hu, L. Wei, Z. Zhou, Y. L. Ran, Z. Li, M. Y. Gao, Adv. Mater. 2006, 18, 2553. [113] Q. J. Jia, J. F. Zeng, R. R. Qjao, L. H. Jing, L. Peng, F. L. Gu, M. Y. Gao, J. Am. Chem. Soc. 2011, 133, 19512. [114] J. F. Zeng, L. H. Jing, Y. Hou, M. X. Jiao, R. R. Qiao, Q. J. Jia, C. Y. Liu, F. Fang, H. Lei, M. Y. Gao, Adv. Mater. 2014, 26, 2694. [115] Z. Li, H. Chen, H. B. Bao, M. Y. Gao, Chem. Mater. 2004, 16, 1391. [116] S. J. Liu, B. Jia, R. R. Qiao, Z. Yang, Z. L. Yu, Z. F. Liu, K. Liu, J. Y. Shi, O. Y. Han, F. Wang, M. Y. Gao, Mol. Pharmaceut. 2009, 6, 1074. [117] S. H. Sun, H. Zeng, J. Am. Chem. Soc. 2002, 124, 8204. [118] J. Park, K. J. An, Y. S. Hwang, J. G. Park, H. J. Noh, J. Y. Kim, J. H. Park, N. M. Hwang, T. Hyeon, Nat. Mater. 2004, 3, 891. [119] S. H. Sun, H. Zeng, D. B. Robinson, S. Raoux, P. M. Rice, S. X. Wang, G. X. Li, J. Am. Chem. Soc. 2004, 126, 273. [120] N. R. Jana, Y. F. Chen, X. G. Peng, Chem. Mater. 2004, 16, 3931. [121] J. Park, E. Lee, N. M. Hwang, M. S. Kang, S. C. Kim, Y. Hwang, J. G. Park, H. J. Noh, J. Y. Kini, J. H. Park, T. Hyeon, Angew. Chem. 2005, 117, 2932; Angew. Chem. Int. Ed. 2005, 44, 2872. [122] B. H. Kim, K. Shin, S. G. Kwon, Y. Jang, H. S. Lee, H. Lee, S. W. Jun, J. Lee, S. Y. Han, Y. H. Yim, D. H. Kim, T. Hyeon, J. Am. Chem. Soc. 2013, 135, 2407. [123] M. H. Oh, T. Yu, S. H. Yu, B. Lim, K. T. Ko, M. G. Willinger, D. H. Seo, B. H. Kim, M. G. Cho, J. H. Park, K. Kang, Y. E. Sung, N. Pinna, T. Hyeon, Science 2013, 340, 964. [124] H. W. Duan, M. Kuang, X. X. Wang, Y. A. Wang, H. Mao, S. M. Nie, J. Phys. Chem. C 2008, 112, 8127. [125] J. Huang, L. H. Bu, J. Xie, K. Chen, Z. Cheng, X. G. Li, X. Y. Chen, ACS Nano 2010, 4, 7151. [126] S. Tong, S. J. Hou, Z. L. Zheng, J. Zhou, G. Bao, Nano Lett. 2010, 10, 4607. [127] B. H. Kim, N. Lee, H. Kim, K. An, Y. I. Park, Y. Choi, K. Shin, Y. Lee, S. G. Kwon, H. B. Na, J. G. Park, T. Y. Ahn, Y. W. Kim, W. K. Moon, S. H. Choi, T. Hyeon, J. Am. Chem. Soc. 2011, 133, 12624. [128] E. Taboada, E. Rodriguez, A. Roig, J. Oro, A. Roch, R. N. Muller, Langmuir 2007, 23, 4583. [129] U. I. Tromsdorf, O. T. Bruns, S. C. Salmen, U. Beisiegel, H. Weller, Nano Lett. 2009, 9, 4434. [130] F. Q. Hu, Q. J. Jia, Y. L. Li, M. Y. Gao, Nanotechnology 2011, 22, 245604. [131] L. Sandiford, A. Phinikaridou, A. Protti, L. K. Meszaros, X. J. Cui, Y. Yan, G. Frodsham, P. A. Williamson, N. Gaddum, R. M. Botnar, P. J. Blower, M. A. Green, R. T. M. de Rosales, ACS Nano 2013, 7, 500. [132] Z. Li, P. W. Yi, Q. Sun, H. Lei, H. L. Zhao, Z. H. Zhu, S. C. Smith, M. B. Lan, G. Q. Lu, Adv. Funct. Mater. 2012, 22, 2387. [133] R. H. Kodama, J. Magn. Magn. Mater. 1999, 200, 359. [134] H. Kim, M. Achermann, L. P. Balet, J. A. Hollingsworth, V. I. Klimov, J. Am. Chem. Soc. 2005, 127, 544. [135] J. H. Gao, B. Zhang, Y. Gao, Y. Pan, X. X. Zhang, B. Xu, J. Am. Chem. Soc. 2007, 129, 11928. [136] Z. Q. Tian, Z. L. Zhang, P. Jiang, M. X. Zhang, H. Y. Xie, D. W. Pang, Chem. Mater. 2009, 21, 3039. [137] J. S. Lee, M. I. Bodnarchuk, E. V. Shevchenko, D. V. Talapin, J. Am. Chem. Soc. 2010, 132, 6382. [138] H. W. Gu, R. K. Zheng, X. X. Zhang, B. Xu, J. Am. Chem. Soc. 2004, 126, 5664. [139] S. L. He, H. W. Zhang, S. Delikanli, Y. L. Qin, M. T. Swihart, H. Zeng, J. Phys. Chem. C 2009, 113, 87. [140] K. W. Kwon, M. Shim, J. Am. Chem. Soc. 2005, 127, 10269.

[141] S. T. Selvan, P. K. Patra, C. Y. Ang, J. Y. Ying, Angew. Chem. 2007, 119, 2500; Angew. Chem. Int. Ed. 2007, 46, 2448. [142] J. H. Gao, W. Zhang, P. B. Huang, B. Zhang, X. X. Zhang, B. Xu, J. Am. Chem. Soc. 2008, 130, 3710. [143] H. McDaniel, M. Shim, ACS Nano 2009, 3, 434. [144] M. Zanella, A. Falqui, S. Kudera, L. Manna, M. F. Casula, W. J. Parak, J. Mater. Chem. 2008, 18, 4311. [145] S. Deng, G. Ruan, N. Han, J. O. Winter, Nanotechnology 2010, 21, 145605. [146] T. D. Nguyen, Colloids Surf., B 2013, 103, 326. [147] L. Carbone, P. D. Cozzoli, Nano Today 2010, 5, 449. [148] C. J. Xu, S. H. Sun, Adv. Drug Delivery Rev. 2013, 65, 732. [149] J. H. Gao, H. W. Gu, B. Xu, Acc. Chem. Res. 2009, 42, 1097. [150] M. A. Correa-Duarte, M. Giersig, L. M. Liz-Marzán, Chem. Phys. Lett. 1998, 286, 497. [151] A. L. Rogach, D. Nagesha, J. W. Ostrander, M. Giersig, N. A. Kotov, Chem. Mater. 2000, 12, 2676. [152] T. Nann, P. Mulvaney, Angew. Chem. 2004, 116, 5511; Angew. Chem. Int. Ed. 2004, 43, 5393. [153] A. Schroedter, H. Weller, R. Eritja, W. E. Ford, J. M. Wessels, Nano Lett. 2002, 2, 1363. [154] Y. Chan, J. P. Zimmer, M. Stroh, J. S. Steckel, R. K. Jain, M. G. Bawendi, Adv. Mater. 2004, 16, 2092. [155] D. K. Yi, S. T. Selvan, S. S. Lee, G. C. Papaefthymiou, D. Kundaliya, J. Y. Ying, J. Am. Chem. Soc. 2005, 127, 4990. [156] R. Koole, M. M. van Schooneveld, J. Hilhorst, C. D. Donega, D. C. ‘t Hart, A. van Blaaderen, D. Vanmaekelbergh, A. Meijerink, Chem. Mater. 2008, 20, 2503. [157] M. Darbandi, R. Thomann, T. Nann, Chem. Mater. 2005, 17, 5720. [158] R. He, X. G. You, J. Shao, F. Gao, B. F. Pan, D. X. Cui, Nanotechnology 2007, 18. [159] V. Salgueiriño-Maceira, M. A. Correa-Duarte, M. Spasova, L. M. Liz-Marzán, M. Farle, Adv. Funct. Mater. 2006, 16, 509. [160] J. Kim, J. E. Lee, J. Lee, J. H. Yu, B. C. Kim, K. An, Y. Hwang, C. H. Shin, J. G. Park, J. Kim, T. Hyeon, J. Am. Chem. Soc. 2006, 128, 688. [161] J. Guo, W. L. Yang, C. C. Wang, J. He, J. Y. Chen, Chem. Mater. 2006, 18, 5554. [162] N. Insin, J. B. Tracy, H. Lee, J. P. Zimmer, R. M. Westervelt, M. G. Bawendi, ACS Nano 2008, 2, 197. [163] T. R. Sathe, A. Agrawal, S. M. Nie, Anal. Chem. 2006, 78, 5627. [164] J. Kim, J. E. Lee, J. Lee, Y. Jang, S. W. Kim, K. An, H. H. Yu, T. Hyeon, Angew. Chem. 2006, 118, 4907; Angew. Chem. Int. Ed. 2006, 45, 4789. [165] Y. H. Li, T. Song, J. Q. Liu, S. J. Zhu, J. Chang, J. Mater. Chem. 2011, 21, 12520. [166] V. Roullier, F. Grasset, F. Boulmedais, F. Artzner, O. Cador, V. Marchi-Artzner, Chem. Mater. 2008, 20, 6657. [167] Y. F. Tan, P. Chandrasekharan, D. Maity, C. X. Yong, K. H. Chuang, Y. Zhao, S. Wang, J. Ding, S. S. Feng, Biomaterials 2011, 32, 2969. [168] G. Ruan, G. Vieira, T. Henighan, A. R. Chen, D. Thakur, R. Sooryakumar, J. O. Winter, Nano Lett. 2010, 10, 2220. [169] J. H. Park, G. von Maltzahn, E. Ruoslahti, S. N. Bhatia, M. J. Sailor, Angew. Chem. 2008, 120, 7394; Angew. Chem. Int. Ed. 2008, 47, 7284. [170] F. Caruso, M. Spasova, A. Susha, M. Giersig, R. A. Caruso, Chem. Mater. 2001, 13, 109. [171] N. Gaponik, I. L. Radtchenko, G. B. Sukhorukov, A. L. Rogach, Langmuir 2004, 20, 1449. [172] X. Hong, J. Li, M. J. Wang, J. J. Xu, W. Guo, J. H. Li, Y. B. Bai, T. J. Li, Chem. Mater. 2004, 16, 4022. [173] B. Zebli, A. S. Susha, G. B. Sukhorukov, A. L. Rogach, W. J. Parak, Langmuir 2005, 21, 4262.



17

www.advmat.de

REVIEW

www.MaterialsViews.com [174] R. Wilson, D. G. Spiller, I. A. Prior, K. J. Veltkamp, A. Hutchinson, ACS Nano 2007, 1, 487. [175] C. F. Tu, Y. H. Yang, M. Y. Gao, Nanotechnology 2008, 19, 105601. [176] H. Y. Xie, C. Zuo, Y. Liu, Z. L. Zhang, D. W. Pang, X. L. Li, J. P. Gong, C. Dickinson, W. Z. Zhou, Small 2005, 1, 506. [177] H. M. Fan, M. Olivo, B. Shuter, J. B. Yi, R. Bhuvaneswari, H. R. Tan, G. C. Xing, C. T. Ng, L. Liu, S. S. Lucky, B. H. Bay, J. Ding, J. Am. Chem. Soc. 2010, 132, 14803. [178] X. Y. Sun, K. Ding, Y. Hou, Z. Y. Gao, W. S. Yang, L. H. Jing, M. Y. Gao, J. Phys. Chem. C 2013, 117, 21014. [179] D. S. Wang, J. B. He, N. Rosenzweig, Z. Rosenzweig, Nano Lett. 2004, 4, 409. [180] H. S. Cho, Z. Y. Dong, G. M. Pauletti, J. M. Zhang, H. Xu, H. C. Gu, L. M. Wang, R. C. Ewing, C. Huth, F. Wang, D. L. Shi, ACS Nano 2010, 4, 5398. [181] B. Fernandez, N. Galvez, R. Cuesta, A. B. Hungria, J. J. Calvino, J. M. Dominguez-Vera, Adv. Funct. Mater. 2008, 18, 3931. [182] M. P. Nikitin, T. A. Zdobnova, S. V. Lukash, O. A. Stremovskiy, S. M. Deyev, Proc. Natl. Acad. Sci. USA 2010, 107, 5827. [183] E. S. Shibu, K. Ono, S. Sugino, A. Nishioka, A. Yasuda, Y. Shigeri, S. Wakida, M. Sawada, V. Biju, ACS Nano 2013, 7, 9851. [184] D. P. Cormode, T. Skajaa, M. M. van Schooneveld, R. Koole, P. Jarzyna, M. E. Lobatto, C. Calcagno, A. Barazza, R. E. Gordon, P. Zanzonico, E. A. Fisher, Z. A. Fayad, W. J. M. Mulder, Nano Lett. 2008, 8, 3715. [185] W. J. M. Mulder, R. Koole, R. J. Brandwijk, G. Storm, P. T. K. Chin, G. J. Strijkers, C. D. Donega, K. Nicolay, A. W. Griffioen, Nano Lett. 2006, 6, 1. [186] R. Koole, M. M. van Schooneveld, J. Hilhorst, K. Castermans, D. P. Cormode, G. J. Strijkers, C. D. Donega, D. Vanmaekelbergh, A. W. Griffioen, K. Nicolay, Z. A. Fayad, A. Meijerink, W. J. M. Mulder, Bioconjugate Chem. 2008, 19, 2471. [187] M. M. van Schooneveld, E. Vucic, R. Koole, Y. Zhou, J. Stocks, D. P. Cormode, C. Y. Tang, R. E. Gordon, K. Nicolay, A. Meijerink, Z. A. Fayad, W. J. M. Mulder, Nano Lett. 2008, 8, 2517. [188] W. J. M. Mulder, K. Castermans, J. R. van Beijnum, M. G. A. O. Egbrink, P. T. K. Chin, Z. A. Fayad, C. W. G. M. Lowik, E. L. Kaijzel, I. Que, G. Storm, G. J. Strijkers, A. W. Griffioen, K. Nicolay, Angiogenesis 2009, 12, 17. [189] R. Hu, Y. C. Wang, X. Liu, G. M. Lin, C. H. Tan, W. C. Law, I. Roy, K. T. Yong, RSC Adv. 2013, 3, 8495. [190] M. Ostendorp, K. Douma, T. M. Hackeng, A. Dirksen, M. J. Post, M. A. M. van Zandvoort, W. H. Backes, Cancer Res. 2008, 68, 7676. [191] M. Oostendorp, K. Douma, T. M. Hackeng, M. J. Post, M. A. M. J. van Zandvoort, W. H. Backes, Magn. Reson. Med. 2010, 64, 291. [192] L. Prinzen, R. J. J. H. M. Miserus, A. Dirksen, T. M. Hackeng, N. Deckers, N. J. Bitsch, R. T. A. Megens, K. Douma, J. W. Heemskerk, M. E. Kooi, P. M. Frederik, D. W. Slaaf, M. A. M. J. van Zandvoort, C. P. M. Reutelingsperger, Nano Lett. 2007, 7, 93. [193] G. A. F. van Tilborg, W. J. M. Mulder, P. T. K. Chin, G. Storm, C. P. Reutelingsperger, K. Nicolay, G. J. Strijkers, Bioconjugate Chem. 2006, 17, 865. [194] R. Bakalova, Z. Zhelev, I. Aoki, H. Ohba, Y. Imai, I. Kanno, Anal. Chem. 2006, 78, 5925. [195] R. Bakalova, Z. Zhelev, I. Aoki, K. Masamoto, M. Mileva, T. Obata, M. Higuchi, V. Gadjeva, I. Kanno, Bioconjugate Chem. 2008, 19, 1135. [196] H. S. Yang, S. Santra, G. A. Walter, P. H. Holloway, Adv. Mater. 2006, 18, 2890. [197] D. Gerion, J. Herberg, R. Bok, E. Gjersing, E. Ramon, R. Maxwell, J. Kurhanewicz, T. F. Budinger, J. W. Gray, M. A. Shuman, F. F. Chen, J. Phys. Chem. C 2007, 111, 12542.

18


[198] T. Jin, Y. Yoshioka, F. Fujii, Y. Komai, J. Seki, A. Seiyama, Chem. Commun. 2008, 5764. [199] L. W. Liu, W. C. Law, K. T. Yong, I. Roy, H. Ding, F. Erogbogbo, X. H. Zhang, P. N. Prasad, Analyst 2011, 136, 1881. [200] J. Zhu, J. Zhou, D. X. Wei, S. Y. Liu, CrystEngComm 2013, 15, 6221. [201] C. Y. Cheng, K. L. Ou, W. T. Huang, J. K. Chen, J. Y. Chang, C. H. Yang, ACS Appl. Mater. Interfaces 2013, 5, 4389. [202] G. J. Stasiuk, S. Tamang, D. Imbert, C. Poillot, M. Giardiello, C. Tisseyre, E. L. Barbier, P. H. Fries, M. de Waard, P. Reiss, M. Mazzanti, ACS Nano 2011, 5, 8193. [203] G. J. Stasiuk, S. Tamang, D. Imbert, C. Gateau, P. Reiss, P. Fries, M. Mazzanti, Dalton Trans. 2013, 42, 8197. [204] J. Park, S. Bhuniya, H. Lee, Y. W. Noh, Y. T. Lim, J. H. Jung, K. S. Hong, J. S. Kim, Chem. Commun. 2012, 48, 3218. [205] S. C. Erwin, L. J. Zu, M. I. Haftel, A. L. Efros, T. A. Kennedy, D. J. Norris, Nature 2005, 436, 91. [206] D. J. Norris, A. L. Efros, S. C. Erwin, Science 2008, 319, 1776. [207] D. A. Bussian, S. A. Crooker, M. Yin, M. Brynda, A. L. Efros, V. I. Klimov, Nat. Mater. 2009, 8, 35. [208] J. H. Yu, X. Y. Liu, K. E. Kweon, J. Joo, J. Park, K. T. Ko, D. Lee, S. P. Shen, K. Tivakornsasithorn, J. S. Son, J. H. Park, Y. W. Kim, G. S. Hwang, M. Dobrowolska, J. K. Furdyna, T. Hyeon, Nat. Mater. 2010, 9, 47. [209] D. Mocatta, G. Cohen, J. Schattner, O. Millo, E. Rabani, U. Banin, Science 2011, 332, 77. [210] X. H. Gao, Y. Y. Cui, R. M. Levenson, L. W. K. Chung, S. M. Nie, Nat. Biotechnol. 2004, 22, 969. [211] J. A. Lee, S. Mardyani, A. Hung, A. Rhee, J. Klostranec, Y. Mu, D. Li, W. C. W. Chan, Adv. Mater. 2007, 19, 3113. [212] S. Santra, H. S. Yang, P. H. Holloway, J. T. Stanley, R. A. Mericle, J. Am. Chem. Soc. 2005, 127, 1656. [213] S. Wang, B. R. Jarrett, S. M. Kauzlarich, A. Y. Louie, J. Am. Chem. Soc. 2007, 129, 3848. [214] H. S. Choi, W. Liu, P. Misra, E. Tanaka, J. P. Zimmer, B. I. Ipe, M. G. Bawendi, J. V. Frangioni, Nat. Biotechnol. 2007, 25, 1165. [215] H. S. Choi, Nat. Nanotechnol. 2014, 9, 93. [216] Y. A. Yang, O. Chen, A. Angerhofer, Y. C. Cao, J. Am. Chem. Soc. 2006, 128, 12428. [217] A. Nag, S. Sapra, C. Nagamani, A. Sharma, N. Pradhan, S. V. Bhat, D. D. Sarma, Chem. Mater. 2007, 19, 3252. [218] N. Pradhan, X. G. Peng, J. Am. Chem. Soc. 2007, 129, 3339. [219] A. Nag, S. Chakraborty, D. D. Sarma, J. Am. Chem. Soc. 2008, 130, 10605. [220] R. Beaulac, L. Schneider, P. I. Archer, G. Bacher, D. R. Gamelin, Science 2009, 325, 973. [221] R. Beaulac, P. I. Archer, S. T. Ochsenbein, D. R. Gamelin, Adv. Funct. Mater. 2008, 18, 3873. [222] J. J. Zheng, X. Yuan, M. Ikezawa, P. T. Jing, X. Y. Liu, Z. H. Zheng, X. G. Kong, J. L. Zhao, Y. Masumoto, J. Phys. Chem. C 2009, 113, 16969. [223] A. A. Bol, A. Meijerink, J. Phys. Chem. B 2001, 105, 10203. [224] N. Murase, R. Jagannathan, Y. Kanematsu, M. Watanabe, A. Kurita, K. Hirata, T. Yazawa, T. Kushida, J. Phys. Chem. B 1999, 103, 754. [225] V. Ladizhansky, G. Hodes, S. Vega, J. Phys. Chem. B 1998, 102, 8505. [226] S. Jana, B. B. Srivastava, S. Jana, R. Bose, N. Pradhan, J. Phys. Chem. Lett. 2012, 3, 2535. [227] D. J. Norris, N. Yao, F. T. Charnock, T. A. Kennedy, Nano Lett. 2001, 1, 3. [228] K. M. Hanif, R. W. Meulenberg, G. F. Strouse, J. Am. Chem. Soc. 2002, 124, 11495. [229] P. I. Archer, S. A. Santangelo, D. R. Gamelin, Nano Lett. 2007, 7, 1037.





REVIEW

[230] X. Sun, X. Huang, J. Guo, W. Zhu, Y. Ding, G. Niu, A. Wang, D. O. Kiesewetter, Z. L. Wang, S. Sun, X. Chen, J. Am. Chem. Soc. 2014, 136, 1706. [231] S. Gupta, S. V. Kershaw, A. L. Rogach, Adv. Mater. 2013, 25, 6923. [232] B. J. Beberwyck, Y. Surendranath, A. P. Alivisatos, J. Phys. Chem. C 2013, 117, 19759. [233] J. B. Rivest, P. K. Jain, Chem. Soc. Rev. 2013, 42, 89. [234] V. A. Vlaskin, C. J. Barrows, C. S. Erickson, D. R. Gamelin, J. Am. Chem. Soc. 2013, 135, 14380. [235] R. N. Bhargava, D. Gallagher, X. Hong, A. Nurmikko, Phys. Rev. Lett. 1994, 72, 416. [236] B. B. Srivastava, S. Jana, N. S. Karan, S. Paria, N. R. Jana, D. D. Sarma, N. Pradhan, J. Phys. Chem. Lett. 2010, 1, 1454. [237] N. Pradhan, D. M. Battaglia, Y. C. Liu, X. G. Peng, Nano Lett. 2007, 7, 312. [238] J. F. Suyver, S. F. Wuister, J. J. Kelly, A. Meijerink, Phys. Chem. Chem. Phys. 2000, 2, 5445. [239] F. V. Mikulec, M. Kuno, M. Bennati, D. A. Hall, R. G. Griffin, M. G. Bawendi, J. Am. Chem. Soc. 2000, 122, 2532. [240] S. Bhattacharyya, D. Zitoun, A. Gedanken, J. Phys. Chem. C 2008, 112, 7624. [241] C. A. Stowell, R. J. Wiacek, A. E. Saunders, B. A. Korgel, Nano Lett. 2003, 3, 1441. [242] P. V. Radovanovic, D. R. Gamelin, J. Am. Chem. Soc. 2001, 123, 12207. [243] N. Pradhan, D. Goorskey, J. Thessing, X. G. Peng, J. Am. Chem. Soc. 2005, 127, 17586. [244] R. Buonsanti, D. J. Milliron, Chem. Mater. 2013, 25, 1305. [245] N. Pradhan, D. D. Sarma, J. Phys. Chem. Lett. 2011, 2, 2818. [246] W. Chen, J. Z. Zhang, A. G. Joly, J. Nanosci. Nanotechnol. 2004, 4, 919. [247] H. S. Yang, S. Santra, P. H. Holloway, J. Nanosci. Nanotechnol. 2005, 5, 1364. [248] P. Wu, X. P. Yan, Chem. Soc. Rev. 2013, 42, 5489. [249] S. Lee, M. Dobrowolska, J. K. Furdyna, Solid State Commun. 2007, 141, 311. [250] A. A. Bol, A. Meijerink, Phys. Rev. B 1998, 58, 15997. [251] D. M. Hoffman, B. K. Meyer, A. I. Ekimov, I. A. Merkulov, A. L. Efros, M. Rosen, G. Couino, T. Gacoin, J. P. Boilot, Solid State Commun. 2000, 114, 547. [252] H. Y. Chen, S. Maiti, D. H. Son, ACS Nano 2012, 6, 583. [253] R. Beaulac, P. I. Archer, J. van Rijssel, A. Meijerink, D. R. Gamelin, Nano Lett. 2008, 8, 2949. [254] H. Yang, P. H. Holloway, Appl. Phys. Lett. 2003, 82, 1965. [255] A. Ishizumi, Y. Kanemitsu, Adv. Mater. 2006, 18, 1083. [256] O. Chen, D. E. Shelby, Y. A. Yang, J. Q. Zhuang, T. Wang, C. G. Niu, N. Omenetto, Y. C. Cao, Angew. Chem. 2010, 122, 10330; Angew. Chem. Int. Ed. 2010, 49, 10132. [257] Y. A. Yang, O. Chen, A. Angerhofer, Y. C. Cao, J. Am. Chem. Soc. 2008, 130, 15649. [258] C. H. Hsia, A. Wuttig, H. Yang, ACS Nano 2011, 5, 9511. [259] R. Thakar, Y. C. Chen, P. T. Snee, Nano Lett. 2007, 7, 3429. [260] R. S. Zeng, T. T. Zhang, G. Z. Dai, B. S. Zou, J. Phys. Chem. C 2011, 115, 3005. [261] R. Beaulac, P. I. Archer, X. Y. Liu, S. Lee, G. M. Salley, M. Dobrowolska, J. K. Furdyna, D. R. Gamelin, Nano Lett. 2008, 8, 1197. [262] L. H. Jing, K. Ding, S. Kalytchuk, Y. Wang, R. R. Qiao, S. V. Kershaw, A. L. Rogach, M. Y. Gao, J. Phys. Chem. C 2013, 117, 18752. [263] N. Lewinski, V. Colvin, R. Drezek, Small 2008, 4, 26. [264] N. Chen, Y. He, Y. Y. Su, X. M. Li, Q. Huang, H. F. Wang, X. Z. Zhang, R. Z. Tai, C. H. Fan, Biomaterials 2012, 33, 1238. [265] S. L. Castro, S. G. Bailey, R. P. Raffaelle, K. K. Banger, A. F. Hepp, Chem. Mater. 2003, 15, 3142.

[266] K. T. Yong, I. Roy, R. Hu, H. Ding, H. X. Cai, J. Zhu, X. H. Zhang, E. J. Bergey, P. N. Prasad, Integr. Biol. 2010, 2, 121. [267] J. Park, S. W. Kim, J. Mater. Chem. 2011, 21, 3745. [268] D. Aldakov, A. Lefrancois, P. Reiss, J. Mater. Chem. C 2013, 1, 3756. [269] J. Kolny-Olesiak, H. Weller, ACS Appl. Mater. Interfaces 2013, 5, 12221. [270] D. Magana, S. C. Perera, A. G. Harter, N. S. Dalal, G. F. Strouse, J. Am. Chem. Soc. 2006, 128, 2931. [271] K. Somaskandan, G. M. Tsoi, L. E. Wenger, S. L. Brock, Chem. Mater. 2005, 17, 1190. [272] S. J. C. H. M. Vangisbergen, M. Godlewski, T. Gregorkiewicz, C. A. J. Ammerlaan, Phys. Rev. B 1991, 44, 3012. [273] P. H. Borse, D. Srinivas, R. F. Shinde, S. K. Date, W. Vogel, S. K. Kulkarni, Phys. Rev. B 1999, 60, 8659. [274] R. Martín-Rodríguez, R. Geitenbeek, A. Meijerink, J. Am. Chem. Soc. 2013, 135, 13668. [275] U. T. D. Thuy, A. Maurice, N. Q. Liem, P. Reiss, Dalton Trans. 2013, 42, 12606. [276] J. C. G. Bunzli, Chem. Rev. 2010, 110, 2729. [277] K. Li, D. Ding, C. Prashant, W. Qin, C. T. Yang, B. Z. Tang, B. Liu, Adv. Healthcare Mater. 2013, 2, 1600. [278] G. Beaune, B. Dubertret, O. Clement, C. Vayssettes, V. Cabuil, C. Menager, Angew. Chem. 2007, 119, 5517; Angew. Chem. Int. Ed. 2007, 46, 5421. [279] Z. L. Cheng, A. Al Zaki, J. Z. Hui, V. R. Muzykantov, A. Tsourkas, Science 2012, 338, 903. [280] A. K. Iyer, G. Khaled, J. Fang, H. Maeda, Drug Discovery Today 2006, 11, 812. [281] J. B. Liu, M. X. Yu, C. Zhou, S. Y. Yang, X. H. Ning, J. Zheng, J. Am. Chem. Soc. 2013, 135, 4978. [282] J. T. Robinson, G. Hong, Y. Liang, B. Zhang, O. K. Yaghi, H. Dai, J. Am. Chem. Soc. 2012, 134, 10664. [283] C. H. Wang, C. J. Liu, C. C. Chien, H. T. Chen, T. E. Hua, W. H. Leng, H. H. Chen, I. M. Kempson, Y. Hwu, M. Hsiao, T. C. Lai, J. L. Wang, C. S. Yang, H. M. Lin, Y. J. Chen, G. Margaritondo, Mater. Chem. Phys. 2011, 126, 352. [284] Y. Hou, R. R. Qiao, F. Fang, X. X. Wang, C. Y. Dong, K. Liu, C. Y. Liu, Z. F. Liu, H. Lei, F. Wang, M. Y. Gao, ACS Nano 2013, 7, 330. [285] C. Y. Liu, Z. Y. Gao, J. F. Zeng, Y. Hou, F. Fang, Y. L. Li, R. R. Qiao, L. Shen, H. Lei, W. S. Yang, M. Y. Gao, ACS Nano 2013, 7, 7227. [286] M. R. Kano, Y. Bae, C. Iwata, Y. Morishita, M. Yashiro, M. Oka, T. Fujii, A. Komuro, K. Kiyono, M. Kaminishi, K. Hirakawa, Y. Ouchi, N. Nishiyama, K. Kataoka, K. Miyazono, Proc. Natl. Acad. Sci. USA 2007, 104, 3460. [287] V. Biju, T. Itoh, M. Ishikawa, Chem. Soc. Rev. 2010, 39, 3031. [288] E. M. Hendriksen, P. N. Span, J. Schuuring, J. P. W. Peters, F. C. G. J. Sweep, A. J. van der Kogel, J. Bussink, Microvasc. Res. 2009, 77, 96. [289] R. Hardman, Environ. Health Persp. 2006, 114, 165. [290] D. Maysinger, J. Lovric, A. Eisenberg, R. Savic, Eur. J. Pharm. Biopharm. 2007, 65, 270. [291] A. M. Derfus, W. C. W. Chan, S. N. Bhatia, Nano Lett. 2004, 4, 11. [292] J. Lovric, S. J. Cho, F. M. Winnik, D. Maysinger, Chem. Biol. 2005, 12, 1227. [293] S. J. Cho, D. Maysinger, M. Jain, B. Roder, S. Hackbarth, F. M. Winnik, Langmuir 2007, 23, 1974. [294] R. Bakalova, H. Ohba, Z. Zhelev, M. Ishikawa, Y. Baba, Nat. Biotechnol. 2004, 22, 1360. [295] M. Green, E. Howman, Chem. Commun. 2005, 121. [296] B. I. Ipe, M. Lehnig, C. M. Niemeyer, Small 2005, 1, 706. [297] L. Ye, K. T. Yong, L. W. Liu, I. Roy, R. Hu, J. Zhu, H. X. Cai, W. C. Law, J. W. Liu, K. Wang, J. Liu, Y. Q. Liu, Y. Z. Hu,



19

www.advmat.de

REVIEW

www.MaterialsViews.com X. H. Zhang, M. T. Swihart, P. N. Prasad, Nat. Nanotechnol. 2012, 7, 453. [298] P. H. Kuo, E. Kanal, A. K. Abu-Alfa, S. E. Cowper, Radiology 2007, 242, 647. [299] A. Palasz, P. Czekaj, Acta Biochim. Pol. 2000, 47, 1107. [300] L. C. Adding, G. L. Bannenberg, L. E. Gustafsson, Cardiovasc. Drug Rev. 2001, 19, 41.

20


[301] H. B. Na, I. C. Song, T. Hyeon, Adv. Mater. 2009, 21, 2133. [302] S. Kim, Y. T. Lim, E. G. Soltesz, A. M. De Grand, J. Lee, A. Nakayama, J. A. Parker, T. Mihaljevic, R. G. Laurence, D. M. Dor, L. H. Cohn, M. G. Bawendi, J. V. Frangioni, Nat. Biotechnol. 2004, 22, 93. [303] A. M. Smith, M. C. Mancini, S. M. Nie, Nat. Nanotechnol. 2009, 4, 710.



Probing the Cytotoxicity Of Semiconductor Quantum Dots.

Multiple Exciton Generation in Semiconductor Quantum Dots.

Electron states in semiconductor quantum dots.

Silicon Metal-oxide-semiconductor Quantum Dots for Single-electron Pumping.

Quantum Dots as Multifunctional Materials for Tumor Imaging and Therapy.

Aptamer-Modified Semiconductor Quantum Dots for Biosensing Applications.

Realizing ferromagnetic coupling in diluted magnetic semiconductor quantum dots.

Continuing progress toward controlled intracellular delivery of semiconductor quantum dots.

Andreev molecules in semiconductor nanowire double quantum dots.

Auger-assisted electron transfer from photoexcited semiconductor quantum dots.

Tumor-Targeted Multimodal Optical Imaging with Versatile Cadmium-Free Quantum Dots.

Enhanced carrier multiplication in engineered quasi-type-II quantum dots.

An ultrasensitive method for the determination of melamine using cadmium telluride quantum dots as fluorescence probes.

Compact, Polyvalent Mannose Quantum Dots as Sensitive, Ratiometric FRET Probes for Multivalent Protein-Ligand Interactions.

The application of CdSe quantum dots with multicolor emission as fluorescent probes for cell labeling.

Dopamine functionalized-CdTe quantum dots as fluorescence probes for l-histidine detection in biological fluids.

Imaging Live Cells Using Quantum Dots.

Polymersomes containing quantum dots for cellular imaging.

Quantum dots as a possible oxygen sensor.

Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes.

Engineering iodine-doped carbon dots as dual-modal probes for fluorescence and X-ray CT imaging.

Magnetically driven quantum heat engine.

Mind your P's and Q's: the coming of age of semiconducting polymer dots and semiconductor quantum dots in biological applications.

Gold-silica quantum rattles for multimodal imaging and therapy.