magnetically engineered semiconductor quantum dots as multimodal imaging probes

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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 *

Dr. L. H. Jing, K. Ding, Dr. I. M. Kempson, Prof. M. Y. Gao Institute of Chemistry, Chinese Academy of Sciences Bei Yi Jie 2 Zhong Guan Cun , Beijing 100190 , China E-mail: [email protected] Dr. S. V. Kershaw, Prof. A. L. Rogach Department of Physics and Materials Science & Centre for Functional Photonics City University of Hong Kong Tat Chee Avenue , Kowloon , Hong Kong S.A.R E-mail: [email protected] Dr. I. M. Kempson Ian Wark Research Institute University of South Australia Mawson Lakes , S.A. 5095 , Australia

DOI: 10.1002/adma.201402296

information, thus improving the effi cacy and sensitivity of clinical imaging diagnos-tics. To date, the combinations of imaging techniques such as positron emission tomography (PET)/computer tomo-graphy (CT) and PET/magnetic resonance imaging (MRI) have already developed into commercial imaging instruments that are being adopted clinically. Fur-thermore, optical imaging (OI) tech-niques have shown superior potential in extracting detailed biomedical information with high imaging sensitivity and with low cost imaging facilities in comparison to clinically used MRI, CT and PET methods.

Fluorescent inorganic nanocrystals having optical properties that are governed by their composition, size, and surface chemistry offer specifi c advantages for optical imaging. Semiconductor quantum dots (QDs), [ 8–24 ] carbon dots, [ 25–28 ] graph ene [ 29,30 ] and silicon dots, [ 31–34 ] noble

metal clusters, [ 35–39 ] and lanthanide-doped up-conversion nanocrystals [ 40–42 ] have all shown potential in extracting detailed biological information at subcellular levels in vitro with high imaging sensitivity. However, due to the poor spatial resolu-tion and optical penetration in tissue, the complementarity of these probes with magnetic resonance imaging (MRI), which is one of most important clinical tools nowadays for visualizing internal anatomical structures with extremely high spatial reso-lution, is strongly desirable. In this context, the combination of optical imaging techniques and MRI offers a powerful com-bination of imaging modalities for more accurate biomedical detection. [ 43,44 ]

Development of multimodal optical + MRI imaging probes obviously relies on the design and subsequent fabrication of nanostructures offering both modalities within a single plat-form. Nanometer-sized semiconductor QDs are well known as powerful fl uorescent probes because of their outstanding optical properties governed by the quantum confi nement effect. Their emission window covers a broad spectral range from the visible into the near-infrared, enabling us to optimize detec-tion/imaging performance. They are easily functionalized by a variety of surface modifi cations thereby: facilitating targeted delivery; prolonging systemic circulation (which is impor-tant for biocompatibility) and exploiting the enhanced perme-ability and retention (EPR) effect in tumors; allowing for the

Light-emitting semiconductor quantum dots (QDs) combined with magnetic resonance imaging contrast agents within a single nanoparticle platform are considered to perform as multimodal imaging probes in biomedical research and related clinical applications. The principles of their rational design are outlined and contemporary synthetic strategies are reviewed (heterocrystal-line 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), identifying the strengths and weaknesses of different approaches. Some of the opportunities and benefi ts that arise through in vivo imaging using these dual-mode probes are highlighted where tumor location and delineation is demonstrated in both MRI and fl uorescence modality. Work on the toxicological assessments of QD/magnetic nanoparti-cles is also reviewed, along with progress in reducing their toxicological side effects for eventual clinical use. The review concludes with an outlook for future biomedical imaging and the identifi cation of key challenges in reaching clinical applications.

1. Introduction

Multimodal imaging using nanostructures synergistically inte-grated with multiple functional entities has ignited intense research interest worldwide, offering revolutionary imaging tools for biomedical applications. [ 1–7 ] Integrating the compli-mentary merits of different imaging modalities is an effec-tive approach to extract accurate and reliable biomedical

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functional nanoparticles. Furthermore, QD-based nanostruc-tures imparted with magnetic properties offer the opportunity for multifunctional bioimaging and biomedical applications. To date, magnetically engineered QDs are commonly synthe-sized 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 fl uorescence/magnetic-resonance multimodal imaging. We fi rst 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 spe-cial 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 exam-ples with regard to in vivo tumor imaging of these probes, and discuss the related toxicity concerns. We conclude with an out-look 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 con-fi nement, decreasing the crystal size gives rise to an increasing bandgap. [ 9 ] This results in strongly size-dependent QD absorp-tion 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 profi les, benefi cial for color purity and precise tunability of emission; broad excitation range com-bined with high molar absorption coeffi cients, 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 inter-ference from biological background noise (i.e., auto-fl uores-cence). [ 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 Cd 3 (P,As) 2 , [ 52,53 ] III–V In(P,As), [ 54,55 ] IV–VI Pb(S,Se), [ 56,57 ] I–VI Ag 2 (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 fl uoro-phores in biomedical fi elds.

Owing to the strong dependence of both QD stability and their fl uorescence 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

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 semi-conductor 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-Maximilians-Universität in Munich, where he completed his habilita-tion 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.

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channels for photogenerated charge carriers. Effi cient passiva-tion of such surface trap states is therefore particularly impor-tant to maintain and further improve PL QYs and the stability of QDs against photobleaching. In this respect, core@shell nano-structures with a wide bandgap semiconductor shell grown on a narrower bandgap semiconductor core are a particularly effi cient solution for surface passivation. Of prime considera-tion 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 suit-able shell thickness allowing for nanoparticle epitaxial growth are important to avoid these issues. To date, epitaxial growth of II–VI CdSe QDs ( E g,bulk ≈ 1.74 eV) with ZnS shell ( E g,bulk ≈ 3.61 eV) or CdS shell ( E g,bulk ≈ 2.49 eV) has been most fre-quently used, based on the organic phase thermal decompo-sition 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 com-parison with the organic phase based approach. Since water is a strong polar solvent, it can not only coordinate with cad-mium ions in different forms depending on the pH of the system, but also readily induces complicated dynamics for sur-face capping molecules. [ 19 ] By choosing a mercapto acid (e.g., thio glycolic acid, mercaptopropionic acid, or glutathione) as a surface stabilizing agent, [ 78 ] on the basis of pioneering investiga-tions of Henglein, [ 79 ] and Rogach and Weller, [ 80,81 ] an important breakthrough towards strongly fl uorescent aqueous CdTe QDs ( E g,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 sulfi de which deposits on the surface of the CdTe QDs in combination with Cd 2+ 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 CuInS 2 and CuInSe 2 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 fulfi ll 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 com-monly 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 CuInS 2 core and the ZnS shell is low enough to allow epitaxial shell growth. However, shell overgrowth on CuInS 2 QDs typically induces a signifi cant hyp-sochromic shift of the emission wavelengths, indicating some changes in composition or size of the underlying fl uorescent cores. It has been proposed that due to the small difference between the ionic radius of Zn 2+ and Cu + , Zn 2+ ions readily

diffuse into the CuInS 2 core lattice which exhibits a chalco-pyrite structure. The indiffusion results in a slightly modifi ed form of zinc blende lattice in which Cu + and In 3+ ions occupy the positions of the displaced Zn 2+ ions, eventually leading to an interfacial gradient in composition. [ 63,66 ] Alternatively, the hypsochromic shift may also result from a surface reconstruc-tion [ 61 ] or etching of the cores. [ 64 ] The exact mechanisms are yet to be verifi ed, and will likely lead to better-defi ned ZnS shell structures on CuInS 2 core QDs in the future.

The colloidal stability of core-only or core@shell QDs in com-plex 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 poly-mers [ 91–95 ] can both improve their colloidal and chemical stabili-ties 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 fun-damental 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 fi eld. 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 prin-cipal processes, namely longitudinal (or spin-lattice) relaxation characterized by a relaxation time T 1 , and transverse (or spin-spin) relaxation characterized by a relaxation time T 2 .

MRI contrast agents principally work by shortening the T 1 or T 2 relaxation times of surrounding water protons, [ 97,98 ] and can generally be divided into two categories, i.e., T 1 and T 2 con-trast agents, yielding signal brightening or darkening in the images, respectively. The effi ciency of the contrast agents to shorten longitudinal ( T 1 ) and transverse ( T 2 ) relaxation times of water protons are quantifi ed by the concentration-independent relaxivities r 1 and r 2 , respectively. Higher values of r 1 or r 2 (which correspond to stronger reduction in T 1 or T 2 ) 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 Gd 3+ , Mn 2+ , and Fe 3+ . [ 99–102 ] In particular, paramagnetic Gd 3+ -based (e.g., Gd-DTPA, DTPA = diethylenetriaminepentaacetic acid) and Mn 2+ -based (e.g., Mn-DPDP, DPDP = dipyridoxal diphosphate) small molecular chelates have been developed as effi cient type T 1 contrast agents, benefi ting from a large number of unpaired electrons with parallel spin and a spin-relaxation time match-able with the Larmor precession frequency of protons within a suitable magnetic fi eld. [ 100 ] However, due to the potential toxicity of Gd 3+ and Mn 2+ ions, chelates with low dissociation rates and high excretion rates are required in order to reduce

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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 specifi c 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 nanopar-ticle platforms, such as manganese oxides (e.g., MnO, Mn 3 O 4 , etc.) [ 97,102–104 ] and gadolinium-containing nanoparticles (e.g., Gd 2 O 3 , NaGdF 4 , etc.) [ 105–108 ] as T 1 MRI contrast agents and molecular imaging probes have started to receive increasing attention.

Negative contrast agents most commonly utilize super-paramagnetic iron oxide nanoparticles (SPIONs) due to high biocompatibility and long circulation time with appropriate surface modifi cation, i.e., magnetite (Fe 3 O 4 ) and maghemite (Fe 2 O 3 ). [ 98,109–116 ] Such nanoparticles become super-para-magnetic when their size is below a critical scale where they behave as individual magnetic domains, and therefore they are predominantly used as T 2 contrast agents. [ 98 ] Owing to con-tinuing 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 in-depth investigation of relaxometric properties associated with the nanoparticle size. [ 124–126 ] In principle, SPIONs also shorten the longitudinal relaxation time, but their innately high mag-netic moments prevented them from being utilized as T 1 con-trast agents. Recent investigations show that magnetic iron oxide nanoparticles below 5 nm are potentially useful as T 1 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 T 1 / T 2 contrast enhancement. [ 114 ] Such optimization of the relaxometric prop-erties 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 semi-conductor QDs and MRI contrast agents are defi ned by factors such as size, composition, structure and/or surface chemistry. Rational integration of these two components into multifunc-tional nanoplatforms should enable versatile fl uorescence/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. Essen-tial considerations include optical and relaxometric properties; the toxicity of the constituent elements; colloidal dispersibility;

and desirable surface properties. Current strategies to integrate fl uorescent QDs with MRI contrast agents generally include four distinct approaches: heterocrystalline growth; co-encapsu-lation or assembly of preformed QDs and magnetic nanoparti-cles; 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 pre-formed super-paramagnetic nanocrystals via high temperature decomposition of the respective precursors results in the for-mation of two distinct functional domains, as has been demon-strated for core@shell structures such as Co@CdSe, [ 134 ] FePt@Cd(S,Se,Te) (Figure 1 a) [ 135,136 ] and FePt@Pb(S,Se) [ 137 ] ; and heter-odimer structures such as FePt-(Cd,Zn,Pb)S (Figure 1 b), [ 138,139 ] FePt-Pb(S,Se), [ 137 ] γ -Fe 2 O 3- (Zn,Cd,Hg)S, [ 140 ] γ -Fe 2 O 3 -CdSe [ 141 ] and Fe 3 O 4 -Cd(S,Se) (Figure 1 c and 1 d). [ 142,143 ] The resulting structural arrangement strongly depends on the lattice mis-match between the QD and the magnetic component, but also on the synthesis parameters such as reaction tempera-ture, 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 1 a), whilst a higher reaction tempera-ture (e.g., 280–300 °C) promoted the formation of heterodi-mers through the partial coalescence of domains (FePt-CdS in Figure 1 b). [ 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 multifunc-tional 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 unde-sirable interface interactions between the fl uorescent and the magnetic domains. To maintain or balance the physical prop-erties 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, inter-face 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 fl uorescent 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 instabili-ties between the two crystal lattices. [ 145 ] For more details on the

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

3.2. Co-encapsulation/Assembly of Preformed QD and Magnetic Nanocrystals

Co-encapsulation typically involves the inclusion of dis-crete preformed QDs and magnetic nanocrystals into silica or polymers beads, micelles or liposomes. Maintaining spa-tial separation between the fl uorescent QDs and magnetic nanoparticles helps to avoid the emission quenching of the former which is often encountered in the heterocrystals con-sidered above. Silica encapsulation of QDs can be performed either by the Stöber process [ 150–154 ] or by the reverse (water-in-oil) 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., Fe 3 O 4 , γ -Fe 2 O 3 ) are particularly successful examples. [ 155,158–162 ] As an alternative to encapsula-tion, 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 Fe 3 O 4 nanoparticles, driven by hydrophobic interactions between the stabilizing ligands of the nanoparticles and hydrophobic octa-decyl chain modifi ed pores. [ 163 ] Surface attachment of nano-particles on silica spheres through covalent bonding has also

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 fi lms 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 mag-netic nanoparticles. This is commonly achieved by the following two strategies: i) geometric confi nement of nanocrystals into porous polymer materials such as microbeads via hydrophobic interactions, [ 165 ] amphiphilic micelles via hydrophobic interac-tions, [ 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 fi rst strategy, water-soluble CdTe QDs stabilized by thio glycolic acid and Fe 3 O 4 nanoparticles stabilized by citric acid were simultane-ously loaded into ca. 10 nm diameter pore channels of 5.6 µm diameter porous polymer microcapsules; [ 171,173 ] fl uorescence quenching was minimized by separation of the Fe 3 O 4 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 struc-ture are more suitable for achieving chemically robust struc-tures, and these can be produced by radical polymerization of hydrophobic monomer droplets containing organic-soluble nanocrystals. Avoiding the aggregation of inorganic nanopar-ticles 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 effi ciently 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 modifi ed mini-emulsion poly-merization method is based on the simultaneous transfer of CdTe and Fe 3 O 4 nanoparticles from an aqueous medium into the styrene phase using polymerizable DVMAC (didecyl-p-vinylbenzylmethylammonium chloride) surfactant as a phase transfer agent and polymerizable OVDAC (octadecyl-p-vinylb-enzyldimethylammonium chloride) surfactant as an emulsi-fi er. [ 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 Fe 3 O 4 nanoparticles with a silica shell regulated the internal structure of the composite beads, and minimized re-absorp-tion of the fl uorescence emission of the QDs by Fe 3 O 4 . On the downside, the resulting structures became relatively large, typi-cally 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 modifi cation, 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 pos-sibility of optical encoding by the use of different QDs. A high loading with magnetite results in much stronger magnetic

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Figure 1. Core@shell and heterodimer structures of QDs and mag-netic 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. Repro-duced with permission. [ 138 ] Copyright 2004, American Chemical Society. c,d) HRTEM images of Fe 3 O 4 -CdSe heterodimers (c) with the corre-sponding SAED analysis (d). Reproduced with permission. [ 142 ] Copyright 2008, American Chemical Society.


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moments than is possible with individual Fe 3 O 4 nanoparticles, improving both magnetic guidance (direction of administered magnetic particles via an externally applied magnetic fi eld) 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 recep-tors 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 ]

forces. As an example, in the absence of any linker molecules, positively charged polyethylenimine capped CdSe@ZnS QDs can effi ciently assemble onto negatively charged citric acid capped Fe 3 O 4 nanorings through electrostatic interac-tions, [ 177 ] while amphiphilic poly(4-vinylpyrollidone) capped Fe 3 O 4 nanoparticles can overcoat hydrophobic 1-dodecanethiol capped CuInS 2 @ZnS QDs through hydrophobic–hydrophobic interactions. [ 178 ] Alternatively, upon crosslinking via linker molecules, CdSe@ZnS QDs could bind onto the surface of γ -Fe 2 O 3 nanocrystals capped with thiol-containing poly-mers providing terminal functional thiol groups as chemical linkers, [ 179 ] while streptavidin capped CdSe@ZnS QDs can be successfully assembled on Fe 3 O 4 capped with biotin-derived ligands. [ 71 ] Also for these nanostructures, reabsorption of inci-dent and/or emitted light by Fe 3 O 4 or γ -Fe 2 O 3 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 environ-mental conditions.

3.3. Conjugation of Paramagnetic Chelates onto QDs

Among the paramagnetic metal chelates, Gd chelates are most commonly used to directly coat onto QDs. The resulting con-jugates are expected to possess enhanced relaxometric proper-ties, amplifying MRI signals due to slow tumbling rates, and allow for high-performance T 1 -weighted MR imaging. Gd chelates (e.g., Gd-DTPA, Gd-DOTA (DOTA = 1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid), etc.) and their deriva-tives 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 3 a) [ 2,184–189 ] or molecular coupling techniques such as the biotin-streptavidin interaction (Figure 3 b). [ 190–192 ] Cova-lent bonding makes use of reactive functional groups such as silane-, thiol-, carboxyl- or amine- moities to connect Gd che-lates 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 dis-tearyl amide (DSA) chains to produce a paramagnetic chelating lipid (Gd-DTPA-DSA), which was simultaneously assem-bled together with PEGylated lipid onto hydrophobic CdSe@ZnS QDs via hydrophobic interactions with surface ligands (Figure 3 a). The resulting PEGylated water-soluble paramag-netic QD-based micelles can remain relatively small (diam-eters < 10 nm) despite achieving high payloads, each carrying up to 150 Gd-DTPA-DSA lipids. Importantly, an ionic relaxivity r 1 , 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 fi eld 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 r 1 , QD of 2000 mM −1 s −1 of these nano-structures renders them attractive candidates for T 1 -weighted imaging.

Apart from the direct coating of QDs, Gd-DTPA-DSA together with PEGylated lipids can be physically adsorbed

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Figure 2. Co-encapsulation of preformed CdTe QDs and magnetic Fe 3 O 4 nanocrystals inside polymer microbeads. a) TEM image of polystyrene beads simultaneously incorporated with red CdTe QDs and Fe 3 O 4 @SiO 2 particles (the scale bar corresponds to 100 nm). b–d) Three confocal fl uorescence 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 Fe 3 O 4 @SiO 2 particles. The photographs were taken in ultraviolet light before and after a per-manent magnet (0.5 T) was fi xed in between the vials. Reproduced with permission. [ 175 ] Copyright 2008, IOP Publishing.


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onto the surface of hydrophobically modifi ed silica particles incorporated with CdSe-based QDs. [ 186,187 ] The resulting struc-tures were ca. 35 nm in size, and carried an increased payload of up to 3200 Gd-DTPA-DSA units per QD particle. They exhib-ited 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. fi rst 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

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 nano-structures 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 pio-neering example of this design was reported by Holloway and co-workers. [ 196 ] CdS:Mn@ZnS QDs (3 nm) were fi rst encapsu-lated 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 intro-duce 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 photo-stable. Their ionic relaxivities r 1,Gd and r 2,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 conju-gates carrying ca. 45 Gd ions per particle showed ionic/QD particle relaxivities of 23/1019 mM −1 s −1 and 54/2438 mM −1 s −1 at 1.4 T for r 1 and r 2 , 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 cou-pling reaction between Gd-chelating ligands and the surface capping ligands of QDs such as CdSeTe@CdS, [ 198 ] CdTe@ZnS, [ 199 ] CdS, [ 200 ] and CuInS 2 @ZnS, [ 201 ] or utilizing mono-, di- or multi-dentate thiol-containing Gd-chelating ligands directly coordinating with the surface cations of QDs as dem-onstrated for InP@ZnS (Figure 3 c) [ 202,203 ] and CdSe@ZnS [ 204 ] QDs. Nevertheless, the high binding affi nity of the chelating ligand may heavily etch the QDs before it coordinates with the paramagnetic metal ions for forming the magnetic metal che-lates on the QD surface.

The conjugation of magnetic chelates onto QDs strongly depends on the coordination reaction, providing fl exibility 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 cor-related with the metal ion-proton distance. With Gd 3+ 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 Gd 3+ ions from the surface, and the chelated metal ions can suffer from leaching in vivo due to the trans-chelation induced by pro-teins. Moreover, detachment of the Gd-chelating ligands from the QD surface may lead to inaccurate (and unstable) imaging information.

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Figure 3. QDs conjugated with paramagnetic chelates. a) Schematic rep-resentation 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 RGD-sequence in a cyclic confi rmation were also conjugated to the nanopar-ticle to provide specifi city for α ν β 3 -integrin, an angiogenesis-specifi c endothelial cell surface receptor. Reproduced with permission. [ 185 ] Copy-right 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 coor-dinating with the surface cations of InP@ZnS QDs. Reproduced with permission. [ 202 ] Copyright 2011, American Chemical Society.


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Doping of the crystalline lattice of semiconductor QDs with paramagnetic transition metal ions is yet another attrac-tive approach toward fl uorescent/paramagnetic dual-modal probes. [ 205–209 ] The resulting nanostructures combine the advantages of the very small size (e.g., <5 nm), tunable and strong emission, [ 8,9,13,46,48,210,211 ] and T 1 contrast enhance-ment. [ 7,212,213 ] Their small size could favour the fast excretion of intravenously administered probes, reducing possible side effects as well as their non-specifi c retention in the major organs. [ 214,215 ] The incorporation of paramagnetic ions into the lattice of II–VI and I–III–VI QDs prevents their leaking into the surrounding medium, thus ensuring the stability of the MR signal. Different liquid phase-based chemical strate-gies for introducing paramagnetic transition metal dopants into QDs have been established. [ 206,216–226 ] These generally include co-precipitation, [ 223–225 ] organometallic precursor thermolysis, [ 218,227 ] inorganic cluster precursor thermol-ysis, [ 228,229 ] and very recently, emerging cation exchange [ 230–233 ] and cation diffusion doping techniques. [ 234 ] Following early research on Mn-doped ZnS QDs by Bhargava, [ 235 ] signifi -cant progress has been achieved in paramagnetic Mn 2+ doping of different QDs such as II–VI QDs including Zn(S,Se) [ 218,223,227,236–238 ] and Cd(S,Se), [ 208,221,229,234,239,240 ] III–V QDs including In(P,As). [ 241 ]

There are a number of synthesis parameters that can criti-cally affect the doping effi ciency and the PL QY of both dopant emission and excitonic emission of the QD host. The synthesis temperature (particularly the stages when the Mn is added and thereafter) and also the point in a multiple step synthesis when the Mn precursor is introduced, can signifi cantly affect how the Mn atoms are partitioned within the QD host struc-ture. Without such attention to detail it is even possible that the Mn dopant could be totally expelled from the host in a process known as the self-purifi cation effect. [ 206 ] However, by suitably adjusting the synthesis conditions and by choosing an

appropriate target location in the host QD the latter effect can be acceptably reduced.

Mn-doping in QDs can be achieved via three main approaches: i) Mn dopant introduction along with the host QD precursors ( Figure 4 a), [ 227,239 ] ii) before host nucleation (nuclea-tion doping) (Figure 4 b) and iii) during the shell coating pro-cess (growth doping) in either isocrystalline or heterocrystalline core@shell structured QDs (Figure 4 c). [ 216,218,242,243 ] The fi rst approach refers to the simultaneous introduction, nucleation, and growth of both dopant and host precursors in a reaction system. In particular for the latter two cases, the key challenge is to decouple the doping process from the host’s nucleation and/or growth. [ 218,242,243 ] Nucleation doping is performed with a mixed dopant and host precursor during the nucleation step. The precursor reactivities and reaction conditions (e.g., precursor ratio) can tune the concentration of dopants in the resulting nuclei. After nucleation, the reaction conditions are changed so as to make the dopant precursors inactive (par-ticipate no further in the growth), and so the overgrowth of the host becomes the only process, thus burying the dopants in the center of the QDs. In the extreme case, nuclei can be formed from pure dopant chalcogenides, followed by the over-growth of a host shell, leading to a core(dopant)/shell structure (Figure 4 b). In the growth doping approach, a host nucleus is fi rst formed and then growth quenched by lowering the reac-tion temperature. Under the new conditions, reactive dopant precursors are introduced and doping occurs in the absence of further host growth (Figure 4 c). After dopant growth, by again altering the conditions, a re-growth of the host (as an isocrystalline shell) or other semiconductor material (hetero-crystalline shell, e.g., doped CdS@ZnS) on the surface-doped nucleus is performed. The above decoupling techiques allows control over the radial distribution of the dopants and can lead to high PL QYs (>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

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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.


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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 infl uences the photolumines-cence properties of QDs. In general, in un-doped QDs, the pho-toexcited 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 pro-cess. [ 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 radia-tive recombination, exciton non-radiative trapping, and exciton-Mn 2+ ion energy transfer.

As a consequence of strong exciton-Mn 2+ energy transfer, highly effi cient Mn 2+ dopant impurity emission (Figure 4 ) can be realized for the majority of Mn 2+ doped Zn(S,Se) and Cd(S,Se) QDs. The Mn 2+ states residing within the bandgap of the host QDs give rise to a characteristic orange Mn 2+ dopant emission center at around 585 nm (ca. 2.1 eV), as determined by the radiative transition from the fi rst excited state, 4 T 1 , to the ground state 6 A 1 . [ 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 com-position (subject to the Mn 2+ excited state being bracketed by the QD bandgap). [ 227,245 ] The emission intensity strongly relies on effi cient 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 Mn 2+ ions into a QD host lattice can favor the enhancement of dopant emis-sion, 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 dimen-sions 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 photo-luminescence 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 ] CdS x Se 1- 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 un-doped cores. In the case of wide bandgap QDs such as ZnS, ZnSe, and CdS the lowest level of the Mn 2+ ligand-fi eld 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 (Mn 2+ ) level and the ground state. Doping therefore results in quenched QD excitonic pho-toluminescence whilst Mn 2+ dopant emission is effi ciently

sensitized by the host, as shown in Figure 5 a. [ 221,261 ] Since the energy of the excitonic transitions in QDs strongly depends on their size, while the energy of the Mn 2+ ligand-fi eld tran-sition 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 5 b). [ 261 ] Specifi cally for CdSe QDs, there was no Mn 2+ dopant emission for the sizes >3.3 nm, as above this diameter the lowest conduction level of the QD host fell below the Mn 2+ excited states. As a consequence of the blocked energy transfer from CdSe QD host to Mn 2+ , 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 recombina-tion channels for the QD excitons.

The inclusion of even small numbers of dopant ions per QD can introduce structural defects (and signifi cant lattice strain) if the dopant ionic radius does not fi t easily within the host lattice. The solution to this class of problem can be found, for example, by introducing a spacer between the emit-ting 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 semicon-ducting material doped with Mn 2+ ions. To date, Mn-doped ZnS shells on organic solution-grown CdSe ( Figure 6 a) [ 213,252 ] and on aqueous-grown CdTe QD cores (Figure 6 b) [ 262 ] maintaining strong excitonic emission with QYs up to 20% and 45%, respec-tively, 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 sta-bility of the QD cores.

Of critical issue is the eventual release of heavy elements such as Cd 2+ which causes such QDs [ 263,264 ] to be cytotoxic. The cytotoxicity of Cd 2+ ions is currently an unavoidable problem in

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Figure 5. Two possible relaxation mechanisms realized in the Mn 2+ -doped semiconductor QDs with a wide (a) and a narrow (b) bandgap. a) In the wide-bandgap material, effi cient energy transfer from the QD host to Mn 2+ quenches their excitonic emission and sensitizes the Mn 2+

4 T 1 → 6 A 1 emission. b) In the narrow-bandgap material, Mn 2+ 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.


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transferring these imaging probes to clinical application. Zinc chalcogenide QDs are less toxic, [ 218,243 ] but the smaller exciton Bohr radius (and wide bandgap) of these materials requires the excitation photons to have much higher energy. Apart from pro-voking optical damage to tissue, the reduced tissue penetration depth of this excitation light is a limiting factor in their bioim-aging applications. Recent attention has therefore been strongly shifted towards I–III–VI QDs, such as CuIn(S,Se) 2 as promising Cd-free candidates for in vivo applications. [ 60–64,66,70,86,265–269 ] Such QDs can be excited by incident light with wavelengths of up to 600 nm, and their emission covers a wide range from the visible to the near-infrared (NIR). PL QYs of up to 60% when coated by a ZnS shell can be achieved. In addition, their longer PL lifetimes (in the range of several hundreds of nano-seconds, as compared to several tens of nanoseconds for II–VI QDs) make them particularly appealing for visualizing cellular processes through time-gated elimination of interfering back-ground auto-fl uorescence and scattering of (pulsed) excitation light. Therefore, magnetically engineered CuIn(S,Se) 2 -based QDs hold great potential as dual-modal imaging probes with lower toxicity and suitable optical properties. We recently

reported Mn-doped CuInS 2 QDs with a Zn gradient in the CuInS 2 core and a ZnS outer shell, i.e., CuInS 2 @ZnS:Mn, where Mn ions were mainly located in the ZnS shell. [ 66 ] The ZnS shell enhanced the fl uorescence of the underlying CuInS 2 core, and prevented heavy fl uorescence quenching caused by Mn-doping.

For semiconductor shells doped with par-amagnetic ions to be utilized as T 1 contrast agents, it is crucially important to deter-mine the dopant’s location, as it strongly infl uences their relaxometric properties. Electron spin resonance (ESR) spectroscopy is a powerful tool for assessing the suc-cessful inclusion of paramagnetic ions into semiconductor lattices, and for character-izing the dopant's local chemical environ-ment. It can discriminate between dopants incorporated into the crystalline lattice, or simply attached to the surface of QDs. For Mn ions, the ground state 6 A 1 of Mn 2+ splits into six Zeeman splitting components ( m S = ±1/2, ±3/2, ±5/2) under an applied magnetic fi eld. One resonance results in a six-line hyperfi ne splitting spectrum possessing a signature of the electron-nuclear hyperfi ne coupling of Mn 2+ (electron spin S = 5/2, nuclear spin I = 5/2), which can be sensitively probed using ESR spectroscopy. The cova-lent nature of the different Mn 2+ sites can be revealed via hyperfi ne splitting, allowing Mn 2+ ions located within the nanocrystal lat-tice (on substitutional positions) to be distin-guished from Mn 2+ coordinated within other compounds or at other types of site. [ 221,270 ] Accordingly, Mn 2+ ions at surface ionic sites or sites with signifi cant lattice distortion

should show much larger hyperfi ne splitting than Mn 2+ ions on internal sites within ordered lattices. [ 221,270,271 ] Mn 2+ ions substituted for Zn 2+ and Cd 2+ on covalently bound tetrahedral sites in cubic bulk ZnS and CdTe lattices typically show hyper-fi ne splitting constants of 64 × 10 −4 cm −1 and 57 × 10 −4 cm −1 respectively. Much larger values of around 90 × 10 −4 cm −1 , con-sistent with a predominantly octahedral environment, have been identifi ed with either interstitial or surface lattice bound Mn 2+ locations. [ 272 ] For Mn-doped CdSe QDs, [ 239 ] and InP QDs, [ 271 ] hyperfi ne splitting constants of 83 × 10 −4 cm −1 and 82.5–87.6 × 10 −4 cm −1 respectively have been observed, though it has also been shown that more complex core@shell struc-tures such as CdSe@ZnS:Mn, CdTe@ZnS:Mn can substan-tially infl uence the splitting constant values. [ 213 ] In terms of deciding upon the best doping structure, it is helpful to know that Mn 2+ ions have high binding energies at the zinc blende (001) facets of II–VI nanocrystals. [ 205 ] Furthermore, since Mn 2+ ions are a better match to Zn 2+ rather than Cd 2+ in terms of ionic radii (Mn 2+ (0.80 Å), Zn 2+ (0.74 Å), Cd 2+ (0.97 Å)), then it is preferable to dope Mn 2+ ions into a ZnS shell rather than a Cd-based core. As for thinner shells (e.g., 1 or 1.5 monolayer

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Figure 6. Core-shell QDs doped with Mn ions in the shell. a) TEM images of 4.7 nm Mn-doped core@shell CdSe@Zn 1− x Mn x S QDs synthesized by an organic phase-based high temperature thermal decomposition approach, together with absorption and PL spectra for the composi-tion x = 5%, with core sizes changing from top to bottom as 8.0, 4.6, 3.8, and 3.5 nm. Repro-duced with permission. [ 213 ] Copyright 2007, American Chemical Society. b) 4.3 nm Mn-doped core@shell CdTe@ZnS:Mn QDs synthesized by an aqueous-phase-based approach (scale bar in the inset corresponds to 2 nm), together with temporal evolution of the absorption and PL spectra for different growth times. Reproduced with permission. [ 262 ] Copyright 2013, American Chemical Society.


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or even less), the splitting constant (close to 90 × 10 −4 cm −1 ) is similar to that observed for isolated Mn 2+ on the QD surface lat-tice. [ 213,262 ] This can be attributed to isolated Mn 2+ 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 pre-viously 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 hyperfi ne splitting indicates that a thicker shell provides a more ordered matrix for Mn 2+ . [ 213 ] To summarize, while ESR can not accurately determine the Mn 2+ radial location (numerically), it acts as an effective guide charac-terizing the binding nature of the Mn 2+ 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 r 1,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 CuInS 2 @ZnS:Mn. [ 66 ] The longitudinal ionic relaxivity r 1,Mn of Mn 2+ strongly depends on the tumbling time of the paramag-netic Mn 2+ 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 r 1 relaxivity. Thus, the above high r 1 values can be attributed to the slowed global tumbling time of Mn 2+ ions localized in the surface shell lattice of above shell-doped QD. This is in line with the observa-tions that the relaxivities of paramagnetic Gd chelates can be increased after conjugation onto QD surfaces as we discussed in Section 3.3.

Ionic relaxivity r 1,Mn for either CdTe@ZnS:Mn [ 262 ] or CuInS 2 @ZnS:Mn [ 66 ] QDs is inversely correlated with Mn-doping 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 neigh-boring Mn 2+ ions with increasing Mn 2+ dopant concentration. This detracts from the relaxometric properties of ‘isolated’ ions which are the largest contributor to the relaxivity enhance-ment. Interestingly and in contrast to the ionic relaxivity ( r 1,Mn ) behavior, the QD particle relaxivity ( r 1,QD ) values increased with rising dopant levels. [ 262 ] The QD particle relaxivity r 1,QD values of 4.3 nm diameter CdTe@ZnS:Mn QDs increased from 574.92 to 727.10 mM −1 s −1 upon increasing the Mn dopant concentra-tion. [ 262 ] Paramagnetic ions embedded into the ZnS shell of QD are major contributors to the relaxivity enhancement due to highly effi cient 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 Mn 2+ 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 thick-ness 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 hyper-fi ne 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 Mn 2+ doping, rare-earth elements bearing the unique magnetic and optical properties associated with f-electron energy levels (e.g., Gd 3+ , Dy 3+ , Ho 2+ , Yb 3+ , Eu 3+ , 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, signifi cant progress over the past ten years has been achieved in constructing QD-based multimodal nano-materials. 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 fl uorescence 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 -Fe 2 O 3 and CdSe@ZnS nano-particles with fi nal 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-fl uo-rescence. [ 278 ] Importantly, these multimodal probes successfully retained their optical and magnetic properties within a complex biological environment. Current research anticipates that mag-netically 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 visu-alization of tumor metastases. Furthermore, the nanoparticles can be functionalized for specifi c targeted delivery. The fol-lowing section specifi cally 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 char-acteristic of tumors, nanoparticles can be passively extrava-sated via the enhanced permeability and retention (EPR) effect. [ 279–282 ] The EPR effect can result in more than 25 times

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tissue. [ 283 ] Poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-

TPGS) copolymer co-encapsulated with Fe 3 O 4 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 fi ndings were further confi rmed by ex vivo fl uores-cence 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 sig-nifi cantly increased the background for in vivo fl uorescence imaging and limited accurate presentation of the organs.

Following our previous studies on imaging tumors in vivo with Fe 3 O 4 [ 109,112,114,116 ] and NaGdF 4 , [ 284 ] or magnetic/up-conver-sion fl uorescent NaGdF 4 :Yb,Er nanoparticles, [ 285 ] we developed a biocompatible molecular probe based on 3.6 nm PEGylated CuInS 2 @ZnS:Mn QDs with an extremely low cytotoxicity. [ 66 ] The IC 50 (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 dif-ferent 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 signifi cant fl uorescence 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 refl ect the nature of cancers as it can be taken as a metastatic model, we further studied PEGylated CuInS 2 @ZnS:Mn QD uptake in intraperitoneally inoculated tumors in mice which can mimic the metastasis of colorectal cancers. Figure 8 shows T 1 -weighted MR images acquired before and after intrave-nous nanoparticle delivery. The T 1 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 biodis-tribution 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 fl uorescence 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 clear-ance pathway. Although the tumor T 1 contrast had become very weak 24 h post-injection, the fl uorescence imaging showed that there remained a detectable optical signal from the har-vested tumor. With respect to the fl uorescence signal from the stomach, careful observation revealed that it was due to the contents of the stomach rather than accumulation of nanopar-ticles within the organ tissue itself. In addition, the above dual-modal probes are still progressing towards to their application

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 signifi cant delivery of nan-oparticles, 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 specifi city compared to passive delivery relying on the EPR of tumors.

4.2. Active Targeting of Tumors

Active targeting to enhance specifi c and effi cient delivery of probes can be achieved by covalently conjugating QDs with tumor-specifi c targeting moieties. Functional groups include small molecules (e.g., folic acid and hyaluronic acid), peptides (e.g., cyclic arginine-glycine-aspartic acid (RGD), cyclic aspar-agine-glycine-arginine (NGR), HIV-1 TAT, proteins (e.g., anti-bodies, 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 imma-ture vasculature. [ 288 ] In this context, active targeting is highly relevant for imaging and early detection.

Shi and co-workers investigated ex vivo tumors using assem-blies of CdSeTe@ZnS and Fe 3 O 4 nanoparticles (ca. 150 nm overall size). [ 180 ] The nanocarrier was capped with biodegrad-able poly(lactic- co -glycolic acid) (PLGA) and anti-prostate spe-cifi c 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-specifi c probes can effectively target LNCaP prostate cancer cells and tumors expressing PSMA. This study confi rmed preferential association with tumor tissue by ex vivo fl uorescence imaging, but unfortunately it was not extended to MRI.

Ostendorp et al. conducted in vivo MR imaging with QD-based particles targeting CD13, a protein overexpressed by angi-ogenic blood vessels. [ 190 ] Biotinylated Gd-DTPA dendrimeric wedge and CD13-specifi c cNGR peptide were simultaneously assembled onto the surface of streptavidin coated CdSe@ZnS QDs by the streptavidin-biotin interaction. The resulting cNGR-labelled 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 fi ndings 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 CdSe-based probes conjugated with α ν β 3 -specifi c RGD peptide for angiogenic targeting. [ 2,185,186,188 ] Gd-DTPA chelating lipid and PEGylated lipid were simultaneously assembled onto the hydro-phobic QDs, in order to achieve MRI contrast and biocompat-ibility, respectively. Effective targeting of tumor angiogenesis

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over-expressing integrin α ν β 3 was demonstrated for in vivo fl uorescence/MR imaging. [ 188 ] Furthermore, replacement of the PEGylated lipid and RGD peptide with macrophage-spe-cifi c high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I), resulted in the construction of a QD core/HDL-mimicking multimodality probe. [ 184 ] This was demonstrated to enable fl uorescence/MR imaging of atherosclerosis in vivo. More recently, Cd-free InP@ZnS QDs capped with PEGylated phos-pholipid 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 fl uorescence imaging further demon-strated that anti-caludin-4 antibody conjugated paramagnetic probes can target and label the Panl-1 tumor in vivo with high contrast. [ 189 ]

4.3. Toxicity Concerns

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 pharmaco-kinetics. A full understanding of degradation, excretion, per-sistence and immune response is needed. Here, we introduce some of these studies with regard to individual QD and mag-netic 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 gener-ation of reactive oxygen species and radicals during irradiation by light. [ 292,294–296 ] A number of studies showed that surface modifi cation 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 effi cient renal clearance and the elimina-tion 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 biochem-ical 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 accumula-tion 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 Ag 2 S nanocrystals will expand in vivo biomed-ical 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 profi les. 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 Gd 3+ and Mn 2+ , free Gd 3+ ions pose the risk of inducing nephrogenic system fi brosis in patients with impaired kidney function. [ 127,298 ] In addition, the release of Gd 3+ ions and Mn 2+ ions may cause toxicity by following Ca 2+ pathways, altering physiological pro-cesses. [ 102,299,300 ] For example, the Mn 2+ ion is an analog of Ca 2+ which can lead to intracellular transport and accumulation

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Figure 7. In vivo fl uorescence imaging of a tumor using PEGylated CuInS 2 @ZnS:Mn QDs. Upper frame: in vivo fl uorescence 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 CuInS 2 @ZnS:Mn QDs. Lower frame: temporal evolution of the integrated fl uorescence signals recorded from the tumor region. Reproduced with permission. [ 66 ] Copyright 2014, Elsevier.


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leading to hepatic failure, cardiac toxicity and even induce neu-rotoxicity. [ 102,301 ] Nevertheless, it has been demonstrated that association with a chelating ligand, or specifi c nanoparticle architectures can act to decrease toxicity. [ 66 ] In addition, elimi-nation pathways of the nanoparticles can be balanced by par-ticle 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 deter-mined by intricate mechanisms and is unique to each specifi c kind of QD. Additionally, toxicity has variable presentation depending on tissue type and variable meaning depending on the specifi c 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 fi eld 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 clin-ical in vivo application.

5. Conclusions and Outlook

The motivation for research into multimodal imaging probes is primarily to provide a highly effi cient platform to assist in fundamental biomedical research, imaging and clinical appli-cations. An ideal scenario for in vivo imaging would see their clinical application for highly specifi c contrast enhancement in diagnostic applications of MRI for a myriad of diseases and morbidities. The fl uorescent properties would subsequently guide and align surgery with high accuracy. The economic fea-sibility of such an approach for population screening would not currently be realistic, however, more selectively applied diagnos-tics, 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 identifi cation in MR imaging. This informa-tion would provide decision making on therapeutic or palliative courses of action. Confi dence in surgical options for excision would be facilitated by visual identifi cation of cancerous tissue, clearly delineated from healthy tissue.

With such purposes in mind, design and control over nano-particle 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 syn-thesis techniques to optimize magnetic properties while main-taining 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 reproduc-ible 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 pos-sible 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 defi nitively 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 fl uorescence 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 fi rst (NIR-I, 650–950 nm) and

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Figure 8. In vivo MR and ex vivo fl uorescence imaging of a tumor using PEGylated CuInS 2 @ZnS:Mn QDs. Upper panel: T 1 -weighted MR images acquired pre- and post intravenous injection of the PEGylated CuInS 2 @ZnS:Mn QDs into the mouse bearing intraperitoneally transplanted tumors. The tumor and kidney are color-coded to better show the con-trast enhancing effects. Left frame of the lower panel: temporal T 1 values of tumor and kidney sites. Right frame of the lower panel: ex vivo fl uor-escence 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.


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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-fl uorescence, low signal loss and thus greater signal/background ratio. Furthermore, reducing the emission full width at half maximum (FWHM) in these spec-tral 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 profi les 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 T 1 and T 2 contrast agents have different imaging abilities for different organs, QD particles integrated with dual T 1 and T 2 functionali-ties may provide further opportunities.

Reliable surface modifi cation strategies will undergo con-tinuous advancements for both imaging and theranostics with the smallest probe sizes achievable. Suitable surface coatings will promote longer blood circulation time, improve active tar-geting, conjugation and in general improve the probes’ speci-fi city and selectivity. In the context of “smart” QD-based mul-timodal probes, other functionalities will also be increasingly introduced, such as sensitive responses to pH, hypoxia, pro-tease, 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 neces-sary to achieve. There remain many challenging requirements and yet also many opportunities for further rationally balancing the optical and magnetic properties for high performance mul-timodal imaging probes.

Acknowledgements The authors acknowledge fi nancial 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: September 1, 2014

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magnetically engineered semiconductor quantum dots as multimodal imaging probes

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