Surface engineering of inorganic nanoparticles for imaging and therapy

ADR-12361; No of Pages 27 Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

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Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

Surface engineering of inorganic nanoparticles for imaging and therapy☆ Jutaek Nam a, Nayoun Won a, Jiwon Bang b, Ho Jin a, Joonhyuck Park b, Sungwook Jung b, Sanghwa Jung a, Youngrong Park a, Sungjee Kim a, b,⁎ a b

Department of Chemistry, Pohang University of Science and Technology (POSTECH), San 31, Hyojadong, Namgu, Pohang 790-784, South Korea School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), San 31, Hyojadong, Namgu, Pohang 790-784, South Korea

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 8 December 2011 Accepted 24 August 2012 Available online xxxx

Many kinds of inorganic nanoparticles (NPs) including semiconductor, metal, metal oxide, and lanthanidedoped NPs have been developed for imaging and therapy applications. Their unique optical, magnetic, and electronic properties can be tailored by controlling the composition, size, shape, and structure. Interaction of such NPs with cells and/or in vivo compartments is critically determined by the surface properties, and sophisticated control over the NP surface is essential to control their fate in biological environments. We review NP surface coating strategies using the categories of small surface ligand, polymer, and lipid. Use of small ligand molecules has the advantage of maintaining the minimal hydrodynamic (HD) size. Polymers can be advantageous in NP anchoring by combining multiple affinity groups. Encapsulation of NPs in polymers, lipids or surfactants can preserve the as-synthesized NPs. NP surface properties and reaction conditions should be carefully considered to obtain a bioconjugate that maintains the physicochemical properties of NP and functionalities of the conjugated biomolecules. We highlight how the surface properties of NPs impact their interactions with cells and in vivo compartments, especially focused on the important surface design parameters such as HD size, surface charge, and targeting. Typically, maximal cellular uptake can take place in the intermediate NP size range of 40–60 nm. Clearance of NPs from blood circulation is largely dependent on the degree of uptake by reticuloendothelial system when they are larger than 10 nm. When the HD size is below 10 nm, NPs show broad distribution over many organs. Reduction of HD size below the limit of renal barrier can achieve fast clearance of NPs. For maximal tumor accumulation, NPs should have long blood circulation time and should be large enough to prevent rapid penetration. NPs are also desired to rapidly clear out from the body after the mission before they cause toxic side effects. However, efficient clearance from the body to avoid side effects may result in the reduction in residence time required for accumulation in target tissues. Smart design of NP surface coating that can meet the conflicting demands can open a new avenue of NP applications. Surface charge and hydrophobicity need to be carefully considered for NP surface design. Positively charged NPs more adsorb on cell membranes and consequently show higher level of internalizations when compared with negatively charged or neutral NPs. NPs encounter a large variety of biomolecules in vivo, where non-specific adsorptions can potentially alter the physicochemical properties of the NPs. For optimal performance, NPs are suggested to have neutral surface charge at physiological conditions, small HD size, and minimal non-specific adsorption levels. Zwitterionic NP surface coating by small surface ligands can be a promising approach. Toxicity is one of most critical issues, where proper control of the NP surface can significantly reduce the toxicities. © 2012 Elsevier B.V. All rights reserved.

Keywords: Nanoparticle Surface Imaging Therapy Quantum dot Nanomedicine Hydrodynamic size Charge Targeting Conjugation

Contents 1. 2.

Introduction . . . . . . . . . . Inorganic nanoparticle . . . . . . 2.1. Semiconductor nanoparticle 2.2. Metal nanoparticle . . . . 2.3. Metal oxide nanoparticle .

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☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Inorganic nanoparticle platforms”. ⁎ Corresponding author at: Department of Chemistry, Pohang University of Science and Technology (POSTECH), San 31, Hyojadong, Namgu, Pohang 790-784, South Korea. Tel.: +82 54 279 2108; fax: 82 54 279 1498. E-mail addresses: [email protected] (J. Nam), [email protected] (N. Won), [email protected] (J. Bang), [email protected] (H. Jin), [email protected] (J. Park), [email protected] (S. Jung), [email protected] (S. Jung), [email protected] (Y. Park), [email protected] (S. Kim). 0169-409X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.addr.2012.08.015

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2.4. Lanthanide-doped nanoparticle Surface coatings and functionalization . 3.1. Surface ligand molecule . . . . 3.2. Polymeric coating . . . . . . . 3.3. Lipid and micelle . . . . . . . 3.4. Bioconjugation . . . . . . . . 4. Surface design for imaging and therapy 4.1. Hydrodynamic size . . . . . . 4.1.1. Cellular interaction . . 4.1.2. In vivo biodistribution . 4.2. Surface charge . . . . . . . . 4.2.1. Cellular interaction . . 4.2.2. In vivo biodistribution . 4.3. Targeting . . . . . . . . . . . 4.4. Cell labeling . . . . . . . . . 4.5. Biocompatibility and toxicity . . 5. Conclusion . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

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1. Introduction

2. Inorganic nanoparticle

Emergence of nanotechnology has offered many opportunities in various research fields across chemistry, physics, biology, and medicine. One of the research areas that has shown the most prominent progress is nanomedicine, where nanoparticle (NP)-based imaging and therapy have shown the potential for unparalleled performance over conventional tools. Particularly, inorganic NPs have received great attention because of their outstanding properties. For example, semiconductor and metal NPs have many advantages over small conventional molecules that include high molar extinction coefficient, high resistance to photo-degradation, and size/shapedependent tunable absorbance/scattering/fluorescence properties, which can be useful in various imaging and therapy applications [1–3]. Their size/shape-dependent tunable optical properties can enable on-demand design, and many inorganic NPs have been used for imaging and therapy applications [4–8]. We review representative classes of inorganic NPs in Section 2, which includes semiconductor, metal, metal oxide, and lanthanide-doped NPs. Inorganic NPs can be designed to enhance the accumulation in the site of interest when administrated in vivo. The unique size scale of inorganic NPs with much larger sizes than small molecules can enable their preferential accumulations in tumor through the enhanced permeability and retention effect [9,10]. Targeting can be also achieved by conjugating NPs with targeting molecules using their flexible surface functionalities [11–13]. For such applications, NPs need to be carefully controlled for the surface properties. Inorganic NPs often need to be rendered into aqueous solutions by modifying their surface coating [14–16]. Proper surface modification is important to retain the colloidal stability in complex biological environments. In Section 3, we provide an overview of different surface coatings for inorganic NPs as categorized by the molecules introduced; small surface ligand, polymer, and lipid. As the dimensions of inorganic NPs are comparable to the biological units such as proteins [1], interactions with biomolecules can significantly alter physicochemical properties of NPs [17,18]. Surface engineering of inorganic NPs is also critical to regulate such interactions and to design effective probes for biomedical applications. Bioconjugation strategies for the NPs will be also discussed. In Section 4, we discuss surface design of NPs for imaging and therapy. We highlight the relationship between surface properties of inorganic NPs and their interaction with cells and in vivo compartments, especially focused on the issues regarding the hydrodynamic (HD) size, surface charge, targeting, and cell labeling. Finally, we review the effect of surface design of NPs on their potential toxicity and biocompatibility issues.

Many kinds of inorganic NPs have been developed as nanoprobes for imaging and therapy applications. Their unique optical, magnetic, and electronic properties can be fine-tuned by controlling the composition, size, shape, and structure of the NPs, which allows on-demand design and utilizations. In this section, we will briefly introduce representative classes of inorganic NPs that are frequently used for imaging and therapy applications. They are semiconductor, metal, metal oxide, and lanthanide-doped NPs. Fig. 1 shows physical properties of these inorganic NPs with representative examples for their imaging and/or therapeutic applications. 2.1. Semiconductor nanoparticle Semiconductor NPs or quantum dots (QDs) are fluorescent nanocrystals with their typical size in the range of 1–10 nm. The size regime shows quantum phenomena such as atomic-like electronic structure and discrete energy levels, which results in novel optical and electronic properties that cannot be observed in bulk semiconductor materials [19–21]. Electron–hole pairs (exitons) can be generated upon optical or electronic excitation of QDs, and recombination of the exitons can result in photoluminescence (PL) emission. The optical absorption/emission properties of QDs can be tuned by their size, shape, and chemical composition. QDs can provide distinct advantages over conventional organic dyes or fluorescent proteins, which includes the large absorption coefficient, bright PL emission (~ 10–100 times brighter than that of single organic dye), narrow and symmetric emission profile, and high photochemical stability [1,11]. The high photostability and notable brightness of QDs can allow long‐term acquisition of PL emissions with a good signal‐to‐ noise ratio. This can be advantageous for cellular labeling [15,22–24], single molecular tracking [25–27] and in vivo imaging [28–31]. QDs have continuous and broad absorption spectra, which suites well for achieving simultaneous and multi-color signals by single wavelength excitation of multiple QDs that show distinctive emission bands. Their narrow and symmetric emission profiles allow effective unmixing of the PL signals. The emission wavelength regime of QD spans from UV, visible, to infrared, and thus opens a large spectral window for multiplexed imaging [24,30,31]. In early days, colloidal QDs are synthesized in aqueous solution using ionic precursors and stabilizing polymers or surfactants [32–34]. The QDs typically exhibit polydisperse distribution in size and shape and have limited crystallinity. Later, QD synthesis has been improved by using pyrolysis method at high temperature with

Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015

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organometallic precursors in organic solvents. This method produces bright and high quality QDs with controlled size and shape distribution and improved crystallinity [14,35,36]. Overgrowth of large band-gap inorganic shells onto the core QD can further enhance the PL brightness and stability. The shell layer reduces surface dangling bonds that serve as trap sites, and results in bright PL emission over an extended period [37–40]. Over the past two decades, cadmium chalcogenide QDs such as CdS [35,41], CdSe [35], CdTe [35] QDs have been extensively studied. Especially, CdSe/ZnS (core/shell) QD has been well studied for the synthesis and for biological applications among others [11]. Because of the potential toxicity concerns by the heavy metal ions such as Cd 2+, other alternative QDs that do not contain heavy metal elements have been investigated, which includes ZnTe/ZnSe (core/shell) QD [16], InP QD [15,38] and CuInS(Se)2 QD [39,42]. For bioimaging applications that demand deep tissue penetrations, near-infrared (NIR) is more advantageous for the QD emission because it provides longer tissue penetrations by the reduced photon scatterings and autofluorescence. Many NIR emitting QDs, including PbSe [40], CdTe/CdSe (core/shell) [29,43], PbS [44], and InAs QDs [45], have been developed. For example, CdTe/CdSe QDs injected intradermally into living pigs could be taken up by sentinel lymph nodes and could clearly visualize the lymph nodes in 1 cm depth in tissue [29]. Such NIR emitting QDs also pose the potential hazard from heavy metal ion contents, which may limit them from future clinical trial. Ag2S [46] QD is an alternative that is being actively studied for this NIR wavelength regime. 2.2. Metal nanoparticle Metal NPs consist of metallic elements with at least one dimension between 1 and 100 nm. As metals are abundant elements in periodic table with diverse physical properties, metal NPs can possess a variety of properties that are determined by a set of physical parameters such as composition, size, shape, and structure. Recent advances in the synthesis of metal NPs provide tools to fine-tune their optical, catalytic, electronic, and magnetic properties by controlling such parameters [47–49]. Two distinct properties of metal NPs for biomedical applications are superparamagnetism and surface plasmon resonance (SPR). When ferromagnetic NPs are reduced below to a critical size, ambient thermal energy can be sufficient to switch and randomize the magnetic spin direction, resulting in a net magnetization of zero. This behavior is called superparamagnetism. Such NPs do not have permanent magnetic moments in the absence of an external field, however they can quickly respond to an external magnetic field [50]. The critical size is dependent on the material, and is typically less than 20 nm. The transition temperature from ferromagnetism to superparamagnetism is also determined by the size of NPs. Typically, smaller NPs show lower transition temperature [50]. Superparamagnetic NPs include many single-composition metal NPs such as Co [51], Fe [52], and Ni NPs [53] and alloyed metal NPs such as FePt [54–56], CoPt [57,58], CoPt3 [59], and FeCoPt [60] NPs. These NPs have demonstrated the potential for imaging and therapy applications such as magnetic resonance imaging (MRI) and magnetic induction hyperthermia therapy [61]. SPR is a phenomenon that free electrons oscillate collectively at the interface of metal and surrounding medium in resonance with external electromagnetic fields [2]. Metal NPs can resonantly absorb and scatter incident light upon excitation of their surface plasmon oscillations. Their absorption cross-sections can be orders of magnitude larger than those of strongly absorbing organic molecules [62]. The SPR-induced strong light scattering from metal NPs can be exploited for biological imaging via dark-field optical microscopy [63–65] and by optical coherence tomography (OCT) [66–68]. The large absorption cross-section has allowed their use in photoacoustic tomography (PA) imaging [69–73] and photothermal cancer therapy [74–80].

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Metal NPs can also have large absorption coefficients for X-ray, and can be used for imaging contrast agents for computed tomography (CT) [81,82]. Metal NPs can induce strong surface-enhanced Raman scattering, which can be exploited for diagnosis or imaging applications [83–85]. Noble metal NPs have attracted great interest for such applications because they have pronounced SPR effect that can be easily tuned by their size, shape, and structure via flexible synthetic routes [86–89]. For example, SPR characteristics of spherical gold NPs are typically limited in the visible wavelength region. However, the SPR characteristics can be easily shifted to NIR region by switching the gold nanostructures to nanorod, nanoshell, or nanocage [69,71–78]. These SPR characteristics in NIR region can be advantageous for biomedical applications that demand deep tissue penetrations. In some cases, metal NPs can have PL that can be used for imaging applications. Metal clusters that consist of tens of atoms with the diameter smaller than ~ 2 nm can often show PL properties from discrete and size-tunable electronic transitions [90]. This kind of PL emission from metal nanoclusters can be tuned by their composition and size [91,92]. Metal NPs can also exhibit PL properties by multiphoton excitations. For example, two-photon luminescence of gold NRs has successfully demonstrated the potential for imaging contrast agents [93,94]. 2.3. Metal oxide nanoparticle Metal oxides exhibit a wide variety of structures, properties, and phenomena. Transition metal oxides have been used in many important technology areas, including magnetic ferrites, ferroelectric oxides (barium strontium titanate (BST), lead zirconate titanate (PZT)), superconductors (YBa2Cu3O7 − x), ionic conductors (yittria-stabilized zirconia (YSZ)), phosphors, and photocatalysts (TiO2). Among them, we will focus on magnetic metal oxides for biomedical applications such as MRI and magnetic induction hyperthermia. Typically magnetic oxide NPs show the critical size typically around 10–20 nm which is dependent on the material. In this size regime, each NP becomes a single magnetic domain and shows superparamagnetic behavior when the ambient temperature is above the so-called blocking temperature. Such NP can have a large magnetic moment and can behave like a giant paramagnetic atom showing a fast response against applied magnetic fields with negligible remanence (residual magnetism) and coercitivity (the field required to bring the magnetization to zero). These features make the superparamagnetic metal oxide NPs very attractive for a broad range of biomedical applications because they do not easily form agglomerations at room temperature. Before one can utilize the magnetic metal oxide NPs for MR signal contrast agents, synthesis of high-quality NPs is desired in terms of the size, crystalline phase, and stoichiometry. Many publications have described efficient synthetic routes to shape-controlled, highly stable, and monodisperse NPs. Iron oxide NPs (Fe2O3, Fe3O4) are one of the most well studied metal oxide NP systems, for which many synthetic routes have been developed such as co-precipitation, thermal decomposition and/or reduction, micelle synthesis, and hydrothermal synthesis [95–97]. These synthetic procedures can be applied to the preparations of other metal oxide NPs including cobalt oxide (CoO and Co3O4) [98], NiO [99], MnO [100], metal ferrites (NiFe2O4, MgFeO4, MnFeO4 and CoFe2O4) [101–103] and magnetically doped aluminum oxide (CoAl2O3, CuAl2O3 and NiAl2O3) NPs [104]. MRI has been a powerful medical diagnostic tool due to its noninvasive nature and multidimensional tomographic capability with a relatively high spatial resolution, however its low-signal sensitivity has been problematic. Iron-oxide-based magnetic NPs (e.g., superparamagnetic iron oxide (SPIO) and its related systems) have been widely explored for MRI signal-enhancing applications [102,105–109]. Magnetic NPs can modulate T2 relaxation time of nearby water molecules, and can contrast the T2-weighted MRI images. Another

Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015

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interesting application by magnetic NPs is for hyperthermia treatments [110–112]. When magnetic NPs are exposed to a varying magnetic field, heat can be generated by the magnetic hysteresis loss, Néel-relaxation, and Brown-relaxation. As the result, magnetic NPs can be a powerful local heat source that can destroy tumor cells [113].

Nanoparticle (NP) Semiconductor NP

Metal NP

2.4. Lanthanide-doped nanoparticle Lanthanide-doped NP consists of host material and one or several kinds of lanthanide ions which replace the original ions in the host material. They can have PL and/or paramagnetic properties, according

Properties of NP Electron-hole pair

Surface plasmon resonance

Applications

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Metal oxide NP Magnetic Resonance

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i)

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Lanthanidedoped NP

Upconversion

n)

p)

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q)

Magnetic Resonance

Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015

J. Nam et al. / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

to the kinds of doped lanthanide ions. Especially, upconversion luminescence, emission of shorter wavelength than the excitation light, can be easily achieved using lanthanide-doped NPs [114]. Upconversion luminescence is advantageous for imaging applications because of the deep tissue penetration by the excitation at longer wavelengths and absence of auto-fluorescence [114–116]. Upconversion luminescence can also exhibit narrow emission bandwidth, resistance against photobleaching, non-blinking emission, and long emission lifetime [117–119]. Upconversion NPs can adopt ytterbium ions as a sensitizer that can absorb NIR light around 975 nm and erbium (III), thulium (III), europium (III), or holium (III) ions as an activator [115,116,120]. The activators have the energy states that match well for the energy transfers in the upconversion process. The roles of host materials include isolating doped ions from outer environment and facilitating efficient energy transfers between lanthanide ions. Optimal host materials should have low lattice phonon energy, high chemical stability, and high transparency. NaYF4 has been widely used as a host material because it can achieve the highest reported quantum efficiency for upconversion luminescence [120–124]. Other fluoride-based materials such as LaF3 [125], LiYF4 [126], NaYbF4 [127], and oxide-based materials such as CeO2 [128] and YVO4 [129] have also been studied. Paramagnetic ions such as gadolinium (Gd) can be used for the NP dopant for MRI applications [130–132]. The confined Gd ion can have higher magnetic resonant relaxitivities than those of individual metal-chelate compounds because of the slower tumbling rate and higher payload of magnetic centers [132]. Multifunctional probes for MRI and optical imaging have also been studied [133–137]. For example, NaYF4:Tm 3+/NaGdF4 core/shell NP can be used as a dual imaging probe by utilizing the NIR emission from thulium (Tm) ions and MRI contrast from Gd ions [137]. This dual imaging modality can provide rich biological information by combining the high sensitivity of optical imaging and the high resolution power of MRI. Lanthanide-doped NPs are considered relatively biocompatible as toxicity levels of the host material elements and the lanthanide ions are relatively low [138,139].

3. Surface coatings and functionalization Syntheses of inorganic NPs can be performed in aqueous or in organic phase. Pyrolysis method in organic solvent typically yields high-quality NPs because it allows higher reaction temperature. However, the resultant NPs often demand surface-modifications to obtain colloidal stability in biological media and/or to functionalize the surface for biomedical applications. Many strategies have been developed for the surface-modifications, and they can be categorized by the molecules they introduce; small surface ligand, polymer, and lipid. In this section, we will discuss the surface coating and functionalization of inorganic NPs mainly focused on the cases of QDs. Many QDs are prepared in organic solvents, and phase-transfers of QDs to aqueous solutions with desired functional groups have been extensively studied. The strategies developed for QDs are generally applicable to other inorganic NPs as well. Representative strategies for NP bioconjugations will also be discussed.

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3.1. Surface ligand molecule Use of small ligand molecules that can replace initial assynthesized surface coating has been a popular strategy for NP surface modification. This strategy has the advantage of maintaining the minimal hydrodynamic hydrodynamic (HD) size. These surface ligand molecules usually have two feature parts of anchoring and functional groups. The former anchors the ligand onto the surface of NPs with high affinity, while the latter endows colloidal stability and functional groups for further conjugations. The choice of anchoring group depends on the composition of NPs because of their unique chemical interactions with specific atoms or crystal facets. For example, QDs and noble metal NPs have the surfaces that bind with thiols, disulfides, phosphines, and amines [11,140]. On the other hand, metal oxide NP surfaces typically bind with phosphonic acids and carboxylic acids [141]. Particularly, many kinds of thiols have been used for QDs and noble metal NPs because of their strong binding affinity. Simple monothiolate molecules were the first to replace initial surface coating of QDs and to achieve colloidal stability in aqueous media. Nie et al. reported simple ligand exchange of QDs with mercaptoacetic acid for biological applications [23]. The exchange method is simple and effective, however it poses problems such as easy detachment of the surface ligands as the result of dynamic interactions with NP surfaces and oxidations [142]. The loss of surface ligands by detachment causes NP aggregations as NPs suffer from the colloidal instability. Multidentate thiolated molecules have also been developed to further increase the stability. Dithiolated molecules can anchor onto NP surfaces in a stronger fashion and can provide NPs with long-term colloidal stability, and dihydrolipoic acid (DHLA) and its derivatives have been most widely studied [143,144]. Tetradentate thiols, bis(DHLA)-PEG-OCH3, have also been reported as providing excellent colloidal stability to QDs and Au NPs in various conditions [145]. Dithiocarbamate shows very strong binding to QD surfaces, however it often results in etching of QDs which accompanies spectral shifts in QD optical properties and reduction in the PL quantum yield [146,147]. Metal-affinity coordination has also been adopted for anchoring of small surface ligands onto QD surfaces. Hexahistidine motif (His6-tags) exhibits strong binding on Cd and Zn rich QD surfaces by the imidazole moiety anchoring, and can allow facile conjugations with peptides, dyes, DNA or proteins [148–151]. The polyimidazole shows effective QD binding by its multidentate anchoring effect. Liu et al. have shown that imidazolebased copolymer ligands with controlled chain length can be prepared by using RAFT (radical addition-fragmentation chain transfer)mediated synthesis [152]. The polyimidazole polymers can provide QDs with good colloidal stability in a wide pH range (pH 5–10.5), compact HD size (b 10 nm), and high PL quantum yield (>50%). Such polyimidazoles can be advantageous over thiolate molecules because they are less susceptible to oxidation. Development of effective anchoring groups that can strongly bind to inorganic NPs for an extended period without altering the NP's physicochemical properties is in constant pursuit for better NP surface coating. Functional group part of NP surface ligands dictates many properties of NPs, including colloidal stability, adsorption, and conjugation

Fig. 1. Properties and applications of inorganic NPs. a) Fluorescence imaging of mouse 3T3 fibroblast cells using quantum dots (QDs) [22]. b) Multiplexed fluorescence image depicting five-color QD staining of fixed human epithelial cells [11]. c) Fluorescence imaging for detecting human prostate cancer with targeted QDs [30]. d) Multiplexed fluorescence imaging of five different lymph nodes using five different QDs [31]. e) Three-dimensional (3-D) OCT view of sentinel lymph nodes morphology with poly(ethyleneglycol)-coated gold nanorods (PEGylated NRs) [68]. f) 3-D CT angiogram image of the heart and great vessels with PEGylated gold NPs [81]. g) Photoacoustic imaging for detection of human melanoma with targeted gold nanocages [202]. h) Surface-enhanced Raman spectra for the detection of human squamous cell carcinoma using targeted gold NPs [83]. i) Photothermal therapy of tumor-bearing mice using PEGylated gold NRs [78]. j) Magnetic resonance (MR) detection of human breast cancer cells without (a) and with (b) targeted iron oxide NPs [107]. k) MR imaging of human colon tumor using targeted iron oxide NPs [108]. l) MR images of a metastatic lymph node before (a) and after (b) administration of iron oxide NPs [109]. m) Magnetic hyperthermia treatments of tumor-bearing mice using superparamagnetic CoFe2O4@MnFe2O4 NP (core–shell NP) [113]. n) Upconverted luminescence imaging of NIH 3T3 murine fibroblast cells with NaYF4:Yb3+/Er3+ NPs [118]. o) In vivo multiplexed photoluminescence imaging of mouse obtained by simultaneously using NaYF4:Yb3+/Tm3+ NP (La NP) and QD (QD800) [115]. p) T1-weighted MR images of human breast cancer cells with NaGdF4:Yb3+/Er3+ NPs [136]. q) Color-mapped MR images of a mouse with Tm3+/Er3+/Yb3+ co-doped NaGdF4 NPs [134]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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polymers have many chains that can guarantee the colloidal stability of NPs via electrostatic or steric dispersion. Polymers can allow multiple interactions with NP surface or with initial NP surface coating, and can sustain strong anchoring to NPs. Examples of the polymers used for NP surface coating are listed in Tables 1 and 2 with the typical physicochemical properties of the resultant NPs. Table 1 lists the representative examples of the exchange strategy, and Table 2 shows the cases of the encapsulation strategy. Thiols have been widely used for an anchoring unit to NPs, however they sometimes lack long-term stability and cause alteration in the NP properties [142,160]. Aldana et al. have shown that photochemical instabilities of thiol-coated QDs are closely related to the diffusion of oxygen species from the bulk solution onto the interface between the QD surface and surface coating layer, which results in photooxidations of the thiols [161]. Dense packing of NP surface coating can improve the anchoring stability of thiols. Wang et al. have designed organic dendron ligands with thiols that can provide a closely packed thin ligand shell on the surface of QDs and Au NPs [162]. Dendron surface-coated CdSe QDs have maintained the colloidal stability up to 40 h under UV illumination, while QDs coated with small monothiol ligands lost the stability within a few hours. When the dendron ligands were cross-linked, the stability of QDs could be further improved against chemical, photochemical, and thermal treatments [163]. Polymers with relatively weak anchoring moieties can be another alternative to the thiol-based polymers because they can reduce the risk of deteriorating the NP properties while providing overall strong binding ability by the multidentate anchoring. Polyethylenimine (PEI) can exchange initial surface coating of QDs using the amine groups for anchoring, and PEG moieties can be conjugated to the PEI polymers for colloidal stability in buffer solutions and in cell culture media [164,165]. Wang et al. have reported poly(N, N-dimethylaminoethyl methacrylate) for NP surface coating, where the tertiary amines in the polymer were used for the NP anchoring [166]. Smith and Nie suggested tri-block copolymers, poly(acrylic acid) conjugated with thiols and amines, for the QD surface coating by exchange strategy [167]. The resultant QDs showed the HD size below 10 nm, PL quantum yield about 50%, and colloidal stability for over 6 months. Phosphines passivate QDs effectively as a major component of the growth ligands. However, monomeric phosphines are labile, and a considerable concentration of free phosphines is required in solution to keep the QDs well passivated. Kim et al. proposed oligomeric phosphines for QD surface coating which can yield more stable QDs in aqueous media as preserving the optical properties than the cases of thiolate surface ligand or monomeric phosphine [168]. This result clearly shows that weaker anchoring moieties can be more effective for surface modifications when they are multiply combined as a polymeric form. Kim et al. showed that polymers that contain phosphine oxide and PEG can be extensively used for surface coating of various NPs including Au, Pd, Fe2O3, and QD NPs [169]. Amphiphilic polymers are typically used for NP surface coating by encapsulation. Hydrophobic chains of the polymer surround NPs as typically intercalating into the hydrophobic initial surface coating of NPs, while the hydrophilic part provides water solubility and

capability. Carboxylic acids have been most widely used for the functional group part because they can provide NPs with colloidal stability by the charge repulsion and flexible conjugation sites [23,143]. However, carboxylic acids sometimes show limited colloidal stability for NPs because their charge repulsion can be limited by pH or ionic strength. Strongly charged surface molecules with quaternary amine, tertiary amine, or sulfonic acid can overcome the limitation and can show robust colloidal stability over broad pH and ionic strength ranges [153]. Functional groups that are relatively large in size and neutral in charge can be also used for NP surface coatings. Poly(ethylene glycol) (PEG) has been widely studied for NP surface coating as colloidally stabilizing the NPs in aqueous media by steric stabilization [144,152,154]. Similarly, dextran coating has also been demonstrated to preserve the optical properties and colloidal stability of NPs [155]. PEG and dextran have been extensively used for biomedical applications, and their excellent properties such as anti-fouling can be transferred to NPs by the surface coating. However, this comes with the cost of large increase in the HD size. HD size of NPs with PEG surface coating typically approaches the size of proteins. Adding large HD size to NPs can limit the accessibility of NPs in confined cellular compartments in vitro and biodistribution/renal clearance pathways in vivo. Surface ligand molecules with zwitterionic functional groups can be a candidate to overcome the problem. Zwitterionic functional group can provide NPs with overall neutral surface charge and can endow high colloidal stability in aqueous media. DHLA-derivatives that contain zwitterionic functional groups have shown very high QD colloidal stability regardless of the pH or ionic strength [156–158]. The zwitterionic surface coating can be very compact with the ligand HD thickness less than 2 nm, and can minimize non-specific adsorptions [156]. Park et al. have shown that even partial coverage of zwitterionic surface coating on QDs (e.g., mixed surface coating with 50% zwitterionic surface and the other 50% surface coating with other functional groups such as carboxylic acids or primary amines) can retain the advantages of purely zwitterionic QD surface coating in terms of the colloidal stability and non-specific adsorption level. This can allow further conjugations for highly specific targeting while retaining the advantages of the zwitterionic surface [156]. 3.2. Polymeric coating Polymer-based surface modification of inorganic NPs can be categorized into two strategies of exchange and encapsulation methods [159]. For the exchange strategy, polymers are replacing the initial NP surface coating and directly attach to the NP surface. This strategy is similar to the cases of small surface ligands except that the introducing NP surface coating is composed of polymers. For the encapsulation strategy, amphiphilic polymers are typically exploited. The polymers encapsulate NPs via hydrophobic interactions between hydrophobic portion of the polymer chains and initial hydrophobic surface coating of NPs. Hydrophilic portion of the polymer chains faces the aqueous media, and renders the NPs soluble in aqueous media. This approach keeps the initial surface coating of NPs and can be more effective in preserving the physicochemical properties of as-synthesized NPs. Both strategies can achieve improved colloidal stability when compared with small molecules or lipids because

Table 1 Examples of polymers used for inorganic NP exchange method and their physicochemical properties of the resultant NPs. Surface anchoring groups

Ligands

Polymer M.W. (kDa)

Nanoparticle

HD size (nm)

Q. Y. (%)

Ref.

Amine

Branched poly(ethyleneimine) Polyethylene glycol grafted polyethyleneimine Poly(ethylene oxide)–polyethylenimine Poly(N,N-dimethylaminoethyl methacrylate)

0.8 and 25 10 2, 5 7–35

Oligomeric phosphine ligand

1–2

10–20 21–22 10–40 2.7–6.3 N.A. N.A.

N.A. 60 20 1–10 18–46 20–40

[308] [164] [165] [166]

Phosphine

CdSe/ZnS QD CdSe/CdS/ZnS QD CdSe/CdS QD CdSe QD CdSe/ZnS QD CdSe/ZnS QD

[168]

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Table 2 Examples of polymers used for inorganic NP encapsulation method and their physicochemical properties of the resultant NPs. Hydrophilic back bone

Hydrophobic chain

Polymer M.W. (kDa)

Nanoparticle

HD size (nm)

Q. Y. (%)

Ref.

Poly(acrylic acid)–PEG Poly(acrylic acid) Poly(maleic anhydride)–PEG Poly(maleic anhydride) cross-linked by bis(6-aminohexyl)amine Poly(maleic anhydride) Poly(maleic anhydride)–dimethylamino propylamine

Polybutylacrylate and polyethylacrylate Alkylamine (octyl, dodecyl, hexadecyl, octadecyl) 1-octadecene 1-tetradecene

100 2 30–50 7.3 1.7 18.5

N.A. ~17 24–46 19–24 N.A. 13–18 ~12

N.A. 15–45% 35–55% N.A. N.A. N.A. N.A.

[30] [170] [172] [174]

styrene 1-decene

CdSe/ZnS QD CdSe/ZnS QD CdSe/CdS/ZnS QD CdSe/ZnS CoPt3, Au, Fe2O3 CdSe/ZnS QD CdSe QD

determines the surface properties. Poly(acrylic acid) (PAA) derivatives such as alkyl acrylate derivatives have been used for the amphiphilic polymer NP surface coating [170]. Derivatized alkyl chains in the polymers were intercalated with hydrophobic initial NP surface coating, which resulted in the stable encapsulation. The underivatized carboxylic acids in the PAA polymer could be further used for conjugation. Conjugation of PEG to the polymer could further improve the biocompatibility and blood circulation [30]. Wu et al. have shown that PAA derivative surface coated NPs can be further conjugated with biomolecules, which was successfully utilized to label various targets at a sub-cellular level [171]. Maleic anhydride-based polymers have also been exploited for the encapsulation of NPs. Yu et al. have demonstrated the encapsulation of hydrophobic NPs using poly(maleic anhydride-alt-1-octadecene) [172]. The maleic anhydride groups in the polymer turn into carboxylic acids after the phase transfer into aqueous solutions and provide colloidal solubility to NPs, while octadecene moieties intercalate with the initial NP surface coating. The maleic anhydrides can be easily modified with various molecules that contain amines or hydroxyl groups, which can be advantageous for functionalization and bioconjugation [173]. Pellegrino et al. have encapsulated various NPs such as CoPt3, Au, CdSe/ZnS, and Fe2O3 NPs using poly(maleic anhydride alt-1tetradecene) and further stabilized the NPs by crosslinking the maleic

[175] [173]

anhydrides with bis(6-aminohexyl)amines [174]. Though the polymer encapsulation can easily preserve the optical properties of as-synthesized NPs and can provide long-term colloidal stability in aqueous media, it suffers from undesired large increase in the HD size of the NPs. For example, HD size of QDs after encapsulation with polymers exceeds 10 nm even when low molecular weight polymers with less than ten repeating units are used [175]. This large HD size may restrict their biological applications because the large HD size can cause significant effect on their intracellular trafficking and in vivo biodistribution. 3.3. Lipid and micelle Lipids can surface-coat inorganic NPs by forming lipid bilayer which is similar to the cell membrane bilayer structure [176]. NPs can be encapsulated by lipids through interdigitation of the hydrophobic tails with the hydrophobic initial NP surface coating, while hydrophilic head groups face outside and provide the colloidal stability in aqueous media. Encapsulation of NPs in micelles of lipids or surfactants can preserve the optical properties of as-synthesized NPs and can prevent oxidative deterioration of the initial surface coating. Facile functionalization of NPs can be achieved by modifying the surfactants or lipids with various terminal groups. Dubertret et al.

Fig. 2. Scheme for the formation of lipid encapsulated NPs by lipid film hydration method (a) and microemulsion method (b).

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have demonstrated that QDs can be efficiently encapsulated by functionalized phospholipid micelles [177,178]. Lipid film hydration method was used for the NP surface coating, in which QDs and phospholipids were mixed in chloroform which was followed by evaporation of the chloroform and addition of water to the heated mixture (Fig. 2a). The micelles are composed of a mixture of PEGphosphatidylethanolamine (PEG-PE) and phosphatidylcholine (PC). They can effectively encapsulate single QDs and showed enhanced colloidal stability over PC or PE. The phospholipid micelles retain optical properties of the QDs without altering the initial NP surface coating, and PEG on their outer surface can minimize non-specific interactions with biomolecules. By replacing a part of PEG-PE phospholipids with an amino-PEG-PE during the micelle formation, functional molecules such as targeting peptides can be conjugated to the QDs [177,179,180]. Travert-Branger et al. have used oligomerized amphiphilic PEG-phospholipids for QD surface coating by encapsulation, which showed enhanced stability [181].

Surfactants can also effectively form micelles and have been widely used to encapsulate various inorganic NPs. Brinker group developed a simple microemulsion procedure to incorporate hydrophobic gold NPs into the hydrophobic interiors of surfactant micelles (Fig. 2b) [182]. An aqueous solution of surfactant is added to the NPs in organic solvent. Oil-in-water microemulsion is created under vigorous stirring, and evaporation of the organic solvent promotes the transfer of the NPs into the aqueous phase. Cationic, anionic, and non-ionic surfactants can all form NP micelles, allowing facile control of micelle surface charge and functionality. This technique was extended to the synthesis of water-soluble, biocompatible QD micelles [183]. Swami et al. have transferred dodecylamine-capped gold NPs from an organic solvent layer to aqueous layer using a cationic surfactant, cetyltrimethylammonium bromide [184]. The cationic surfactants can form interdigitated bilayer with hydrophobic initial surface coating of gold NPs via hydrophobic interactions. The resultant NPs can be dispersed in water, showing good colloidal stability

Table 3 Representative bioconjugation chemistry of inorganic NPs. Reaction

Schematic drawing

Covalent conjugation Carbodiimide chemistry

Michael addition

Click chemistry (azide-alkyne cycloaddition)

Diels–Alder cycloaddition (cycloalkane–tetrazine cycloaddition)

Hydrazone ligation

Non-covalent conjugation

Electrostatic conjugation

Metal-affinity coordination

Biotin–avidin interaction

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even in high ionic strength and over a wide pH range. This method has also been applied to the surface coating of lanthanide-doped NaYF4 NPs and QDs [115,121,185]. 3.4. Bioconjugation For many biological applications, inorganic NPs need to be further conjugated with biomolecules such as antibodies, oligonucleotides, or small molecules. The demand for bioconjugation is regardless of the surface modification strategy or the type of surface coating. For the conjugations, both covalent and non-covalent interactions have been used. The covalent interactions include carbodiimide coupling, Michael addition, cycloaddition, and hydrazone ligation, and the non-covalent interactions include electrostatic conjugation, metalaffinity coordination and biotin–avidin interaction (Table 3). Stable NP bioconjugates can be achieved by using covalent coupling methods that exploit several chemical reactions. Utilization of endogenous functional groups in biomolecules, such as carboxylic acid, amines, or thiols is common for bioconjugation. For example, carbodiimide chemistry, typically using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), has been a very popular strategy, which covalently crosslinks carboxylic acid with amine [23,156,157]. Michael addition has also been widely used for the bioconjugation between maleimides on NP surface and thiols in biomolecules [28,186,187]. Alternatively, biomolecules can be engineered to have specific functional groups for coupling reactions. Click chemistry, an azide-alkyne cycloaddition each of which is not displayed by biomolecules, can be used for a bio-orthogonal conjugation method [188,189]. This bio-orthogonal coupling can be achieved in a facile, selective, and efficient way even in complex biological environments. For example, inverse-electrondemand Diels–Alder cycloaddition between cycloalkene and tetrazine was exploited for in situ bio-orthogonal conjugation, in which NPs and biomolecules were conjugated on the surfaces or within cytosols of live cells [190–192]. Hydrozone or oxime ligation reactions between

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aromatic aldehyde and either 6-hydrazinopyridine or aminooxyacetyl group can form stable covalent linkage with high reaction rate and conversion yield when aniline is used as the catalyst [193]. Blanco-Canosa et al. reported that the product of hydrazone ligation reaction between 4-formylbenzoyl and 2-hydrazinonicotinoyl group had a unique optical signature at 354 nm, which enabled the monitoring and direct quantification of the conjugation process [194]. Non-covalent interactions have also been widely exploited for NP bioconjugations. Electrostatic interactions can afford to produce bioconjugates with good colloidal stability and target specificity. Mattoussi et al. attached engineered recombinant proteins that contain positively charged domains in the Fc region with negatively charged QDs using electrostatic interaction, and showed that the biological activity of proteins can be effectively preserved after the conjugation [143]. Bhang and Won et al. have shown that hyaluronic acid (HA), a highly negatively charged polysaccharide, can form stable conjugates with positively charged QDs via multiple electrostatic attraction [195]. The HA–QD conjugates retained the PL emission properties of QDs, and successfully visualized lymphatic vessels (Fig. 3). Coupling by electrostatic attraction is a simple and facile conjugation method as it does not require additional chemical reagents or catalysts. However, the conjugates are generally considered to be less stable than those by covalent crosslinking because of the possible decoupling when their charges are shielded, for example, under high salt environments. Metal-affinity coordination can be used to produce stable NP conjugates. Boeneman et al. have reported the intracellular bioconjugation of His6-tagged proteins with carboxylate terminated QDs, in which nickel ions (Ni 2 +) coordinated to both by chelations and mediated the bindings [196]. Utilization of biotin–avidin interaction is another popular strategy for a highly stable non-covalent bioconjugation. For example, streptavidincoated NPs can be conjugated with many biotinylated antibodies or biotinylated polymers by the strong biotin–avidin motif interaction [24,25,171,197].

Fig. 3. Fluorescence (top) and transmission (bottom) microscope images of mice ears after subcutaneous injection of HA–QD conjugate (left) and unconjugated QD (right), respectively. Lymphatic vessels are clearly visualized by the HA–QD conjugates [195].

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In addition to the conjugation chemistry, there are a few more things that need to be considered for NP bioconjugation. For example, the bioconjugation may affect the activity of the biomolecule in the resultant conjugate [198]. Carbodiimide chemistry is widely used for NP antibody conjugations because most antibodies have many primary amines and carboxylic acids. However, the abundance of conjugation sites may result in random attachments of the antibodies on NP surface. Antigen binding sites can be blocked by non-selective formation of amide bonds at the vicinity of active Fab region, which should result in poor targeting efficiency. Michael addition can be more sitespecific because accessibility of thiol group is rare in native antibodies and is mostly placed in the Fc region [199]. In general, NP surface properties and reaction conditions should be carefully considered for any NP conjugation to obtain a bioconjugate that maintains the physicochemical properties of NP and functionalities of the conjugated biomolecules.

4. Surface design for imaging and therapy Surface property mainly dictates the interactions of NPs with external environments because core NP itself is passivated inside by the surface coating. Proper surface design of NP is crucial to fully exploit the NPs for desired biological applications. In this section, we will discuss some important surface design parameters such as HD size, surface charge, and targeting, as focused on their effects on the cellular and in vivo interactions (Fig. 4). NP surface design for cellular labeling will also be addressed. For in vivo applications and clinical translations, toxicity of NP is a major concern. The issue of NP surface design for minimum potential toxicity will be also dealt with.

Fig. 4. Surface properties of NPs, such as HD size, surface charge, and targeting critically affect their interactions with cells and in vivo compartments. The sophisticated control over the NP surface is essential to control their fate in biological environments.

4.1. Hydrodynamic size Inorganic NPs can have various HD sizes by the surface coating as well as the NP core size. Particularly, the choice of surface coating can greatly affect the HD size. For example, polymeric coating typically results in larger HD size of identical NPs than the cases of surface ligand molecule or lipid surface coating. HD size is a critical design parameter for the development of imaging and therapeutic agent because it can largely affect the cellular interaction, in vivo circulation, and tissue permeation. We will focus on cellular interactions of NPs by the HD size, which will be followed by the interactions in vivo. 4.1.1. Cellular interaction Cells can internalize small molecules, such as oxygen, amino acid, sugars and ions through membrane diffusion or via membrane protein channels. However, NPs and macromolecules larger than a few nanometers in size are generally considered as not being able to pass through the membranes by diffusion and should be mediated by the membrane-bound vesicles that trigger NPs to enter the cells via a series of process termed endocytosis [200]. Endocytosis is a process by which cells capture extracellular molecules in vesicles derived from the plasma membrane and occurs by multiple mechanisms that fall into two broad categories of phagocytosis and pinocytosis (Fig. 5). Phagocytosis is the uptake of large pathogen such as yeast or bacteria by specialized cells such as macrophages and neutrophils. Pinocytosis occurs in most cells and has at least four basic mechanisms: macropinocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, and clathrin- and caveolae-independent endocytosis. Macropinocytosis is an actin-based process that allows the large particles to enter the cells by large vesicle over 1 μm. Other putative pinocytosis mechanisms are classified by the protein that involves with the vesicle formation. Clathrin-mediated endocytosis is known to be a major route of endocytosis that clathrin assists the formation of the coated pit. Caveolea-mediated endocytosis is the uptake through plasma membrane invagination, caveolae that consists of cholesterol, fatty acid, and inserted caveolin protein. Clathrin-, caveolea-independent endocytosis mechanisms have reported, but remain poorly understood. Inorganic NPs with broad size ranges from a few to several hundred nanometers enter cells through endocytosis [15,79,115,156,195,201]. Although endocytotic uptake is general for a broad range of NPs, its efficiency is largely dependent on the HD size of the NPs. Several groups have demonstrated the optimal size for efficient cellular uptake of NPs. Chithrani et al. reported the relationship between the particle size and cellular uptake of gold NPs using various cell lines [202,203]. Among the particles with 10–100 nm in diameters, 50 nm shows the largest cellular accumulation, indicating an optimal size for efficient NP uptake into cells (Fig. 6). They have also investigated the relationship between the size and cellular uptake/removal of NPs. The amounts of NPs in cells measured at a certain time point represent dynamic processes where removal and uptake of NPs are reaching an equilibrium. It was found that the uptake rate is highest for 50 nm-sized NPs whereas the removal rate is faster for the smaller NPs. 50 nm gold NPs showed the largest cell uptake as the result of balance between the fastest endocytosis and moderate exocytosis rate. Similarly, Osaki et al. demonstrated that 50 nm-sized artificial glycovirus which was composed by plasmid DNA and micellar glycocluster particles entered HeLa cells more efficiently than 5 nm-sized micellar glycocluster compartments or 15 nm-sized QD conjugated sugar balls [204]. It is claimed that endocytosis is highly size-dependent with enhanced uptake as increasing particle size within 5–50 nm range. Wang et al. showed the optimal size of gold NP for efficient cellular uptake to be around 45 nm, and the cellular uptake becomes smaller as increasing the particle size from 45 to 110 nm [205]. Many factors, such as NP ligand density, membrane adhesion areas, membrane stretching and bending may be involved in the size-dependent uptake of NPs [206–209]. However, the cellular

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Fig. 5. Schematic illustration of major endocytic pathways [200].

uptake efficacy can be simply explained by the balance between thermodynamic driving force for wrapping and the receptor diffusion kinetics [202,203]. From the view point of receptor-mediated endocytosis, wrapping of NPs by membrane is driven by chemical energy that is released through ligand–receptor interactions. This wrapping is a key step for endocytosis of NPs, and it accompanies elastic deformation of the membrane which acts as thermodynamic barrier for endocytosis [207]. Small NPs have fewer ligands for interaction with membrane receptors, and adsorption of NPs may not produce enough energy to completely wrap the NP on the surface. They may dissociate from the receptors before being engulfed by the membrane as the result of low binding affinity. In contrast, larger NPs can present multivalent binding with membrane receptors due to the larger surface area and larger

number of ligands, which can produce sufficient energy for the membrane wrapping. However, such interactions use a large number of membrane receptors, which may cause receptor depletion nearby the area of the NPs. This can preclude endocytosis of forthcoming NPs by limiting the receptor diffusion kinetics. It seems that the maximal cellular uptake can take place in the intermediate size range of 40–60 nm where the ligand–receptor interaction and the membrane receptor depletion can be reasonably balanced. Although it has shown that small NPs may not be optimal for cellular uptake, engineered surface coating of NP can increase the cellular accumulation. Nam et al. has reported a 10 nm-sized “smart” gold NP that is designed to aggregate in mild acidic intracellular environments by its pH-responsive charge-converting surface [79]. This surface engineering resulted in the NP aggregations

Fig. 6. Uptake of gold NPs into HeLa cells. (a) Number of NPs by the vesicle diameter versus the NP size. (b–f) TEM images of gold NPs trapped in 14, 30, 50, 74, and 100 nm diameter endocytotic vesicles [202].

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in intracellular environment, and huge accumulations of NPs could be achieved by effectively blocking the exocytosis by the increased aggregate size (Fig. 7). 4.1.2. In vivo biodistribution HD size also greatly influences the biodistribution and clearance of NPs in vivo. For in vivo applications, NPs are often administered into blood circulation via intravenous injections, which can result in broad distribution of NPs in many organs. The biodistribution and clearance of intravenously administrated NPs are largely dependent on their HD size. Generally, the majority of NPs are found in liver and spleen because of facile uptake by reticuloendothelial system (RES). The RES is usually responsible for clearing particles from blood circulation, which can readily eliminate NPs with HD larger than 10 nm [210,211]. Clearance of NPs from blood circulation is largely dependent on the degree of uptake by RES cells when they are larger than 10 nm, and this typically results in shorter plasma half-lives for larger NPs. However, when the HD size is reduced to sub-10 nm, less accumulation is found in RES and more broad distribution over many organs can be observed as smaller NPs are more capable of penetrating various organ barriers that are highly size-dependent [212]. For example, the HD size limit for renal barrier was reported to be ~ 5.5 nm [213] and for the penetration into lung ~ 34 nm [214], in which only NPs smaller than these limits can enter the organs. Reduction of HD size below the limit of renal barrier can achieve fast clearance of NPs through urinary excretions. Choi et al.

studied the relationship between HD size and biodistribution and clearance of QDs with zwitterionic surface molecules [213]. They proposed an HD size criterion of 5.5 nm for rapid clearance from the body through the renal filtration and urinary excretion. The reported value is almost consistent with the average pore size (~ 5 nm) of mammalian vasculature, indicating that glomerular filtration in the kidney is controlled by similar effective pore size. NPs with the HD size of ~ 10 nm can extend the blood circulation time by effectively avoiding both clearance mechanisms of RES uptake and renal filtration. To target a specific organ, the HD size should be smaller than the size limit of the organ barrier. Pore size of the endothelial walls can be the primary barrier for NP delivery to desired target tissues. In most cases, endothelial cells are tightly bounded to each other and limit the permeation of NPs. However, significant uptake of NPs can occur in tissues with a leaky blood vasculature such as tumor. This phenomenon is termed as “enhanced permeability and retention” (EPR) effect, which is the most popular strategy for passive tumor targeting of NPs (Fig. 8) [10]. Perrault et al. examined the effect of HD size of NP on passive targeting of tumors in vivo [215]. They prepared gold NPs with the HD size in 20–100 nm ranges by controlling the size of the core particles and the molecular weight of methoxy-poly(ethylene glycol) (mPEG) surface coating. The NPs are smaller than the typical cutoff size of tumor transvascular pore where the smallest pore size is reported to be 100–200 nm [216,217]. As the result, all the NPs can access the tumor through the leaky vasculature by passive targeting. They reported that the highest accumulation in tumor was

Fig. 7. Dark field microscope images of B16 F10 cells and NIH 3T3 cells which were respectively co-incubated with “smart” gold NPs, citrate gold NPs, or with 11-mercaptoundecanoic acid capped gold NPs under different concentration/incubation time conditions. “Smart” gold NPs show the higher accumulation level inside the cells when compared with the cases of other gold NPs which have similar initial HD size and surface charges [79].

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Fig. 8. Schematic representation of passive tumor targeting by enhanced permeability and retention effect. NPs can passively extravasate into tumor through leaky blood vasculature and can result in significant accumulations.

observed with the ~ 60 nm-sized particle, which showed almost 2 orders of magnitude larger accumulations when compared with the ~ 20 nm-sized particle. Tumor accumulation is dependent on the diffusion rate into the tumor and also on the clearance rate out of the tumor. The ~ 60 nm optimal size resulted from the enhanced diffusion into tumor by the long blood circulation and the reduced clearance by a slow permeation rate in the tumor interstitial space (Fig. 9). Popović et al. showed that small NPs can extravasate easily and diffuse away from the vessels, whereas extravasation of large NPs is limited by the transvascular pore barriers in the vessel wall [218]. For maximal tumor accumulation, NPs should have long blood circulation time and should be large enough to prevent rapid penetration through tumor interstitial space as long as they can extravasate into tumor transvascular pores. NP HD size should be carefully controlled to achieve efficient accumulation in target tissue while reducing non-specific uptake by RES. NPs should also allow rapid removal from the body before they cause toxic side effects. However, there is a dilemma in the particle size to simultaneously meet all the requirements. Efficient clearance from the body to avoid side effects may result in the reduction in residence time required for accumulation in target tissues. One way to address this dilemma is to develop a flexible platform that can modulate the size at physiological condition. For example, large, sub-100 nm gold nanoclusters that are consisted of sub-5 nm gold NPs and biodegradable polymers can provide sufficient blood residence time for accumulation in target tissues, while facilitating effective clearance from the body after the polymer bio-degradation [219]. pH-responsive size modulation can also be useful to enhance the NP accumulation in tumor tissues that are generally acidic by hypoxia [79]. Small NPs that can increase their size by aggregation in mild acidic environments would be effectively accumulated after internalization into tumor tissues due to the slow permeation rate by the increased size while most of untargeted NPs can be rapidly cleared from the body by renal pathway. Smart design of NP surface coating that can meet the conflicting demands can open a new avenue of NP applications for imaging and therapy. NPs can be also administrated through oral/intraperitoneal injection, transdermal pathway, and intratracheal instillation. Hillyer et al. studied the size dependence of biodistribution of 4–58 nm gold NPs after oral administration to mice [220]. They found that the NPs can penetrate the gastrointestinal tracts by persorption as degrading the enterocytes in the process of the extrusion from the

villus. Penetration from the gastrointestinal tract into other organs typically decreases with increasing particle size, which results in large accumulations of the smaller particles in many organs with the largest accumulation in kidney among others. In the gastrointestinal tract, NPs can interact with mucus by attaching to the mucin fibers and sometimes can transport across the mucus mesh that may allow entry to the underlying epithelia with the average pore size typically over 100 nm [221]. The mucus mesh pore size is large enough for the passage of most of NPs, however they should overcome the mucus clearance mechanisms to efficiently penetrate the mucus layers. Considering the intestinal mucin turnover time between 50 and 270 min, NPs cannot stay on mucus for more than 4–5 h. Bulk viscosity of healthy human mucus is typically 1000– 10,000 times higher than the viscosity of water, which restricts rapid diffusion of particles within the mucin turnover time. Thus, NPs should avoid sticky adhesion to mucin fibers and be small enough to avoid significant steric hindrance with the dense fiber mesh to obtain rapid diffusion into mucus barrier. For the NPs larger than 10 nm, they were mostly found in small intestine and stomach than other organs including liver and kidney because of their inefficient mucus penetrations. In contrast, when 13 nm gold NPs were administrated into mice via intraperitoneal injection, the majority of particles accumulated in the liver and spleen followed by stomach, small intestine, and kidney, suggesting a different uptake mechanism [222]. The transdermal delivery is also dependent on the size of NPs. Sonavane et al. reported skin penetration of 15–198 nm gold NPs [223]. As the particle size decreased, significantly larger amount of gold NPs were observed in the deeper region of the skin indicating higher permeation rate. Accumulation of larger particles such as 198 nm gold NPs was mostly confined in the epidermis region. It is supposed that NPs were absorbed by follicular penetration through skin appendages such as hair follicles and sweat ducts. Biodistribution pattern was highly NP size dependent for intratracheal instillation as well. Semmler-Behnke et al. showed that small gold NPs (1.4 nm) can pass the air/blood barrier of lungs after inhalation with subsequent distribution in the whole body with significant amounts in blood, liver, skin, and carcass after 24 h, whereas 18 nm particles are almost completely trapped in the lungs [212]. Similarly, Sadauskas et al. reported that 2 nm gold NPs showed higher translocation into systemic circulation when compared with 40 and 100 nm gold NPs which showed noticeable accumulations in liver [224].

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Fig. 9. Size-dependent permeation rates and accumulations of gold NPs in tumor interstitial spaces. (a–i) Relative gold NP distribution to blood vessels (marked by arrows) revealed by silver enhancement staining for 20, 60, and 100 nm NPs at 1, 8, and 24 h post-injections (scale bar in A: 40 μm). (j) Contrast-enhanced images for densitometry analysis. (k) Normalized densitometry signal intensity versus distances from blood vessel centers. Smaller NPs had a significantly higher signal at distances further away from the vessel center, demonstrating a higher migration rate through the interstitial space (n = 10, p b 0.05) [215].

4.2. Surface charge For biomedical applications, NPs should be stable in aqueous media without aggregation. Surface charge primarily determines the dispersion ability of NPs by electrostatic stabilization, where highly charged NP surface is often necessary to guarantee the colloidal stability. NP surface charge also has a vital role in interactions with cells and in vivo compartments. We will focus on cellular interactions of NPs by the surface charge, which will be followed by the interactions in vivo.

4.2.1. Cellular interaction NPs should contact and attach to cell surface to enter the cells. Because cell membranes largely consist of negatively charged domains, such as phospholipids with negatively charged head groups and polysulfated proteoglycans, NPs with positively charged surface are expected to be favored for the membrane adsorptions by electrostatic interaction [225]. Cho et al. have examined the role of surface charge in cellular adsorption and internalization of gold NPs [226]. Using I2/KI etchant and inductively coupled plasma mass spectroscopy (ICP-MS), they quantitatively differentiated surface-adsorbed

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NPs versus internalized NPs. It was observed that positively charged NPs more adsorbed on the cell membranes and consequently showed higher level of internalizations when compared with the negatively charged or neutral NPs (Fig. 10). The result has shown that cell adsorption process was the rate-limiting step that determined the amount of internalized NPs because it was much slower than the internalization process. Positively charged NPs can show larger cellular uptake by facile adsorption on the negatively charged cell surface. Uptake of negatively charged particles was also evident despite of the unfavorable interaction with the negatively charged cell membrane by the charge repulsion. The negatively charged NPs were more efficient in membrane adsorption and subsequent cellular uptake when compared with neutral NPs, presumably due to the interaction with positively charged domains of cell surface though the positive domains should be much scarcer than the negative domains [226]. Neutral NPs showed the least adsorption on the cell surfaces, which has resulted in the lowest level of uptake. This study has demonstrated that electrostatic attractions critically affected the membrane adsorption of NPs which subsequently determined the degree of NP cell internalization. In addition, positively charged NPs can directly pass through cell membranes without mediated by endocytotic pathways, which was demonstrated by their efficient cellular uptake

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even at reduced temperature of 4 °C or in the presence of inhibitors which should prevent the endocytosis [156,226]. The simple diffusive transport across lipid bilayers without mediated by channels or pores is not likely for the mechanism of non-endocytotic cellular uptake of NPs [227]. Wang et al. have shown that charged NPs induce surface reconstruction at the points they adsorb on the lipid bilayers [228]. Binding of negatively charged NPs causes local gelation in otherwise fluid bilayers, while positively charged NPs induce local fluidization of otherwise gelled bilayers. The structure change to more fluidic phase may disrupt bilayer integrity and cause cell penetration of positively charged NPs. Lerueil et al. have shown that various cationic materials including cell penetrating peptide, cationic dendrimers, polymers, and positively charged inorganic NPs induced membrane disrupting hole formation in lipid bilayers [229]. They have demonstrated that all the cationic NPs should be able to either form holes or expand holes at pre-existing defects regardless of other physical properties such as size, shape, chemical composition, and deformability. Since the transport across membrane hole is energy-independent diffusive process, it should be more favorable than energy-dependent endocytotic pathways. This may be another reason why positively charged NPs show enhanced cellular uptake when compared with negatively charged or neutral NPs.

Fig. 10. Schematics illustrating of the interactions between gold NPs and SK-BR-3 cells. (a) Citrate-coated (negatively charged) and poly(vinyl alcohol)-coated (neutral) gold NPs show low affinity with cell membranes. (b) Poly(allyamine hydrochloride)-coated (positively charged) gold NPs display high cell membrane binding affinity [226].

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4.2.2. In vivo biodistribution Surface charge also plays a crucial role in biodistribution and clearance of NPs. As shown by the adsorption on cell surfaces, charged NPs can have large degree of non-specific interactions with biomolecules via electrostatic interactions. However, it is often necessary to avoid such non-specific interactions of NPs for many applications of in vivo imaging and therapy. NPs encounter a large variety of biomolecules in vivo, where non-specific adsorptions can potentially alter the physicochemical properties of the NPs such as the HD size, surface charge, and optical profiles. Aggregations of NPs can also be induced by the non-specific interactions, which should complicate the in vivo applications of NPs. Non-specific interactions with extracellular matrix and non-targeted cell membrane can also hinder the efficient delivery of NPs to targets. When NPs are administrated via intravenous injections, adsorption of plasma proteins may promote undesired recognition and clearance by the RES cells [18]. To overcome aforementioned issues, NPs are suggested to have neutral surface charge and high colloidal stability at physiological conditions. Neutral surface ligands with hydroxyl groups, especially PEG, have been widely used to reduce the non-specific interactions of NPs while maintaining the high colloidal stability [144,154,230,231]. In the case of intravenous injection of NPs, the low non-specific binding of PEGylated NPs with plasma proteins reduces their clearance by the RES, which results in longer blood circulation time and efficient accumulation in tumors [28,30]. The molecular weight of PEG for the anti-fouling NP surface is generally reported to be 5–10 kDa [215,232–235]. However, it is also dependent on the NP core size, in which the combination of smaller-sized NP and longer PEG chains results in the most improved half-life in circulation (Fig. 11) [215]. Alternatively, NPs can be coated with small zwitterionic ligands to obtain the neutral surface. The compactly coated small zwitterionic ligands on NP surface can result in minimum HD size and high colloidal stability under various conditions [157,236,237]. They are effective in reducing non-specific interactions due to the neutral surface charge. Park et al. have systemically studied the effects of zwitterionic QD surface as compared with QDs that are positively or negatively surface charged [156]. The zwitterionic QDs were colloidally stable with nearly neutral surface charge under broad pH range and under high salt conditions. The zwitterionic QDs showed minimal nonspecific adsorptions to various surfaces including polystyrene and bovine serum albumin, and to cell surfaces (Fig. 12). Ideal NP probes are desired to have good colloidal stability, small HD size, and minimal non-specific adsorption levels. The zwitterionic NP surface coating by small surface ligands can be a promising approach to meet the challenges for NP probes.

Fig. 11. Pharmacokinetics mapping of blood half-life against the design parameters of core size and methoxy-PEG (mPEG) molecular weight. 5 gold nanoparticles of different core diameters (18–87 nm) and 3 different mPEG molecular weight brush layers (2, 5, 10 kDa) were used to determine the blood half-life (h) as the function of particle size (nm) and mPEG molecular weight (kDa) [215].

Other administration pathways include oral administration, intratracheal instillation, and transdermal administration. For such administrations, neutral NPs with PEG surface coating have been widely used to reduce the non-specific interactions with complex biomolecules. NPs should adhere to mucus surface to penetrate gastrointestinal tract and subsequently translocate into systemic circulation after oral administration. However, the strong adhesion causes mucociliary clearance that avoids penetration across the mucus layers. PEG chains may provide necessary adhesive interactions due to the inter-diffusion with the mucus network while effectively avoiding undesirably strong particle–mucus adhesive interaction [221]. Lai et al. reported that dense PEG coating greatly improved the transport of NPs by efficient diffusion in undiluted human mucus [238]. The neutral surface charge and negligible protein adsorption resulted in rapid penetration across mucus barriers by effective diffusion of the NPs. The higher surface coverage of PEG improved the transport rate whereas large increase in the molecular weight of PEG resulted in the slower transport [239]. This result suggests that both dense surface coverage and low molecular weight PEG are desired for PEG-coated NPs to rapidly penetrate mucus layer. Passing the air/blood barrier of lungs after intratracheal instillation is less affected by the surface charge of NPs and mainly dependent on their HD size. However, PEG coating can improve the blood circulation time once NPs are translocated into the systemic circulation by avoiding their clearance by RES cells [240]. Transdermal penetration of NPs is largely affected by their surface charge. Lee et al. studied skin permeation of QDs by different surface coatings [241]. QDs with PEG surface coating and QDs with carboxylic acid surface coating were infused in media into the isolated perfused porcine skin flap for 4 h. When arterial extraction was studied for QD quantification, carboxylic acid-coated QD had greater tissue deposition than PEG-coated QD. This result suggests that capillary bed perfusion is dependent on the surface property of NPs, which is supposed to be the result of agglomeration, tissue binding, or the pharmacological activity of QD that have entered the capillary endothelial cells. 4.3. Targeting When conjugated, targeting molecules can help NPs to selectively recognize specific membrane receptors or antigens on target cells. They can also facilitate cell surface adsorption/internalization through specific interactions. There are many kinds of targeting molecules developed so far including proteins (mainly antibodies and their fragments), nucleic acids (aptamers), and other receptor ligands (proteins, peptides, small molecules, etc.) [242]. Targeting molecules can be introduced to NPs using bioconjugation methods as described in Section 3.4, and the type of targeting molecules largely determine the physicochemical properties of the conjugates. See Table 4 for the types and properties of targeting molecules. Here, we will discuss examples of targeting molecules that have been frequently used for NP targeting and properties of the resultant conjugates based on the type of targeting molecule. We will also address current challenges of NPs in targeting applications. Many kinds of proteins for known cell membrane-bound receptors can be used to target specific cell type. Antibodies have been the preferred class of targeting molecule for the last several decades. There are more than ten antibodies approved by US Food and Drug Administration (FDA) for clinical applications including Herceptin (trastuzumab) and Erbitux (Cetuximab) [243]. Because many breast cancer cells overexpress human epidermal growth factor receptor-2 (HER-2), NPs coated with anti-HER-2 antibody such as Herceptin can target breast cancer cells with high specificity [186,199,244,245]. Similarly, epidermal growth factor receptor (EGFR) can be targeted by anti-EGFR antibody such as Erbitux [76,187,246,247]. Endogenous proteins have been also used for the targeted NP delivery to cancer cells. For example, iron-binding protein transferrin has been widely

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Fig. 12. Evaluation of non-specific adsorption levels QDs with different surface coating. a) Non-specific adsorptions of zwitterionic charged (+/−) (top), negatively charged (−) (middle), and positively charged (+) (bottom) QDs on bovine serum albumin surface beads (left) and on polystyrene beads (right); (scale bar: 5 μ m). b) Histogram data of the photoluminescence intensity of HeLa cells co-incubated with (+/−) (top left), (−) (top right), (+) (bottom left) QDs, and a control sample with no QDs (bottom right); ([QD] = 30 nM); incubation times: 30 min: black; 60 min: blue; 90 min: green; 120 min: blue [156]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

used to deliver NPs to the cells that overexpress transferrin receptors [248–250]. Proteins are typically large in size, for example, whole antibodies such as Herceptin and Cetuximab are 15–20 nm in diameter

[242]. Thus, conjugation of whole antibody largely increases HD size of the resultant conjugates. In addition, Fc domain of the antibody can bind to the Fc receptors on normal cells and macrophages, which can

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Table 4 Type and property of various targeting molecules for NPs. Modified from ref. [242]. Type

MW (kDa)

Diameter (nm)

Features

Examples of use in targeting of nanoparticles

Monoclonal antibodies Whole antibodies 150

15–20

High affinity, divalent, many clinically approved examples, contains biologically active constant (Fc) region, long circulation

[76,186,187,199,244–247]

Engineered fragments (monovalent) ScFv 25

3–5

[83,251,252]

Fab′

50

5–10

Nanobody

15

2–3

Lowered affinity, rapid clearance from circulation, renal retention, reduced stability, reduced immunogenicity Can be produced genetically or enzymatically by cleavage of monoclonal antibodies Smallest antigen-binding fragment, single domain, can bind cryptic epitopes

[254]

Engineered fragments (divalent) 100 F(ab′)2

10–15

Diabodies Minibodies

50–80 80

5–10 10

Aptamers RNA/DNA

10–30

2–3

Rapid clearance, automated chemical synthesis, susceptible to nucleases without chemical modification

[257–260]

Receptor-ligands Whole proteins

30–150

Variable

[248–250]

Peptides

0.5–10

Variable

Small molecules

0.1–1.0

0.5–2.0

Produced using recombinant DNA technologies, can be biologically active, susceptible to proteases Facile synthesis and modification, diverse libraries and screening technologies, susceptible to peptidases, renal retention Chemical synthesis, simple modification and coupling chemistries, can be biologically active, highly variable affinities

Improved affinity, can be engineered to a variety of sizes and arrangements of protein domains Mono-specific or bi-specific dimer of ScFv Can be produced genetically

lead to increased immunogenicity [10]. Small antibody fragments can be alternatively used after proper engineering that can retain the targeting affinity and specificity as the original whole antibody. For example, single-chain variable fragment (scFv) that consists of antibody heavy- and light-chain variable domains connected with a flexible peptide linker with 3–5 nm in diameter can be used to direct NPs to target cells with a high binding affinity and specificity [83,251,252]. The NP conjugate with engineered antibody fragments can have minimal HD size and reduced immunogenicity [253,254]. Aptamers are short single strand RNA or DNA oligonucleotides that are capable of binding to target antigens with high affinity and specificity. Specific aptamers for targets can be selected from a large number of random sequences by Systematic Evolution of Ligands by Exponential Enrichment (SELEX) [255]. Aptamers can allow diverse functional groups by conjugation because SELEX is a chemical process that allows wide variety of modifications. In addition, they generally have less immunogenicity which can lead to improved biodistribution [256]. NP surfaces can be easily conjugated with modified aptamers, and the conjugates showed efficient internalization to the target cells [257–260]. Small peptide or molecules have also been exploited for targeting. Small peptide cyclic arginine-glycine-aspartic acid (cRGD) can bind to cell adhesion interin αvβ3 that is abundant on the surface of endothelial cells and other various cancer cells, and thus can be used to specifically deliver NPs to tumor [179,261–264]. Folic acid is a well-known small molecule targeting ligand that binds to folate receptors with high affinity. Folate conjugation on NPs can significantly promote their targeted delivery into cancer cells that overexpress folate receptors [265,266]. Small molecules are preferred for targeting because they allow simple conjugation to NPs by facile chemical modifications. In addition, the inherent small size promises better control of HD size of the resultant conjugates. The property and targeting efficacy of the conjugates are affected not only by the type of targeting molecules but also by surface properties of NPs such as HD size and the surface charge. Chan et al. demonstrated that the internalization of Herceptin-coated gold NPs by the breast cancer cell was most efficient for 40 and 50 nm gold NPs

[253]

[179,261–263] [265,266]

among 2–100 nm size range though all of the NPs showed targeting effect [245]. This optimal size for particle uptake is due to the accurate balance between multivalent crosslinking of membrane receptors and the process of membrane wrapping involved in the receptormediated endocytosis. Similarly, optimal effective size of 44 nm was reported when gold nanocages were conjugated with anti-EGFR antibody and incubated with human glioblastoma cells [247]. The control of NP surface charge is crucial to maintain targeting activity, especially for the protein-based targeting molecules. The structural disturbance of proteins may largely alter their activities because structure and function are closely related for proteins. The strong adsorption on the NP surfaces may cause protein crowding and denaturation, which could reduce the protein activity. Zhang et al. have shown that gold NPs could cause aggregations of adsorbed proteins which resulted in the protein-NP assemblies with the partially unfolded protein structures [17]. NP surface charge is a key parameter that regulates such protein adsorption and denaturation. Neutral ligands such as PEG are preferred for maintaining protein structure while charged surface ligands are more likely to perturb proteins via electrostatic interactions [267]. Even after proper conjugation of targeting molecules, charged surface of NPs can cause non-specific interactions with biomolecules in vivo. This may result in severe reduction of targeting efficacy by shielding the active sites of targeting molecules or removing the conjugates from circulation through RES uptake before they reach the target sites. Because neutral surface is preferred to avoid non-specific interactions, NPs are often coated with PEG before/after conjugation with targeting molecules [179,244,246,250,262,263]. Small surface ligand with zwitterionic characteristics can also be effective in reducing non-specific interactions of NP conjugates. Choi et al. have shown that zwitterionic cystein coated QDs with small HD size (b 6 nm) can target tumors with high specificity after conjugation with small targeting molecules (Fig. 13) [264]. Most of remaining QDs rapidly cleared from body through renal filtration without trapped into RES cells, which was ascribed to the small HD size and suppression of non-specific interactions with biomolecules and non-targeted tissues. Zwitterionic surface ligand molecules can also be used in conjunction with other

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surface molecules that contain functional groups for bioconjugation chemistry [156]. By carefully controlling the ratio of two surface ligand molecules and conjugating with targeting molecules, the mixed surface ligand system can permit specific targeting of biomarkers while maintaining the advantages of zwitterions of minimal non-specific adsorptions and high colloidal stability. Accurate control on the number of targeting molecules per NP remains as a major challenge for sophisticated NP targeting. Contrary to conventional molecule agents which typically have a single conjugation site, NPs usually can have a number of targeting molecules on the surface because they are usually larger than targeting molecules and have multiple conjugation sites. The multiple display of targeting molecules on NPs can enhance the binding affinity as the result of multivalent interactions [245]. However, such multivalent bioconjugates can cause high degree of cross-linking of cell surface receptors, which can activate unwanted cell signaling pathways and can dramatically reduce the receptor mobility [268,269]. Fabrication of monovalent NP bioconjugate is sometimes highly desirable to study biological processes that are sensitive to protein clustering, such as membrane receptor diffusion kinetics. Gel electrophoresis (GE) can be used to isolate bioconjugates with desired valency. Howarth et al. have obtained monovalent streptavidin-coated QDs by conjugating with chimeric streptavidin tetramer with a single active biotin binding subunit and by purifying the monovalent bioconjugate from a statistical mixture using GE [270]. The monovalent bioconjugate has shown minimal disturbance in cellular function because of reduced receptor clustering as well as low degree of internalization by the cells. Similarly, monovalent QD conjugates with peptides or proteins were obtained using GE purification, and specific targeting and tracking of a membrane receptor or cytoplasmic compartment such as microtubules were investigated by monitoring the diffusion kinetics of the conjugates [271–273]. Although GE is a facile method to isolate homogenous monovalent NP bioconjugate, it is applicable only when targeting molecules are sufficiently large to show clear difference in electrophoretic mobilities. In addition, the overall yield is generally low because of the low portion of monovalent bioconjugate within statistical mixture of many possible valencies. To improve such limitations, it is necessary to control the conjugation steps to obtain monovalent conjugate with a high yield. Careful design of the reaction parameters may help to reach to the goal. For example, You et al. have exploited electrostatic repulsion to control the functionalization degree of QDs with tris(hydroxymethyl) methylamine-nitrilotriacetic acid (Tris-NTA)

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[274]. Modulation of the charge repulsion between Tris-NTA by controlling the ionic strength has yielded mainly monovalent QD conjugate without further purifications. It has also been shown that binding of Tris-NTA with His6-tagged proteins produced monovalent QD bioconjugate that could be further used to investigate diffusion kinetics of membrane receptors. This result showed significant advances in controlling the targeting molecule valencies, however universal and flexible control over the targeting molecule valencies remains a challenge to achieve on-demand NP targeting. 4.4. Cell labeling Labeling of cells using inorganic NPs can be useful for many in vitro and in vivo applications. The delivery strategies of NPs into cells can be categorized into physical delivery method and biochemical delivery method [12]. Physical delivery method uses bypass of plasma membrane barriers as evading the endocytic pathways by directly introducing NPs into cells through pores in the cell plasma membrane. Two main such approaches are microinjection and electroporation. For microinjection, NP samples are directly introduced into the cells using a fine-tipped glass microcapillary. This approach can deliver precise amounts of NPs into specific sites. For example, Dubertret et al. introduced phospholipid-encapsulated QDs into early-stage Xenopus embryos via microinjection method and have monitored the embryogenesis process [177]. Electroporation applies a rapid, high-voltage electric field impulse to temporarily generate hydrophilic pores in the cell plasma membrane. This process can deliver NPs into cells with high throughput when compared with the microinjection method. Yoo et al. loaded NIR fluorescent QDs into cancer cells using electroporation, and the QD-labeled cancer cells were used for in vivo tracking of cancer development and progression in xenografted nude mice [275–277]. The labeling method allowed long term monitoring of the QD-labeled cells for more than a month. Although this method can provide high payload efficiency and can be applicable to a large variety of cell types regardless of the types of NPs, it usually suffers from either low yield or high cytotoxicity [12]. Biochemical delivery method decorates NPs with chemical functional groups or targeting molecules to facilitate their passage across plasma membranes. This method can provide high throughput and can be more flexible than the physical approaches because NPs allow diverse surface functionalizations. Surface properties of NPs greatly affect the cell labeling efficiency in biochemical delivery

Fig. 13. Targeting of QDs to human melanoma xenograft tumors. Small zwitterionic QDs conjugated with cRGD (b6 nm in HD size) preferentially accumulate into the αvβ3-positive T(+) tumor when compared with the αvβ3-negative T(−) tumor with the positive-to-negative tumor ratio of 5.1 at 4 h post-intravenous injection. Most of the remaining QDs were excreted through renal clearance and were found primarily in the bladder due to their small size and the low non-specific adsorption level [264].

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methods. The major issue of surface property for cell labeling is surface charge. Because positively charged surface can interact strongly with usually negatively charged cell plasma membrane, highly positively charged surface has been used for NP surface for efficient cell labeling. For example, cell penetration peptides (CPPs) are known to act as an effective mediator for NP cell internalizations due to their highly positive charge [278]. Many CPP sequences are derived from natural sequence present in viruses such as protein transduction domains. Tat peptide derived from the human immunodeficiency virus 1 (HIV-1) has been popularly used to deliver a variety of NPs into cells. For example, QDs coated with Tat peptide have shown an increase of roughly 2 orders of magnitude in intracellular uptake in a variety of mammalian cell types [279]. The Tat coated QDs can enter cells across the plasma membrane via endocytosis mechanism such as lipid-raft-dependent macropinocytosis [280,281]. Lewin et al. have shown that superparamagnetic iron oxide NPs coated with Tat peptides efficiently enter hematopoietic and neural progenitor cells without significantly perturbing the cell viability, differentiation, or proliferation [282]. The cells could be detected by MRI and could be separated and further purified by magnetic separation after in vivo migration, which was useful to track the in vivo distribution and differentiation of the labeled cells. Cationic liposomes such as lipofectamine are also effective to mediate NP entry to cells by making complex with negatively charged NPs through electrostatic interactions [283]. Derfus et al. have reported that cationic liposomes provided the highest delivery efficiency of QDs to live cells among tested transfection reagents (translocation peptides, cationic liposomes, and dendrimers) [284]. The positively charged polymers such as polyethyleneimine (PEI) can also facilitate NP entry into the cells using their high charge density [164]. Lipid bilayer of cell membrane strongly interacts with hydrophobic/ lipophilic molecules, such as long chain fatty acids/amines or lipophilic polymers. As the result, hydrophobicity is also important for cellular uptake of NPs. Lipophilic property of membrane lipids can result in stronger interaction with hydrophobic surface NPs. Introduction of hydrophobic moieties on NP surface can increase the cellular uptake for both negatively charged and positively charged NPs, and the one with balanced hydrophobicity and positive surface charge could achieve the most efficient cell membrane labeling and cellular uptake [285]. For such NPs with mixed surface ligand molecules, the structure of ligand on NPs can also affect their interactions with cell membrane. Verma et al. have shown that NPs with an ordered ribbon-like alternating arrangement of mixed hydrophobic and anionic surface ligand directly passed through cell membrane, while NPs that were coated with the same molecules but in a random arrangement entered cells as encapsulated by endocytotic vesicles (Fig. 14) [286]. This suggests that the NP surface should be very subtly controlled to optimize the cell labeling efficiency. Finally, targeting of NPs can facilitate cell labeling as exploiting the multivalent interactions between the targeting molecules and cell membrane receptors as shown in Section 4.3. The targeting molecules can also direct NPs to specific sub-cellular organelles after entry into the cells, which may help study biological processes that happen within cellular compartments. In many cases, endocytosis results in intracellular locations of NPs in the cytoplasm without targeting specific organelles. The use of nuclear localization signal peptides that typically originated from viruses such as SV40 and adenovirus can facilitate sub-cellular targeting of NPs into nuclei [287–289]. Mixed conjugation of different peptides of cell recognition and nuclear localization sequences can target specific cells and can deliver the NPs into the nuclei with enhanced translocation efficacy [290]. However, the control of intracellular localization of NPs is much complicated when compared with cellular targeting because the intracellular trafficking should be highly dependent on the individual cell type and also on the properties of the NPs that include the size, charge, and surface coating [291,292].

4.5. Biocompatibility and toxicity Toxicity is one of the most critical issues for biological applications of inorganic NPs. The toxicity concerns are primarily related to the NP compositions, where QDs with heavy metal ions are generally considered as potentially toxic whereas noble metal NP and lanthanide-doped NPs are relatively free from such concerns. The leakage of toxic ions such as cadmium, lead, and mercury from QDs may cause serious potential toxicity problems [293]. Chalcogenoxides and cadmium ions can leak from QDs through various chemical pathways that include radical reactions of oxygen under light irradiation [159,294]. The released cadmium ions can cause significant kidney damages [295]. NPs can induce acute or chronic toxicities depending on several factors: size, charge, concentration, surface functionality, and stabilities under oxidative, photolytic, and mechanical conditions [296]. Proper control of the NP surface can significantly reduce the toxicities [297]. The compact and strong surface passivation of NPs can reduce toxicities caused by ion leakage [298]. Derfus et al. reported that CdSe/ZnS QDs with proper surface coating showed reduced cadmium ion release and thus reduced the cytotoxicity [299]. They showed that mercaptoacetic acid (MAA) that was conjugated to bovine serum albumin (BSA) was more effective to reduce the release of cadmium ions than MAA alone because BSA slowed the oxidation process of QD surfaces by acting as a physical diffusion barrier against oxidants. Polymers have also been used to passivate QDs to reduce the oxidation and ion leakage. Kirchner et al. reported that poly(maleic anhydride alt-1-tet-radecene)-coated CdSe/ZnS QDs were more resistant against the release of cadmium ions than mercaptopropionic acid (MPA)-coated CdSe/ZnS QDs [300]. Besides the surface coating, additional inorganic shells on QDs can greatly reduce the ion leakage from the core QDs [299–301]. Surface charge of NP is also important for cytotoxicity [302]. Goodman et al. have studied cytotoxicities of gold NPs that are coated with either positively or negatively charged surfactants, and showed that positively charged NPs presented higher cytotoxicity than negatively charged NPs regardless of the cell types [303]. The higher toxicity of positively charged NPs are due to strong interactions with negatively charged cell membranes, which results in defects in lipid bilayers by the formation of holes, membrane thinning, and/or membrane erosion [229,304]. There are some reports about in vivo toxicity of NPs, however the reported cases are smaller in number than the in vitro studies maybe due to the inherent complexity of in vivo experiments and difficulty in standardization. Hauck et al. reported an in vivo QD toxicity assessment by using CdSe/ZnS QDs surface coated with polymers [305]. QDs were intravenously administrated into Sprague–Dawley rats, and the changes of several hematology markers and liver and kidney damage indicators were investigated for over a month. The results showed only normal variations of these levels within populations of animals when compared with those of control animal models, implying little overt toxicity from cadmium ion leakage or from other factors. Akerman et al. reported that CdSe/ZnS QDs coated with several targeting peptides did not show acute toxicity after 24 h of intravenous injections using small mouse model, though QDs were accumulated in targeted tissues and RES tissues such as liver and spleen [306]. Geys et al. reported that commercial carboxylic-functionalized CdSe/ZnS QDs (negative surface charge) caused more pulmonary vascular thrombosis than commercial amine-functionalized QDs (positive surface charge) [307]. The contact activation pathway in the coagulation cascade is speculated to be more interacted with carboxylic-functionalized QDs. This result seems to be contradictory to the higher cytotoxicity of positively charged NPs in Goodman's result [303]. However, in general, these results imply that undesired interactions of NPs can cause potential toxic problems.

Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015

J. Nam et al. / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

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Fig. 14. Effect of NP surface ligand structure on the cell membrane penetrations of the gold NPs. Images in the top row are schematic illustration of homoligand (left), unstructured (middle), and structured ligand shells (right) on gold NPs with the representative scanning tunneling microscopy images (scale bar: 5 nm). Middle and bottom rows show confocal images of fluorescence (upper panels with the intensity scale bar (a.u.)) and brightfield/fluorescence overlays (lower panels) of mouse dendritic cells co-incubated with gold NPs capped with homoligand (left), unstructured (middle), and structured ligand shells (right) at (a–c) 37 °C and (d–f) 4 °C in serum-free condition. Gold NPs capped with structured ligand shells directly penetrate cell membranes while others enter the cells by endocytosis [286].

5. Conclusion Many kinds of inorganic NPs have been developed for imaging and therapy applications. Their unique optical, magnetic, and electronic properties can be tailored by controlling the composition, size, shape, and structure, which allows on-demand design and utilizations. Representative classes of inorganic NPs have been introduced. Surface properties of NPs determine their fates in biological environments. Judicious control over the surface property parameters such as HD size, surface charge, and targeting can provide many opportunities for their imaging and therapy applications. As many studies have examined and evaluated inorganic NPs for biological applications, we were able to gain some perspectives on the roles of the surface. This report is aimed to review current understanding of how surface properties of NPs impact their interactions

with cells and with various biomolecules in vivo. NP surfacemodification strategies have been reviewed as categorized by the molecules they introduce; small surface ligand, polymer, and lipid. Use of small ligand molecules that can replace initial assynthesized surface coating has been a popular strategy for NP surface modification since this strategy has the advantage of maintaining the minimal HD size. Polymer-based surface modification can be further categorized into two strategies of exchange and encapsulation methods. For exchange strategy, polymers can provide overall strong binding ability by combining multiple anchoring groups with relatively weak affinity. Encapsulation of NPs in polymers, lipids or surfactants can preserve the optical properties of as-synthesized NPs. For NP conjugations, many conjugation routes have been developed that exploit both covalent and non-covalent interactions. It should be stressed that bioconjugation may affect

Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015

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the activity of the biomolecule in the resultant conjugate. NP surface properties and reaction conditions should be carefully considered to obtain a bioconjugate that maintains the physicochemical properties of NP and functionalities of the conjugated biomolecules. Surface property mainly dictates the interactions of NPs with external environments. HD size is a critical design parameter for the development of imaging and therapeutic agent because it can largely affect the cellular interaction, in vivo circulation, and tissue permeation. Typically, maximal cellular uptake can take place in the intermediate NP size range of 40–60 nm where the ligand–receptor interaction and the membrane receptor depletion can be reasonably balanced. “Smart” gold NPs showed an example of engineered surface coating that is designed to aggregate the NPs in target cells, which greatly increased the cellular accumulation. HD size also greatly influences the biodistribution and clearance of NPs in vivo. Clearance of NPs from blood circulation is largely dependent on the degree of uptake by RES cells when they are larger than 10 nm. When the HD size is below 10 nm, NPs show broad distribution over many organs as they become capable of penetrating various organ barriers. HD size limit for renal barrier was reported to be ~ 5.5 nm and for the penetration into lung ~ 34 nm. Reduction of HD size below the limit of renal barrier can achieve fast clearance of NPs through urinary excretions. For maximal tumor accumulation, NPs should have long blood circulation time and should be large enough to prevent rapid penetration within tumor interstitial space. For many clinical applications, NPs are desired to rapidly clear out from the body after the mission before they cause toxic side effects. However, there lies a dilemma in the NP size to simultaneously meet the two requirements. Efficient clearance from the body to avoid side effects may result in the reduction in residence time required for accumulation in target tissues. Smart design of NP surface coating that can meet the conflicting demands can open a new avenue of NP applications for imaging and therapy. For example, small NPs that can increase their size by aggregation on-demand could efficiently accumulate in tumor after internalization due to the slow permeation, while most of untargeted NPs can be rapidly cleared by renal pathway. NP surface charge and hydrophobicity have a vital role in interactions with cells and in vivo compartments. Electrostatic attractions critically affect the membrane adsorption of NPs which subsequently determined the degree of NP cell internalization. In general, positively charged NPs more adsorb on cell membranes and consequently show higher level of internalizations when compared with negatively charged or neutral NPs. NPs encounter a large variety of biomolecules in vivo, where non-specific adsorptions can potentially alter the physicochemical properties of the NPs such as the HD size, surface charge, and optical profiles. For optimal performance, NPs are suggested to have neutral surface charge at physiological conditions, small HD size, and minimal non-specific adsorption levels. Zwitterionic NP surface coating by small surface ligands can be a promising approach to meet the challenges for NP probes. Many kinds of targeting molecules have been used for targeted NP delivery, and the type of targeting molecules largely determines the physicochemical properties of the conjugates. Universal and flexible control over the targeting molecule valencies remains as a challenge to achieve on-demand NP targeting. Labeling of cells using inorganic NPs can be useful for many in vitro and in vivo applications, where NP surface should be very subtly controlled to optimize the cell labeling efficiency. Toxicity is one of the most critical issues for biological applications of inorganic NPs. QDs with heavy metal ions are generally considered as potentially toxic whereas noble metal NP and lanthanide-doped NPs are relatively free from such concerns. Proper control of the NP surface can significantly reduce the toxicities. Gaining full controls over the distribution and targeting of NPs is the ultimate goal for future biomedical applications of inorganic NPs while minimizing the potential toxicity concerns.

Acknowledgements This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea Government (MOST) (20120006280), a grant of the Korea Health 21 R&D Project Ministry of Health & Welfare, Republic of Korea (A101626), the Priority Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011‐0031405), through NRF funded by the Ministry of Education, Science and Technology (20120005973, 20110027727), the NRF Grant (NRF-616-2011-2-C00048).

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Please cite this article as: J. Nam, et al., Surface engineering of inorganic nanoparticles for imaging and therapy, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.08.015