Seeing, Targeting and Delivering with Upconverting Nanoparticles

Perspective Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

pubs.acs.org/JACS

Seeing, Targeting and Delivering with Upconverting Nanoparticles Ghulam Jalani,†,§ Vivienne Tam,†,§ Fiorenzo Vetrone,*,‡ and Marta Cerruti*,† †

Department of Mining and Materials Engineering, McGill University, Montreal, Quebec H3A 0C5, Canada Institut National de la Recherche Scientifique, Centre É nergie, Matériaux et Télécommunications, Université du Québec, Varennes, Quebec J3X 1S2, Canada

J. Am. Chem. Soc. Downloaded from pubs.acs.org by UNIV OF READING on 08/16/18. For personal use only.

‡

structure due to instantaneous deprotonation of PAA chains, resulting in expulsion of drug molecules.4,5 Other polymers such as poly(N,N′-diethylaminoethyl methacrylate) (PDEAMEM)6 can be used to trigger drug release at higher pH values, thus making them useful to deliver drugs in tissues such as the intestine. In both cases, the release continues after the one triggering event until all the loaded drug is delivered.7,8 External triggers such as temperature, light, ultrasound etc. are attractive because they can be controlled remotely and noninvasively, while providing better localization with relatively high local precision.8−10 They are useful for both single and multiple triggering events because these stimuli can be turned on or off externally when desired. Among external triggers, light stands out as an exciting candidate due to its noninvasiveness, high local precision and temporal resolution.11 However, there is an inherent problem with photoregulated systems: they require high-energy ultraviolet (UV) or visible (Vis) light to carry out the phototriggering reactions.12 Both UV and Vis wavelengths have limited penetration inside the tissues because they are largely absorbed by the skin and underlying fat tissues. In addition, UV light is carcinogenic.13 Near infrared (NIR) light is an excellent alternative, because it can penetrate as much as several centimeters through tissues,14 and is nontoxic to living organisms. However, it does not provide enough energy to trigger most photosensitive materials. Thus, light-controlled drug delivery systems have been limited in vivo to areas that are not deeper than a few millimeters.15 To overcome this crucial problem, various solutions have been proposed, including two-photon, 16,17 photoplasmonic,18,19 Förster resonance energy transfer (FRET)-enabled excitation20 and combined upconversion-FRET excitation.21 However, there are some limitations associated with these systems. For instance, two-photon excitation has limited efficiency whereas FRET-based systems are highly dependent on the distance between donor and acceptor molecules and are thus limited to certain donor−acceptor couples.22,23 Upconversion (UC) systems stand out as potential contenders capable of converting NIR light to UV and Vis light, via an anti-Stokes shift, in which multiple photons are absorbed sequentially due to the existence of a real excited intermediate state, as opposed to their simultaneous absorption in two-photon excitation.24,25 The UC phenomenon, first demonstrated at the nanoscale in 2000,26 is inherent to the trivalent lanthanide ions where when an inorganic nanoparticle host rationally doped with lanthanide ions is

ABSTRACT: Efficient control over drug release is critical to increasing drug efficacy and avoiding side effects. An ideal drug delivery system would deliver drugs in the right amount, at the right location and at the right time noninvasively. This can be achieved using light-triggered delivery: light is noninvasive, spatially precise and safe if appropriate wavelengths are chosen. However, the use of light-controlled delivery systems has been limited to areas that are not too deep inside the body because ultraviolet (UV) or visible (Vis) light, the typical wavelengths used for photoreactions, have limited penetration and are toxic to biological tissues. The advent of upconverting nanoparticles (UCNPs) has made it possible to overcome this crucial challenge. UCNPs can convert near-infrared (NIR) radiation, which can penetrate deeper inside the body, to shorter wavelength NIR, Vis and UV radiation. UCNPs have been used as bright, in situ sources of light for on-demand drug release and bioimaging applications. These remote-controlled, NIR-triggered drug delivery systems are especially attractive in applications where a drug is required at a specific location and time such as in anesthetics, postwound healing, cardiothoracic surgery and cancer treatment. In this Perspective, we discuss recent progress and challenges as well as propose potential solutions and future directions, especially with regard to their translation to the clinic.

1. INTRODUCTION Localized and recurring delivery of drugs in the hour of need is of great importance in many clinical conditions such as in the treatment of solid tumors, postsurgical wounds and localized infections. The targeted localization and repeated dosage delivered at each treatment help increase drug efficacy and minimize side effects.1 An optimum drug delivery system would be made from biocompatible and nontoxic materials, protect drugs from harsh chemical environments, and release them when needed by the patient via a noninvasive remotecontrol system. Moreover, the system would work deep inside the body and be trackable externally.2 On-demand drug delivery at a specific site can be triggered by various stimuli, either internal or external.3 Internal triggers, such as pH or enzyme concentration, are useful in applications where a single triggering event is desired. For instance, poly(acrylic acid) (PAA) protonates at higher pH and thus has an extended and open structure. Hydrogels of cross-linked PAA can be used for selective delivery of drugs in the stomach, where low pH (pH < 3) causes the collapse of the polymeric © XXXX American Chemical Society

Received: April 13, 2018

A

DOI: 10.1021/jacs.8b03977 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Perspective

Journal of the American Chemical Society

Additionally, it should possess low phonon energies to minimize energy loss and maximize the radiative emissions. Among various host materials, transition metal halides of Na and Li (e.g., Na/Li-YF4 and NaGdF4) provide the highest upconversion efficiency and excellent physicochemical stability.47 Different methods including thermal decomposition, hydrothermal decomposition, microwave-assisted synthesis have been used to fabricate these UCNPs with different sizes, shapes and crystal structures.48 A detailed account has been published elsewhere.48,49 The synthesized UCNPs can carry various surface ligands depending on the type of fabrication process used. To be useful for biological applications, the UCNPs should possess hydrophilic surface functional groups. Whereas some fabrication processes (e.g., hydrothermal) produce UCNPs already coated with a hydrophilic ligand, other methods, e.g., thermal decomposition (often chosen to produce high quality UCNPs with narrow size distribution), produce UCNPs that are hydrophobic and need to be surface-modified before they can be used in biological applications.48,50,51 Some of the most commonly used surface ligands include hydrophilic polymers (e.g., poly(acrylic acid), polyethylene glycol), silica (SiO2) and biomolecules (e.g., proteins, polysaccharides). Reviews dedicated to this topic have been published previously.48,49,52,53 To create an efficient phototriggered drug delivery system the UCNPs should possess intense emission in the UV region, a wavelength required for most of the photoreactions to occur. In this respect, Yb3+- and Tm3+-doped UCNPs are useful because they produce intense UV and Vis emissions. In addition to peaks in the UV/Vis region, Tm3+ doping also produces NIR emission around 800 nm.33,34 NIR-to-NIR upconversion properties make Yb3+/Tm3+-doped UCNPs excellent candidates for simultaneous in vivo photoreactions and imaging applications.29,33,54

irradiated with a NIR laser (typically 980 or 800 nm), intense multiple emissions ranging from UV to NIR are produced through the absorption of multiple NIR photons.27 A detailed review on the UC can be found in reference 28. To create NIR-triggerable drug delivery systems, UCNPs have been combined with photoresponsive drug carriers to release drugs using NIR light: upon excitation with a NIR laser, the UCNPs upconvert the incident light to UV or Vis, which initiates a photoreaction that releases the drugs.29 Several UCNP-drug carrier combinations have been reported in recent years for the delivery of small30,31 or macromolecular32 drugs in vivo. Besides on-demand drug delivery, UCNPs can also serve as imaging probes. In particular, NIR-to-NIR UCNPs such as NaYF4 NPs doped with Yb3+ and Tm3+ are strong emitters in the NIR region,33,34 which can be used to track the drug carrier in vivo.29,35 Combining these UCNPs with photoresponsive materials can serve as excellent theranostic platforms.36−39 Here, we will briefly discuss fundamental aspects of UCNP systems and provide an overview of these materials. We will then review advances in phototriggered drug delivery through UCNPs, with a focus on clinical translation. Whereas other papers40−42 have covered advances in the biomedical applications of UCNPs, the discussion on the clinical relevance of UCNPs is lacking. Yet, such analysis is required if these technologies are to be designed for clinical applications. This Perspective will focus on this aspect and examine the barriers to clinical translation and future directions the field could take to enhance the clinical translational potential of UCNPs.

2. UCNPS: FUNDAMENTALS, FABRICATION AND SURFACE MODIFICATION The UC is a nonlinear optical process in which two or more low energy photons are converted to a single high energy photon.43,44 Several trivalent lanthanide ions (e.g., Er3+, Tm3+, Ho3+ etc.) possess multiple long-lived 4f electronic states positioned in a ladder-like fashion shielded by outer 5s and 5p orbitals. Long lifetimes (μs to ms) and identical energy spacing among 4f electronic levels enable these ions to sequentially absorb two or more low energy photons and convert them to a single high energy photon.13,45,46 On the other hand, some lanthanide ions, e.g., Yb3+, have a single excited state with large absorption cross section.44 When two types of ions, i.e., Yb3+ (sensitizer) and Er3+, Tm3+, or Ho3+(activator), are combined in a single host, they form an excellent UC system.24 Unlike other multiphoton absorption processes, UC systems use real metastable electronic states with finite lifetimes, which allows the use of inexpensive continuous wave diode lasers as excitation sources.25 Typically, UCNPs are composed of at least three components: sensitizer ions, activator ions and a physicochemically stable host matrix where ions can be doped in an orderly fashion. Yb3+ is the most widely used sensitizer ion while the selection of activator ion depends on the desired emission wavelength: Tm3+, Er3+ and Ho3+ can be used to produce UV/blue, green and red emissions, respectively.24 Tm3+ is especially interesting because it can produce UV (∼350 nm) and NIR (∼800 nm) emissions in addition to Vis wavelengths, which can be used for photoreactions and NIR imaging, respectively. The choice of host matrix depends on several considerations.14,24,34 In general, an optimum host matrix should be physico-chemically stable and possess a crystalline structure with close lattice match to the dopant ions.

3. UCNP-BASED PHOTOTRIGGERED DRUG DELIVERY The UV and Vis light produced in situ by UCNPs can be used in two different ways to create NIR-triggered, on-demand drug delivery systems: it can induce changes in other stimuliresponsive materials (e.g., pH, temperature and redox sensitive materials) or it can initiate a photoreaction in a photoresponsive compound (e.g., photocleavage, or photoisomerization). The first strategy involves an additional component that absorbs the upconverted light and transfers it to the neighboring environment to cause drug release. For example, UCNPs can be combined with gold NPs and thermosensitive polymers (poly(N-isopropylacrylamide)) (PNIPAM) to create NIR-excited, thermosensitive drug delivery systems. The incident NIR light is upconverted to UV and Vis by UCNPs; these wavelengths activate surface plasmons of gold NPs, producing localized heat. This heat is then transferred to PNIPAM, changing its structure from open to closed and releasing the encapsulated cargo.55 The upconverted light can also be used to induce several other reactions, including photopolymerization, photocatalysis, photodegradation, or photodynamic therapy etc.56−60 In this Perspective, we will focus on the UCNP-based systems involving the direct use of upconverted light to cause drug release, from photolabile molecules directly conjugated to the UCNP surface, or from polymeric and silica shells that coat the UCNPs. B


Perspective


4. PHOTORESPONSIVE MOLECULES Photoresponsive molecules change their physical or chemical structure when exposed to light. They can be classified into two major groups according to their response to light: photoisomerizable molecules, which undergo a physical change upon light exposure, and photodegradable molecules, which change chemically. Azobenzene is the most prominent molecule in the first category.61,62 When exposed to light of λ = 320−380 nm, it changes its configuration from extended (trans isomer) to bent (cis isomer), and goes back to extended shape under visible (∼435 nm) irradiation (Figure 1A). Because of this property,

irradiation at 30 mW, the particle showed complete release of 5-FU via the process in Figure 2.71

Figure 2. Cleavage of nitrobenzyl bond via upconverted NIR radiation to release 5-FU from UCNP surface. Adapted with permission from ref 71. Copyright 2014 American Chemical Society.

This process has been extended to other molecules, such as and nitric oxide.73 Although this method of drug release enables fast drug release (on a minute time scale) as the drug is present on the surface of the particle, the drug is unprotected from the environment. Thus, there is the possibility of premature release in living tissue due to the presence of endogenous enzymes. 72 D-luciferin

6. UCNP SYSTEMS WITH SURFACE-COATED POLYMERS UCNP-polymer systems are promising due to their high drug loading ability and quick release, thanks to the open and flexible structure of the polymers. Drugs can be entrapped physically or conjugated chemically to the functional groups on the polymer chains.74,75 Differently from direct conjugation to particle surface, the polymeric coating offers the drug protection from endogenous enzymes. Polymers have been combined with UCNPs in many ways to create phototriggerable drug delivery systems.42 Commonly used polymers include polyethylene glycol (PEG), polyethylene imine (PEI), TWEEN, poly(maleic anhydride-alt-1octadecene) and block copolymers such as polyethylene glycol-polycaprolactone-poly L-lysine, and polystyrene-blockallyl alcohol.42 Polymeric UCNPs composite structures can be divided into two main groups: un-cross-linked or cross-linked systems. 6.1. Un-Cross-Linked Polymer-UCNP Systems. Loose polymer chains can be anchored on the surface of UCNPs via chemical conjugation or self-assembly.42,76 The drug molecules can be physically entrapped in the open, flexible polymer shell via electrostatic interactions among functional groups on polymer chains and drug molecules. When the system is irradiated with NIR light, the upconverted UV/Vis light induce photocleavage/photoisomerization reactions thus changing the chemical/physical structure of the polymers resulting in the liberation of the encapsulated drugs.77 In one such system, Xing et al.78 (Figure 3) synthesized a photoresponsive copolymer modified with folic acid and conjugated it on the surface of silica-coated NaYF4:Yb3+,Tm3+ UCNPs for in vitro and in vivo drug delivery of doxorubicin. When the system was irradiated with a NIR laser to activate drug release, it exhibited a dose-dependent drug release from the polymer, whereas almost no leakage was found when the laser was switched off showing that drug could be released ondemand. This system was then injected intratumorally into mice with folate receptor-expressing tumors, followed by 980 nm laser exposure for 30 min each day, safely inhibiting tumor volume growth over 19 days.

Figure 1. Schematics showing (A) photoisomerization in azobenzenebased systems and (B) photocleavage in systems containing onitrobenzyl moieties.

azobenzene molecules have been used as flexible propellers anchored inside polymeric micelles and mesoporous silica NPs for photoregulated delivery of doxorubicin.63 Photodegradable molecules are cleaved when exposed to light of a specific wavelength. These compounds contain a photolabile moiety and an ester bond in their structure. Prominent examples of photolabile compounds include spiropyran cinnamates, nitrobenzyl, nitrophenethyl and their derivatives such as nitroveratryl (Figure 1B).64−67 When exposed to UV light (λ = 300−400 nm), they undergo irreversible (e.g., nitrobenzyl) or reversible (e.g., cinnamates) chemical cleavage.68 Furthermore, they can be modified and introduced in the chemical structure of other compounds and used as photoremovable bridges, cross-links, or protective groups for on-demand photocontrolled release applications.69 Some photosensitive metal-complexes, which degrade under UV/Vis light can also be used as photoremovable groups. For example, Ru, Ir, and Pt complexed with photolabile compounds can be used as gates for controlled release of encapsulated cargos.70

5. UCNP SYSTEMS WITH SURFACE-BOUND DRUG Drugs can be directly bound to UCNPs with a photolabile bond, which is cleaved upon irradiation to release the drug. As the drug is present on the surface of the UCNP, rapid liberation of the drug is achieved. Fedoryshin et al. conjugated the chemotherapeutic drug 5fluorouracil (5-FU) on o-phosphorylethanolamine modified NaYF4: Yb3+, Tm3+ UCNPs via a photocleavable derivative of o-nitrobenzyl. Following ∼14 min of continuous 980 nm C


Perspective


In another study, Yan et al.80 also developed a photoisomerizable micelle, based on azobenzene molecules as photoregulators. Here, a hydrophilic oligo ethylene glycol methyl ether methacrylate and hydrophobic azobenzenecontaining methacrylate were self-assembled on the surface of NaYF4:Gd3+/Yb3+/Tm3+@NaGdF4 core−shell UCNPs. The upconverted UV and Vis light was used to induce photoisomerization of the azo molecules incorporated in the micelle, thus triggering the release of the encapsulated cargo. These micellar systems were only designed as proof-of-principle demonstrations, however, and had not yet been tested with in vitro and in vivo models for further optimization. 6.2. Cross-Linked Polymer-UCNPs Systems. Polymers can be cross-linked to create three-dimensional (3D) microporous structures to host drugs. For example, hydrogel-crosslinked polymeric systems capable of absorbing large quantities of water and other biological fluids are widely used as drug carriers. Their open and porous structure allows the encapsulation of large amounts of drug in a 3D matrix.81 Hydrogels are especially interesting to carry macromolecular drugs such as proteins, growth factors etc. The long and flexible chains of these macromolecular drugs can be entangled with the polymeric chains of the hydrogel, thus preventing nonspecific drug leakage.82 Yan et al. were the first to develop a photodegradable hydrogel-UCNP hybrid system for NIR-triggered delivery of macromolecules.32 They prepared NaYF4:Yb3+,Tm3+@ NaYF4 core−shell UCNPs decorated with hydrophilic ligands, and dispersed the particles in a polyacrylamide-polyethylene glycol hydrogel cross-linked with a photocleavable cross-linker containing o-nitrobenzyl moieties and a photocleavable ester linkage. Bulk gel-to-sol transition was observed when the hydrogel-UCNP hybrid was exposed to a 980 nm continuous wave diode laser. The disintegration of the hydrogel structure triggered the release of the encapsulated bovine serum albumin (BSA). Although this study offers an attractive platform for ondemand delivery of macromolecules, there are some limitations associated with this system for in vivo use. For instance, long irradiation time (>60 min) was required to disintegrate the hydrogel, mainly because the UCNPs were not close enough to the photoactive sites, and thus the light had to travel over a long distance to reach all the cross-links. Moreover, the proposed hydrogel was not biodegradable and potentially toxic. To overcome these limitations, Jalani et al.29 coated LiYF4:Yb3+,Tm3+ UCNPs with a biodegradable chitosan hydrogel cross-linked with a photocleavable cross-linker (Figure 5). The thin layer of hydrogel coating ensured that all the photocleavable cross-links were in the vicinity of the UCNP core. This enhanced the efficiency of the photocleavage reaction and significantly reduced the irradiation time required to release the drugs encapsulated in the chitosan shell. In fact, the drug release was almost instantaneous under NIR irradiation, and stopped when the laser was turned off. These UCNPs could be easily dispersed in water and administered using a syringe. The system could deliver drugs through 1.5 cm thick tissues without significantly damaging them. In addition, these UCNPs could also be tracked as deep as 2 cm under the tissues, exploiting the strong NIR-to-NIR emission resulting from Tm3+ doping. In fact, in a previous work, they showed that silica-coated LiYF4:Yb3+,Tm3+ UCNPs could be used as trackers for real-time monitoring of hydrogel

Figure 3. Schematic illustration of chemical structure of photoresponsive polymer-UCNPs system for on-demand delivery of doxorubicin in vivo. Adapted from ref 78 by permission of The Royal Society of Chemistry.

Besides pendent polymer-UCNPs structures, self-assembled micelles made from block-co-polymers with hydrophilic and hydrophobic domains can be combined with UCNPs to create triggerable drug delivery systems. For example, Yan et al.79 assembled a micelle made of poly(ethylene oxide)-blockpoly(4,5-dimethoxy-2-nitrobenzyl methacrylate) around NaYF4:Yb3+,Tm3+ UCNPs, and introduced photocleavable nitrobenzyl moieties in the hydrophobic part of the block copolymer (Figure 4). Under NIR excitation, the incident light was converted to UV and Vis light, which cleaved the photolabile ether linkages, causing the disruption of the micelle and the release of the encapsulated payload.

Figure 4. Polymer micelle-UCNPs composite system for NIRtriggered drug delivery. (A) Photodegradation and drug release of drug-containing micelle. (B) Chemical structure of the polymer used to fabricate the micelle before and after photodegradation. (C) Drug release measuring system for simultaneous NIR irradiation and UV− Vis absorption spectroscopy measurement. (D) Drug release profile as a function of irradiation time. Adapted with permission from ref 79. Copyright 2011 American Chemical Society. D


Perspective


Figure 5. (A) Photocleavable hydrogel-coated UCNPs for ondemand macromolecular delivery and NIR imaging. (B) Transmission electron microscopy images of silica-coated UCNPs wrapped with a thin shell of photodegradable hydrogel encapsulating fluorescentbovine serum albumin molecules. (C) Drug release profile under periodic NIR irradiation. Adapted with permission from ref 29. Copyright 2016 American Chemical Society.

degradation in a live intervertebral disc (IVD). 33 A biodegradable chitosan hydrogel embedded with UCNPs was implanted inside the tissue and tissue was cultured under physiological conditions for a period of 3 weeks. The IVDs were periodically irradiated with a NIR laser at preset intervals and imaged using a NIR camera. Diffusion of UCNPs from the site of implantation indicated the extent of degradation. A good correlation was observed with in vitro degradation of the same hydrogel. Hydrogel-UCNP hybrid systems offer a useful platform for the safe encapsulation and controlled delivery of sensitive biomacromolecules, which are often prone to degradation. However, the controlled delivery of small molecules is challenging using hydrogels, due to their open and porous structure. The conjugation of the drugs to the polymer chains via photocleavable linkages prior to combining with UCNPs is one way to address this challenge, as Cho et al. demonstrated by chemically conjugating doxorubicin to acrylated chitosan hydrogels.83

Figure 6. (A) Azobenzene-modified mesoporous silica-coated UCNPs for NIR-triggered release of doxorubicin and (B) drug release profile under periodic irradiation of NIR laser at variable power densities. Adapted with permission from ref 30. Copyright 2013 by John Wiley and Sons.

pores. Moderate laser powers were sufficient to expel the entrapped drug molecules, and TAT peptides conjugated at the surface of UCNPs increased their cellular uptake. An alterntive system was proposed by Yang et al.,85 in which doxorubicn was loaded into the silica shell mesopores of NaYF4:Tm3+,Yb3+@NaYF4 UCNPs and capped with an onitrobenzyl derivative. In the presence of 980 nm radiation, the nitrobenzyl groups were removed and doxorubicin was released through uncontrolled passive diffusion, with 75% of the drug released over a lag time of 20 h following the radiation. Similarly, Zhao et al. synthesized a yolk−shell UCNP system in which a hollow sphere of mesoporous silica was used to encapsulate NaYF4:Tm3+,Yb3+@NaLuF4 UCNPs and the anticancer drug chlorambucil photocaged with amino-coumarin.86 To prevent premature drug release, the photocage was made hydrophobic by two octyl groups and loaded into the hollow cavity of the system. Upon irradiation with 980 nm, the upconverted UV radiation at 380 nm cleaved the phototrigger amino-coumarin to release chlorambucil, while the degraded hydrophobic phototrigger molecules remained within the hollow cavity (Figure 7A,B). A recent study by He et al.87 reported a system for NIRtriggered release system using ultralow excitation intensity of 0.35 W/cm2 (Figure 8). They used mesoporous silica-coated β-phase NaYF4:Yb3+,Tm3+ UCNPs with a photosensitive Ru complex grafted inside the pores. The Ru complex could be easily degraded under the blue light emitted by the UCNPs, thus releasing approximately 42%

7. UCNP SYSTEMS WITH SURFACE-COATED SILICA Silica-coated UCNPs are another attractive class of photoregulated drug delivery systems. Mesoporous silica coatings can be used to encapsulate drugs of various sizes.84 Also, silica coatings provide a hydrophilic and stable surface, which can be further functionalized with targeting ligands and biomolecules.76 Liu et al.30 developed mesoporous silica-coated NaYF4:Yb3+,Tm3+@NaYF4 core−shell UCNPs for NIR-triggered in vitro release of the anticancer drug doxorubicin (Figure 6A,B). They added azobenzene molecules inside the pores of the silica coating, then loaded the drug molecules via electrostatic interactions and hydrogen bonding with the silanol groups of silica. The system was excited by a 980 nm diode laser, and the upconverted UV and Vis radiation caused the azobenzene molecules to switch between the extended and bent isomers, thus pushing the drug molecules out of the silica E


Perspective


When a NP enters a biological environment, it is quickly covered with serum proteins, which can promote activation of the mononuclear phagocyte system (MPS) and subsequent destruction by phagocytic cells.90 To this end, coating the surface of the NPs with polyethylene glycol (PEG) has become standard procedure to reducing protein adsorption through hydrophilicity and steric repulsion.91 Indeed, an in vivo biodistribution study comparing UCNPs coated with either poly(acrylic acid) (PAA) or PEG measured a first-phase blood circulation half-life of 0.13 ± 0.11 min for UCNP-PAA, markedly lower than the 5.1 ± 2.5 min for UCNP-PEG.92 Yet, designing a coating that will endow the particle with a sufficiently long circulation time to reach the target site, yet also permit total renal elimination to limit toxicity is a challenge for all NPs circulating in vivo. NP size also affects blood circulation time. Small particles (less than 10 nm) are eliminated very quickly via renal and hepatobiliary clearance, whereas larger particles are more likely targeted by the MPS.93 However, size affects other factors, as well: if UCNPs are to be loaded with drugs for on-demand delivery, small size will also imply lower drug-loading capacities; also, decreasing particle size decrease quantum yield, thus decreasing emission intensity.94 Some strategies such as reported in a recent study by Homann et al. has shown that 45 nm core−shell UCNPs could achieve quantum yields equivalent to bulk microcrystalline UC phosphor powders.95 8.2. Drug Loading and Release. Because of the long journey NPs must undergo before they can reach target site, it is essential that drug is not leaked into normal tissue, and is instead preserved in NPs until its release at the disease site, thus ensuring maximum efficacy of the drug. Although the photocaging of drugs should prevent leakage until NIR irradiation, it is important that the photolabile linker not be compromised by changes in pH or the presence of endogeneous enzymes. As for drug release, the majority of UCNP-based systems only possess control over the start of the release curve, wherein the release is then driven by diffusive forces and disassociation of physisorbed drug. For example, in a typical design by Yang et al., once the nitrobenzyl groups capping the silica mesopores were removed upon NIR radiation, doxorubicin exited the pores via uncontrolled passive diffusion. Thus, 2 h of NIR radiation was required, followed by a lag time of 20 h, for ∼75% of the drug to be released.85 Precise on−off control of NIR-triggered drug release would enable immediate and repeated drug release with repeated irradiation and the rate of drug delivery could be tailored according to the needs of the patient. With such systems, one could even optimize the laser power and irradiation time to achieve ideal rates of drug release during each “on-state”. 8.3. Cytotoxicity. The FDA safety regulations UCNPs96 need to satisfy before entering the clinic make the long-term cytotoxicity of UCNPs a growing concern. So far, a short 7-day in vivo biodistribution study on rats showed no acute adverse health effects at the dose level of 10 mg/kg.97 The first long-term (115 days) in vivo cytotoxicity study also indicated no overt toxicity of PAA-UCNPs at a dose of 15 mg/ kg.98 The follow-up to this study used particles coated with PAA and PEG (∼30 nm), a larger sample size and the highest reported dose (20 mg/kg) with no side effects over a period of 90 days.92

Figure 7. (A) Silica/UCNP yolk/shell-like system for loading and releasing anticancer chlorambucil and (B) chemical structure of drug molecules conjugated with photoresponsive amino-coumarin before and after NIR irradiation. Adapted with permission from ref 86. Copyright 2013 by John Wiley and Sons.

Figure 8. Silica-coated UCNPs containing Ru-complex photogate for on-demand delivery of doxorubicin. Adapted from ref 87 by permission of The Royal Society of Chemistry.

of the anticancer drug doxorubicin encapsulated inside the porous silica coating after 5 h of irradiation. This system was able to reduce cancer cell viability after 10−30 min of irradiation.

8. CURRENT STATUS AND BARRIERS TO CLINICAL TRANSLATION Though in vivo studies are rapidly becoming integral to the research of UCNPs in drug delivery and bioimaging, the progress of UCNPs into the clinic has been virtually nonexistent. FDA-approved NPs are primarily polymeric and liposomal formulations that rely on long circulation times and the enhanced permeability and retention (EPR) effect to penetrate tumors. For example, Onivyde, a nanoliposomal formulation that delivers the chemotherapeutic irinotecan to solid tumors via the EPR effect was FDA-approved in 2016.88 The only NIR NP probe in clinical trials is the Cornell dot, an ultrasmall silica particle surface-functionalized with peptide cyclo-(Arg-Gly-Asp-Tyr) (cRGDY) for melanoma targeting and labeled with NIR dye Cy5 for whole-body PET-CT tracing.89 The results of the clinical trial indicated a favorable pharmokinetic profile and absence of human toxicity, which seems hopeful for the clinical translation of silica-coated UCNP. 8.1. Blood Circulation Time. One of the longest standing challenges to in vivo use of NPs is prolonging their blood circulation time so that the particles can arrive at their target location. F


Perspective

Journal of the American Chemical Society A recent work by Yu et al.99 indicated that UCNPs accumulate in the liver and spleen over the first 24 h, and are then eliminated through feces over a period of 30 days. Thus, cytotoxicity studies so far point toward low toxicity and gradual clearance even up to particle sizes of 30 nm. However, these studies are still preliminary and further studies could look into varying coatings and sizes to study their effect on cytotoxicity, as well as tracking cellular and organ uptake over time to better understand the in vivo biodistribution of UCNPs. 8.4. Penetration Depth. Despite the ability of NIR to penetrate further into tissue than UV, it is still substantially attenuated with penetration depth. In tissue studies conducted by Henderson et al., low-powered NIR lasers (0.2 and 0.5 W) yielded no detectable energy at a 3 cm depth below the skin surface. High-powered NIR lasers (10−15 W), on the other hand, delivered between 0.5% and 3.0% of their energy through 3 cm of tissue. The limited penetration depth of NIR limits the region of effective drug release to superficial tissue. However, a recent study by Chen et al. showed that NIR (2 W, 980 nm) applied transcranially activated UCNPs implanted in the ventral tegmental area of the brain, located at a depth of 4.5 mm. The NIR energy effective at this depth was sufficient to activate channelrhodopsin-expressing neurons, opening up the possibility of UCNP-activated optogenetics to stimulate deep brain neurons. These findings show that despite penetration depth limitations, UCNPs can still be remotely activated at clinically relevant levels. However, for drug release to be activated in organs located deeper than a few centimeters in the body, a fiber optic cable would have to be implanted via a minimally invasive surgical procedure to transmit sufficient NIR energy to the target area. 8.5. Overheating. Finally, although NIR light is nontoxic to biological tissue, high-intensity NIR can induce overheating and subsequent photodamage. A study by Xie et al. demonstrated HeLa cell death from 980 nm radiation (100 mW) for 5 min.100 One approach to alleviating the overheating effect is the use of 800 nm-excited Nd3+-based UCNPs. As this wavelength is absorbed less by water present in biological tissues, the excitation of these UCNPs at identical laser power and time left cells intact.100 915 nm excited Tm3+/Er3+/Ho3+ NaYbF4 UCNPs were also able to achieve the same effect.101 Another possibility is lowering the laser power; such ultralow intensity excited ruthenium-grafted UCNPs were developed by He et al. as described earlier in the paper.87 Overall, UCNP-based systems safe for clinical use must circumvent the overheating problem, or at least reduce the heating below maximum approved levels.

In addition to in-depth in vivo studies on long-term safety and biocompatibility, as well as continual improvement on material itself (improving quantum yield, narrow size distribution etc.), we propose the following design strategies we postulate can aid the clinical translation of UCNPs. 9.1. Multistage Delivery Systems. The multistage delivery system is an emerging solution in cancer nanomedicine that addresses the problems of mass transport and effective targeting. To ensure long circulation times and sufficient drug loading, a particle size of 12 to 60 nm is ideal, but to then penetrate the tumor tissue homogeneously, smaller particles of 5 to 10 nm are more effective.102 To this end, Fukumura et al. loaded 10 nm quantum dots into a larger gelatin NP (100 nm) that were released when triggered by proteinases at the invasive edge of tumors.103 The quantum dots could then penetrate the dense collagen matrix of a tumor. By replacing the quantum dots with chemotherapeutics, anticancer drugs could be transported into solid tumors. We thus envision a multistage UCNP system with primary targeting to receptors on the tumor surface and smaller 10 nm particles loaded within a polymer or silica coating. The progress of the system to its site would be monitored via luminescence imaging, and release of the smaller particles triggered once it has reached its target. These smaller particles could further be targeted toward a receptor within the tumor, or even a subcellular compartment within cancer cells, which would greatly enhance the specificity of drug targeting. 9.2. Separation of Imaging and Drug Delivery Modes. UCNPs have excellent potential in phototriggered drug delivery and in vivo bioimaging. Yet, relatively few studies have looked into the coupling of both applications into a single theranostic platform. Most of the developed UCNP-based theranostics rely on pH gradients104 or passive diffusion105 for drug release instead of the phototriggering as described in this Perspective. The theranostic probes that trigger drug release with NIR do so while imaging simultaneously. Yet, certain clinical applications require imaging without having to deliver the drug, such as the real-time monitoring of UCNPs to ensure targeting of correct site before triggering drug release. As such, more research is required in the area of NIR-controlled drug release in theranostic probes; further complexity can be added by decoupling imaging and drug delivery modes. 9.3. Real-Time Monitoring of Drug Pharmokinetics. The exact pharmacokinetics of drug release and drug concentration in vivo can give important feedback to doctors as to effectiveness of treatment and facilitate real-time response (adjusting laser power, irradiation time etc.) A FRET-based real-time monitoring system of the drug release process via a redox reaction was demonstrated by Lai et al.106 where the fluorescence of the particle changed based on the amount of drug release. A similar system could be employed in NIR-triggered systems so that the in vivo concentration of drug could be quantified in real-time. Drug release pharmacokinetics could be could be affected by the particular microenvironment at site of release, as well as vary based on the type of tumor or individual treated. Thus, such real-time monitoring would move UCNPs toward more personalized medicine. These are just some ideas that would allow UCNP-based systems to become the next generation of multimodal

9. CONCLUSIONS AND OUTLOOK Among the stimuli-responsive drug delivery vehicles being developed, NIR-controlled therapies have garnered much attention due to the noninvasiveness and specificity of light, as well as the advantages of NIR over UV. The research on UCNPs so far has established it as a promising photoresponsive tool, with applications not only in photoactivated drug delivery but also in multimodal in vivo imaging. Its highly tunable properties offer many opportunities to improve its transport and targeting to the site of interest, as well as the precision of drug release upon NIR radiation. G


Perspective


(17) Wang, X.-d.; Meier, R. J.; Schäferling, M.; Bange, S.; Lupton, J. M.; Sperber, M.; Wegener, J.; Ondrus, V.; Beifuss, U.; Henne, U.; Klein, C.; Wolfbeis, O. S. Adv. Opt. Mater. 2016, 4, 1854−1859. (18) Liu, Q.; Zhan, C.; Kohane, D. S. Bioconjugate Chem. 2017, 28, 98−104. (19) Liu, K.; Xue, X.; Furlani, E. P. Sci. Rep. 2016, 6, 34189. (20) Peng, H. Q.; Niu, L. Y.; Chen, Y. Z.; Wu, L. Z.; Tung, C. H.; Yang, Q. Z. Chem. Rev. 2015, 115, 7502−7542. (21) Su, Q.; Feng, W.; Yang, D.; Li, F. Acc. Chem. Res. 2017, 50, 32− 40. (22) Yu, J.; Cui, Y.; Wu, C. D.; Yang, Y.; Chen, B.; Qian, G. J. Am. Chem. Soc. 2015, 137, 4026−4029. (23) Berney, C.; Danuser, G. Biophys. J. 2003, 84, 3992−4010. (24) Chen, G.; Qiu, H.; Prasad, P. N.; Chen, X. Chem. Rev. 2014, 114, 5161−214. (25) Wang, F.; Liu, X. G. J. Am. Chem. Soc. 2008, 130, 5642−5643. (26) Capobianco, J. A.; Vetrone, F.; D’Alesio, T.; Tessari, G.; Speghini, A.; Bettinelli, M. Phys. Chem. Chem. Phys. 2000, 2, 3203− 3207. (27) Liu, X.; Yan, C. H.; Capobianco, J. A. Chem. Soc. Rev. 2015, 44, 1299−1301. (28) Auzel, F. Chem. Rev. 2004, 104 (1), 139−73. (29) Jalani, G.; Naccache, R.; Rosenzweig, D. H.; Haglund, L.; Vetrone, F.; Cerruti, M. J. Am. Chem. Soc. 2016, 138, 1078−1083. (30) Liu, J. A.; Bu, W. B.; Pan, L. M.; Shi, J. L. Angew. Chem., Int. Ed. 2013, 52, 4375−4379. (31) Tian, G.; Zheng, X. P.; Zhang, X.; Yin, W. Y.; Yu, J.; Wang, D. L.; Zhang, Z. P.; Yang, X. L.; Gu, Z. J.; Zhao, Y. L. Biomaterials 2015, 40, 107−116. (32) Yan, B.; Boyer, J. C.; Habault, D.; Branda, N. R.; Zhao, Y. J. Am. Chem. Soc. 2012, 134, 16558−16561. (33) Jalani, G.; Naccache, R.; Rosenzweig, D. H.; Lerouge, S.; Haglund, L.; Vetrone, F.; Cerruti, M. Nanoscale 2015, 7, 11255− 11262. (34) Mahalingam, V.; Vetrone, F.; Naccache, R.; Speghini, A.; Capobianco, J. A. Adv. Mater. 2009, 21, 4025−4028. (35) Chen, G.; Han, G. Theranostics 2013, 3, 289−291. (36) Xiang, J.; Xu, L. G.; Gong, H.; Zhu, W. W.; Wang, C.; Xu, J.; Feng, L. Z.; Cheng, L.; Peng, R.; Liu, Z. ACS Nano 2015, 9, 6401− 6411. (37) Min, Y. Z.; Li, J. M.; Liu, F.; Yeow, E. K. L.; Xing, B. G. Angew. Chem., Int. Ed. 2014, 53, 1012−1016. (38) Wang, C.; Cheng, L. A.; Liu, Z. A. Biomaterials 2011, 32 (4), 1110−1120. (39) Shan, G. B.; Weissleder, R.; Hilderbrand, S. A. Theranostics 2013, 3, 267−274. (40) Yang, Y.; Aw, J.; Xing, B. Nanoscale 2017, 9, 3698−3718. (41) Yang, Y.; Mu, J.; Xing, B. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1408. (42) Yang, D.; Ma, P.; Hou, Z.; Cheng, Z.; Li, C.; Lin, J. Chem. Soc. Rev. 2015, 44, 1416−1448. (43) Chen, G. Y.; Qiu, H. L.; Prasad, P. N.; Chen, X. Y. Chem. Rev. 2014, 114, 5161−5214. (44) Auzel, F. Chem. Rev. 2004, 104, 139−173. (45) Lu, Y.; Lu, J.; Zhao, J.; Cusido, J.; Raymo, F. M.; Yuan, J.; Yang, S.; Leif, R. C.; Huo, Y.; Piper, J. A.; Paul Robinson, J.; Goldys, E. M.; Jin, D. Nat. Commun. 2014, 5, 3741. (46) Zhang, Y.; Liu, X. Nat. Nanotechnol. 2013, 8, 702−703. (47) Naccache, R.; Yu, Q.; Capobianco, J. A. Adv. Opt. Mater. 2015, 3, 482−509. (48) Wang, M.; Abbineni, G.; Clevenger, A.; Mao, C.; Xu, S. Nanomedicine 2011, 7, 710−729. (49) Lin, M.; Zhao, Y.; Wang, S.; Liu, M.; Duan, Z.; Chen, Y.; Li, F.; Xu, F.; Lu, T. Biotechnol. Adv. 2012, 30, 1551−1561. (50) Boyer, J. C.; Vetrone, F.; Cuccia, L. A.; Capobianco, J. A. J. Am. Chem. Soc. 2006, 128, 7444−7445. (51) Cheng, Z. Y.; Lin, J. Macromol. Rapid Commun. 2015, 36, 790− 827.

theranostic probes able to enhance diagnosis and drug release at a localized site of interest. This is especially crucial in applications such as anesthetics, postwound healing, cardiothoracic surgery and cancer treatment, in which the timing and location of drug release could greatly affect clinical outcomes. Once the gap from lab to clinic is bridged, UCNPs may very well become the leading phototherapy for all these applications.

■

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Fiorenzo Vetrone: 0000-0002-3222-3052 Marta Cerruti: 0000-0001-8533-3071 Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank Natural Sciences and Engineering Research Council (NSERC), Canada Research Chairs(CRC) and Fonds de recherche du Québec−Nature et technologies (FRQNT) for financial support.

■

REFERENCES

(1) Blum, A. P.; Kammeyer, J. K.; Rush, A. M.; Callmann, C. E.; Hahn, M. E.; Gianneschi, N. C. J. Am. Chem. Soc. 2015, 137, 2140− 2154. (2) Brudno, Y.; Mooney, D. J. J. Controlled Release 2015, 219, 8−17. (3) Mura, S.; Nicolas, J.; Couvreur, P. Nat. Mater. 2013, 12, 991− 1003. (4) Kang, X. J.; Dai, Y. L.; Ma, P. A.; Yang, D. M.; Li, C. X.; Hou, Z. Y.; Cheng, Z. Y.; Lin, J. Chem. - Eur. J. 2012, 18, 15676−15682. (5) Liu, B.; Chen, Y. Y.; Li, C. X.; He, F.; Hou, Z. Y.; Huang, S. S.; Zhu, H. M.; Chen, X. Y.; Lin, J. Adv. Funct. Mater. 2015, 25, 4717− 4729. (6) Thomas, M.; Gajda, M.; Naini, C. A.; Franzka, S.; Ulbricht, M.; Hartmann, N. Langmuir 2015, 31, 13426−13432. (7) Qiu, Y.; Park, K. Adv. Drug Delivery Rev. 2012, 64, 49−60. (8) Mura, S.; Nicolas, J.; Couvreur, P. Nat. Mater. 2013, 12, 991− 1003. (9) Karimi, M.; Ghasemi, A.; Zangabad, P. S.; Rahighi, R.; Basri, S. M. M.; Mirshekari, H.; Amiri, M.; Pishabad, Z. S.; Aslani, A.; Bozorgomid, M.; Ghosh, D.; Beyzavi, A.; Vaseghi, A.; Aref, A. R.; Haghani, L.; Bahrami, S.; Hamblin, M. R. Chem. Soc. Rev. 2016, 45, 1457−1501. (10) Alvarez-Lorenzo, C.; Bromberg, L.; Concheiro, A. Photochem. Photobiol. 2009, 85, 848−60. (11) Ferris, D. P.; Zhao, Y. L.; Khashab, N. M.; Khatib, H. A.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2009, 131, 1686−1688. (12) Coti, K. K.; Belowich, M. E.; Liong, M.; Ambrogio, M. W.; Lau, Y. A.; Khatib, H. A.; Zink, J. I.; Khashab, N. M.; Stoddart, J. F. Nanoscale 2009, 1, 16−39. (13) Lim, X. Nature 2016, 531, 26−28. (14) Chen, G. Y.; Shen, J.; Ohulchanskyy, T. Y.; Patel, N. J.; Kutikov, A.; Li, Z. P.; Song, J.; Pandey, R. K.; Agren, H.; Prasad, P. N.; Han, G. ACS Nano 2012, 6, 8280−8287. (15) Carling, C. J.; Viger, M. L.; Huu, V. A. N.; Garcia, A. V.; Almutairi, A. Chem. Sci. 2015, 6, 335−341. (16) Shen, Y.; Shuhendler, A. J.; Ye, D.; Xu, J. J.; Chen, H. Y. Chem. Soc. Rev. 2016, 45, 6725−6741. H


Perspective

Journal of the American Chemical Society (52) Wang, F.; Banerjee, D.; Liu, Y.; Chen, X.; Liu, X. Analyst 2010, 135, 1839−1854. (53) Muhr, V.; Wilhelm, S.; Hirsch, T.; Wolfbeis, O. S. Acc. Chem. Res. 2014, 47, 3481−3493. (54) Baride, A.; Meruga, J. M.; Douma, C.; Langerman, D.; Crawford, G.; Kellar, J. J.; Cross, W. M.; May, P. S. RSC Adv. 2015, 5, 101338−101346. (55) Dai, Y. L.; Ma, P. A.; Cheng, Z. Y.; Kang, X. J.; Zhang, X.; Hou, Z. Y.; Li, C. X.; Yang, D. M.; Zhai, X. F.; Lin, J. ACS Nano 2012, 6, 3327−3338. (56) Lucky, S. S.; Muhammad Idris, N.; Li, Z.; Huang, K.; Soo, K. C.; Zhang, Y. ACS Nano 2015, 9, 191−205. (57) Ai, F.; Ju, Q.; Zhang, X.; Chen, X.; Wang, F.; Zhu, G. Sci. Rep. 2015, 5, 10785. (58) Lu, F.; Yang, L.; Ding, Y.; Zhu, J.-J. Adv. Funct. Mater. 2016, 26, 4778−4785. (59) Lucky, S. S.; Soo, K. C.; Zhang, Y. Chem. Rev. 2015, 115, 1990−2042. (60) Zhou, B.; Shi, B.; Jin, D.; Liu, X. Nat. Nanotechnol. 2015, 10, 924−936. (61) Schattling, P.; Jochum, F. D.; Theato, P. Polym. Chem. 2014, 5, 25−36. (62) Samanta, S.; McCormick, T. M.; Schmidt, S. K.; Seferos, D. S.; Woolley, G. A. Chem. Commun. 2013, 49, 10314−10316. (63) Yao, C.; Wang, P.; Li, X.; Hu, X.; Hou, J.; Wang, L.; Zhang, F. Adv. Mater. 2016, 28, 9341−9348. (64) Zhao, H.; Sterner, E. S.; Coughlin, E. B.; Theato, P. Macromolecules 2012, 45 (4), 1723−1736. (65) Zhu, C. C.; Ninh, C.; Bettinger, C. J. Biomacromolecules 2014, 15 (10), 3474−3494. (66) Chen, S.; Gao, Y.; Cao, Z.; Wu, B.; Wang, L.; Wang, H.; Dang, Z.; Wang, G. Macromolecules 2016, 49, 7490−7496. (67) Wu, S.; Butt, H. J. Adv. Mater. 2016, 28, 1208−26. (68) Mo, S. L.; Wen, Y.; Xue, F. F.; Lan, H. C.; Mao, Y. Y.; Lv, G. L.; Yi, T. Sci. Bull. 2016, 61, 459−467. (69) Bertrand, O.; Gohy, J. F. Polym. Chem. 2017, 8, 52−73. (70) Monti, S.; Manet, I. Chem. Soc. Rev. 2014, 43, 4051−4067. (71) Fedoryshin, L. L.; Tavares, A. J.; Petryayeva, E.; Doughan, S.; Krull, U. J. ACS Appl. Mater. Interfaces 2014, 6 (16), 13600−13606. (72) Yang, Y.; Shao, Q.; Deng, R.; Wang, C.; Teng, X.; Cheng, K.; Cheng, Z.; Huang, L.; Liu, Z.; Liu, X.; Xing, B. Angew. Chem., Int. Ed. 2012, 51, 3125−3129. (73) Garcia, J. V.; Yang, J.; Shen, D.; Yao, C.; Li, X.; Wang, R.; Stucky, G. D.; Zhao, D.; Ford, P. C.; Zhang, F. Small 2012, 8, 3800− 3805. (74) Ulbrich, K.; Hola, K.; Subr, V.; Bakandritsos, A.; Tucek, J.; Zboril, R. Chem. Rev. 2016, 116, 5338−5431. (75) Hunter, A. C.; Moghimi, S. M. Polym. Chem. 2017, 8, 41−51. (76) Bagheri, A.; Arandiyan, H.; Boyer, C.; Lim, M. Adv. Sci. (Weinh) 2016, 3, 1500437. (77) Rwei, A. Y.; Wang, W. P.; Kohane, D. S. Nano Today 2015, 10, 451−467. (78) Xing, Q.; Li, N.; Jiao, Y.; Chen, D.; Xu, J.; Xu, Q.; Lu, J. RSC Adv. 2015, 5, 5269−5276. (79) Yan, B.; Boyer, J. C.; Branda, N. R.; Zhao, Y. J. Am. Chem. Soc. 2011, 133, 19714−19717. (80) Yan, K.; Chen, M.; Zhou, S. X.; Wu, L. M. RSC Adv. 2016, 6, 85293−85302. (81) Li, J. Y.; Mooney, D. J. Nat. Rev. Mater. 2016, 1, 16071. (82) Eskandari, S.; Guerin, T.; Toth, I.; Stephenson, R. J. Adv. Drug Delivery Rev. 2017, 110, 169−187. (83) Cho, Y. I.; Park, S.; Jeong, S. Y.; Yoo, H. S. Eur. J. Pharm. Biopharm. 2009, 73, 59−65. (84) Argyo, C.; Weiss, V.; Brauchle, C.; Bein, T. Chem. Mater. 2014, 26, 435−451. (85) Yang, Y.; Velmurugan, B.; Liu, X.; Xing, B. Small 2013, 9, 2937−2944. (86) Zhao, L. Z.; Peng, J. J.; Huang, Q.; Li, C. Y.; Chen, M.; Sun, Y.; Lin, Q. N.; Zhu, L. Y.; Li, F. Y. Adv. Funct. Mater. 2014, 24, 363−371.

(87) He, S.; Krippes, K.; Ritz, S.; Chen, Z.; Best, A.; Butt, H. J.; Mailander, V.; Wu, S. Chem. Commun. (Cambridge, U. K.) 2015, 51, 431−434. (88) Zhang, H. OncoTargets Ther. 2016, 9, 3001−3007. (89) Phillips, E.; Penate-Medina, O.; Zanzonico, P. B.; Carvajal, R. D.; Mohan, P.; Ye, Y.; Humm, J.; Gonen, M.; Kalaigian, H.; Schoder, H.; Strauss, H. W.; Larson, S. M.; Wiesner, U.; Bradbury, M. S. Sci. Transl. Med. 2014, 6, 260ra149. (90) Shi, J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Nat. Rev. Cancer 2017, 17, 20−37. (91) Gref, R.; Luck, M.; Quellec, P.; Marchand, M.; Dellacherie, E.; Harnisch, S.; Blunk, T.; Muller, R. H. Colloids Surf., B 2000, 18, 301− 313. (92) Cheng, L.; Yang, K.; Shao, M.; Lu, X.; Liu, Z. Nanomedicine (London, U. K.) 2011, 6, 1327−1340. (93) Choi, H. S.; Liu, W.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Itty Ipe, B.; Bawendi, M. G.; Frangioni, J. V. Nat. Biotechnol. 2007, 25, 1165−1170. (94) Zhou, J.; Liu, Z.; Li, F. Chem. Soc. Rev. 2012, 41, 1323−1349. (95) Homann, C.; Krukewitt, L.; Frenzel, F.; Grauel, B.; Wurth, C.; Resch-Genger, U.; Haase, M. Angew. Chem., Int. Ed. 2018, 57, 8765. (96) Tinkle, S.; McNeil, S. E.; Muhlebach, S.; Bawa, R.; Borchard, G.; Barenholz, Y. C.; Tamarkin, L.; Desai, N. Ann. N. Y. Acad. Sci. 2014, 1313, 35−56. (97) Abdul Jalil, R.; Zhang, Y. Biomaterials 2008, 29, 4122−4128. (98) Xiong, L.; Yang, T.; Yang, Y.; Xu, C.; Li, F. Biomaterials 2010, 31, 7078−7085. (99) Yu, J.; Yin, W.; Peng, T.; Chang, Y. N.; Zu, Y.; Li, J.; He, X.; Ma, X.; Gu, Z.; Zhao, Y. Nanoscale 2017, 9 (13), 4497−4507. (100) Xie, X.; Gao, N.; Deng, R.; Sun, Q.; Xu, Q. H.; Liu, X. J. Am. Chem. Soc. 2013, 135, 12608−12611. (101) Zhan, Q.; Qian, J.; Liang, H.; Somesfalean, G.; Wang, D.; He, S.; Zhang, Z.; Andersson-Engels, S. ACS Nano 2011, 5, 3744−3757. (102) Stylianopoulos, T.; Jain, R. K. Nanomedicine 2015, 11, 1893− 1907. (103) Wong, C.; Stylianopoulos, T.; Cui, J.; Martin, J.; Chauhan, V. P.; Jiang, W.; Popović, Z.; Jain, R. K.; Bawendi, M. G.; Fukumura, D. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 2426−2431. (104) Tian, G.; Yin, W.; Jin, J.; Zhang, X.; Xing, G.; Li, S.; Gu, Z.; Zhao, Y. J. Mater. Chem. B 2014, 2, 1379−1389. (105) Zhang, F.; Braun, G. B.; Pallaoro, A.; Zhang, Y.; Shi, Y.; Cui, D.; Moskovits, M.; Zhao, D.; Stucky, G. D. Nano Lett. 2012, 12, 61− 67. (106) Lai, J.; Shah, B. P.; Garfunkel, E.; Lee, K. B. ACS Nano 2013, 7, 2741−2750.

I


Seeing, Targeting and Delivering with Upconverting Nanoparticles

Recommend Documents