Photoswitchable Molecules in Long-Wavelength ... - ACS Publications

Review Cite This: Chem. Mater. 2018, 30, 2873−2887

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Photoswitchable Molecules in Long-Wavelength Light-Responsive Drug Delivery: From Molecular Design to Applications Shiyang Jia,† Wye-Khay Fong,‡,∥ Bim Graham,† and Ben J. Boyd*,‡,§ Medicinal Chemistry, ‡Drug Delivery, Disposition and Dynamics, and §ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia ∥ Department of Health Science & Technology, ETH Zurich, Schmelzbergstrasse 9, LFO E23, 8092 Zurich, Switzerland Downloaded via UNIV OF TOLEDO on June 29, 2018 at 16:16:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

ABSTRACT: Stimuli-responsive nanocarriers can release their bioactive cargo “on demand”, potentially improving the selectivity, specificity, and efficacy of therapeutic drugs. Light of wavelengths between 650−1100 nm is a unique stimulus with many advantages. It is noninvasive and “bio-friendly” and can be manipulated with precision and ease. Many lightresponsive nanocarriers reported in the literature employ photochromic molecules that undergo reversible isomerization upon irradiation, thereby functioning as gates or switches for the release of encapsulated bioactive compounds. This review surveys the design, synthesis, function, and application of onephoton visible and near-infrared light-triggered photoswitchable compounds in the development of long-wavelength lightresponsive nanocarriers. cancerous tissue. Those stimuli includes enzyme,16 pH,17 hypoxia,18 and redox.19 Endogenously responsive systems are not the focus of this review but are mentioned here for completeness. External stimuli-responsive nanocarriers principally comprise systems that are responsive to applied magnetic fields,20,21 electric field,22 ultrasound,23 and light.24 Among these stimuli, light has many advantageous features. In addition to being relatively noninvasive and “bio-friendly”, light is easily manipulated and finely tunable, allowing for precise control over the site, timing and dosage of released species. Unsurprisingly, therefore, light-responsive nanocarriers have attracted major interest within the drug delivery field.15,25,26 Nonionizing light can be broadly divided into three wavelength ranges, namely, ultraviolet (UV, 10−400 nm), visible (400−750 nm), and near-infrared (NIR, 750−1100 nm). Both the wavelength and the power of the light used to trigger cargo release directly influence the effectiveness and safety profile of a light-responsive nanocarrier.25,27 The most important parameters that need to be considered are the tissue penetration depth and phototoxicity of the light employed. Generally speaking, the longer the wavelength of light, the deeper its penetration through skin, for wavelengths up to 900 nm.28−31 For example, the reported penetration depth (attenuation down to 1%) in the skin of light at wavelength 360 nm is 190 μm; 700 nm is 400 μm and 1200 nm is 800

1. INTRODUCTION Advances in materials science have seen an increasing range of nanomaterials employed in the development of nanosystems for the transport and release of molecular cargo (“nanocarriers”), including mesoporous silica nanoparticles,1,2 plasmonic nanoparticles,3,4 polymeric nanoparticles,5 liposomes,6 micelles,7 dendrimers,8,9 hydrogels,10 and other nanoassemblies.11 To facilitate their application as drug delivery agents, efforts have focused particularly on the generation of structurally well-defined nanocarriers possessing good biocompatibility and high loading capacities.12−14 The pharmacokinetics and bioavailability of encapsulated drugs are to a large extent dictated by the physicochemical properties of the nanocarrier, providing an attractive strategy for improving the distribution of, for example, poorly water-soluble drugs.15 The past few years have witnessed particularly strong interest in the development of stimuli-responsive nanocarriers, designed to release bioactive cargo “on demand” in response to specific stimuli. Such systems provide a means of improving the selectivity, specificity, and efficacy of therapeutic drug treatments, as well as delivering patients benefits in reducing injection load and frequency. The stimuli that have been exploited to trigger drug release from nanocarriers can be broadly divided into two classes: endogenous and exogenous or external stimuli. Endogenous stimuli-responsive nanocarriers exploit the fact that physiological differences often exist between diseased and healthy tissue, e.g., the increased metabolic requirements of fast growing tumor cells result in changes to the biochemistry of © 2018 American Chemical Society

Received: January 24, 2018 Revised: April 9, 2018 Published: April 9, 2018 2873

DOI: 10.1021/acs.chemmater.8b00357 Chem. Mater. 2018, 30, 2873−2887

Review

Chemistry of Materials

Figure 1. Photoinduced isomerization of photoswitchable molecules discussed in this review.

μm.32 This is predominantly due to the absorbance characteristics of the endogenous chromophores hemoglobin, oxyhemoglobin, and myoglobin. Another major tissue component, water, has strong absorbance in the NIR and IR regions, leading to increasingly poor penetration for wavelengths above 900 nm.30 The “optical window” or “therapeutic window” refers to the range of wavelengths from ca. 650 to 1100 nm where light has its maximum depth of penetration into tissue. Absorption of large amounts of optical radiation by tissues can result in photochemical reactions or heating effects, which may induce protein denaturation, DNA breakage, or lipid peroxidation, ultimately leading to cell death.27,33 Serious phototoxicity occurs when the irradiation exceeds the maximum permissible exposure (MPE).32 Light energy is dependent upon the per-photon energy, the distance from the light source, the duration, and the intensity of irradiation. It is therefore important for these details to be clearly presented within publications. Photon energy has an inverse relationship with wavelength of light, meaning that light of longer wavelengths is more biocompatible.27 UV light has a low MPE due to its high energy-per-photon and high tissue absorbance, rendering it undesirable for many bioapplications. Visible and NIR light have higher MPEs and are therefore more suited to in vivo and in cellulo use.26 Many light-responsive nanocarriers reported in the literature incorporate photochromic molecules that function as “gates” or “switches” for the release of encapsulated bioactive compounds. Photochromic molecules, also known as photoswitchable molecules, undergo reversible isomerization when exposed to electromagnetic radiation of a specific wavelength.34,35 Photoisomerization usually occurs though one of two main mechanisms, illustrated in Figure 1. The first, exemplified by azobenzenes, is E-to-Z isomerization of a double bond, resulting in significant geometric change. The other is 6π electrocyclization of a triene system, e.g., spiropyrans and diarylethenes, which produces a large change in electronic distribution. The two isomers of a photoswitchable molecule possess distinct chemical, physical and optical properties (e.g., absorbance signature, molecular volume, and molecular charge), which can be utilized to tune the release properties of a host material. Most traditional photoswitchable systems require UV light for excitation; however, recent years have seen a concerted push to develop long-wavelength light-responsive analogues in order to improve biocompatibility.35 These molecular design

efforts have often gone hand-in-hand with ones aimed at enhancing isomerization yield, resistance to photodegradation, the degree of shape change upon isomerization, and ease of incorporation of photoswitchable molecules into host materials. An alternative method that has been utilized to create visible and NIR light-responsive materials is the introduction of upconverting moieties, which convert photon energy from long wavelengths of light to UV wavelength on the atomic scale.36−38 This has been achieved by using photosensitive groups that absorb two photons of visible or NIR light to access higher energy excited states or by combining with upconverting nanoparticles (usually lanthanide-based nanomaterials) that convert visible/NIR light to UV light.39,40 Although promising, this approach suffers from issues pertaining to the low quantum yield of upconversion processes25,41 and is not the focus of this review (interested readers are directed to ref 41). The design and synthesis of photoswitchable molecules and their incorporation into “smart” nanomaterials requires collective cross-disciplinary efforts, especially advanced knowledge from chemistry and photochemistry. This review examines the state-of-the-art in the design, synthesis, and mechanism of one-photon visible and NIR light-responsive photoswitchable compounds, as well as the exploitation of these compounds in the generation of light-responsive nanocarriers. It is divided into four major sections based on the major chemistries involved: (i) azobenzenes, (ii) spiropyrans, (iii) diarylethenes, and (iv) other promising photoswitchable molecules, including hemithioindigos, donor−acceptor Stenhouse adducts, and hexaarylbiimidazoles (Figure 1). A comprehensive understanding of the design and preparation of visible/NIR lightresponsive photochromic-based nanocarriers is intended in this review.

2. AZOBENZENES Azobenzenes consist of an azo group (NN) with appended aryl groups. These compounds undergo an E-to-Z isomerization upon irradiation. The simplest example, azobenzene, features two unsubstituted phenyl groups. Irradiation with 365 nm UV light transforms of the E isomer to the Z form via excitation of π → π* (Figure 2). The reverse Z-to-E isomerization is induced by 450 nm light (or by heating), but the presence of overlapping n → π* bands for both isomers in the vicinity of this wavelength prevents complete photoreversion to the E form.42 2874


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atoms can lower the n-orbital energy of the Z isomer by reducing the electron density in the nearby NN bond.42 With appropriate functionalization, the separation of the n → π* bands of the E and Z isomers of azobenzenes becomes sufficiently large that visible light can be exploited to selectively isomerize both the E and the Z isomers. Bléger et al.,42 for example, have reported an azobenzene derivative featuring para-ester and ortho-fluorine substituents (compound AB1, Figure 2) that can be switched from the E to Z form in 90% yield with green light (λ > 500 nm) and then back to the E form in 97% yield with blue light (λ = 410 nm). The half-life of the Z isomer has been greatly increased to 2 years. Beharry et al. have similarly developed tetra-orthomethoxy-substituted azobenzenes that are switchable with green/blue light.43 Building on this seminal work, Samanta et al.46 prepared a series of peptides cross-linked with tetra-orthomethoxy substituted azobenzene derivatives (e.g., AB2) for which the n → π* absorption bands of the E isomers tailed past 600 nm. Red light (635 nm, 90 mW/cm2) could be used to access the Z isomer of AB2 (ca. 98%), and the E isomer recovered (ca. 85%) via exposure to blue light (450 nm). Thermal reversion to the E form was slow (hours). This group subsequently created a series of thiol-substituted azobenzene derivatives (e.g., AB3) that could also be triggered with 635 nm light, but which exhibited faster thermal Z-to-E back-reaction rates (t1/2 of the order of minutes).47 Yang et al.48,49 have reported BF2-coordinated azobenzenes that exhibit visible and NIR light switching properties. For example, the E isomers of AB4 and AB5 can be converted to the Z forms with 570 and 710 nm light, respectively. The Z isomer of AB5 has a fast thermal relaxation rate (t1/2 = 250 s), while that of AB4 is considerably more stable (t1/2 = 12.5 h). The E form of AB4 is recovered with 450 nm light. 2.2. Application of Azobenzenes in Light-Responsive Nanocarriers. Light-responsive cyclodextrin (CD)-based nanocarriers have been developed in which azobenzenes serve as a light-controllable “gatekeepers”. CD, especially β-CD, has a higher binding affinity for the E isomer of azobenzene than the Z form. When E-azobenzene binds to β-CD, it acts as a nanopore-sealing cap. Upon irradiation, E-to-Z isomerization leads to dissociation from the β-CD, thus opening the nanopore and providing a mechanism for cargo release. This light-sensitive host−guest interaction underpins the functioning of a number of mesoporous silica nanoparticle (MSN)-51,52 and hydrogel-based53−55 light-responsive drug delivery systems. A notable recent example reports the construction of a red light-responsive “supramolecular valve” using tetra-ortho-

Figure 2. Examples of red-shifted azobenzenes featuring fluorine (AB1),42 electron-donating (AB2, R = FK11 peptide with a sequence of WGEACAREAAAREAACRQ),46 and thiol (AB3)47 substitution, an unusual BF2 bridge (AB4),48 and plus a para-dimethylamino substitution (AB5).49 The wavelengths of maximum absorbance in the visible light region (within the specified solvents) are shown, together with the wavelengths that have been used to trigger E-to-Z isomerization, and the half-lives of the Z forms.

2.1. Long-Wavelength Light-Responsive Azobenzene Derivatives. Recent research has demonstrated that introduction of ring substituents significantly influences the absorbance maxima of the E and Z isomers of azobenzene (examples shown in Table 1). The shift in absorbance maxima has been attributed to three factors: (1) the electron-donating group on the rings lead to a red-shift of the absorbance of the E isomer, possibly due to raising the relative energy of the highest occupied molecular orbital (HOMO) in the E-form;43,50 (2) steric interactions reduces the sp2 character of the N atoms, also raising the HOMO energy, leading to the red-shift absorbance;44 and (3) electron-withdrawing groups such as F

Table 1. Various Visible Light-Responsive Azobenzene Derivatives Reported in the Literaturea

R1

R2

λmax of E isomer (nm)

λmax of Z isomer (nm)

H atoms methoxyl groups43 piperidine groups44 F atoms42

H atoms methoxyl groups H atoms F atoms

36445 338 (π → π*), 480 (n → π*) 445 ∼364 (π → π*), 370 (n → π*)

348 (π → π*), 473 (n → π*)43 ∼330 (π → π*), 444 (n → π*) N/A ∼314 (π → π*), 450 (n → π*)

The λmax of Z isomer of the first example was obtained from calculation using the TDDFT (B3LYP/6-31G*) methods.43 Adapted from refs 43,44, and 42.

a

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Chemistry of Materials methoxy-substituted azobenzene and β-CD to control release of doxorubicin (DOX) from MSNs (Figure 3).51 Exposure to red light (625 nm, 60 mW/cm2) for 360 min resulted in release of ca. 38% of encapsulated DOX. Moreover, when the light intensity was tempered by passage through 2 mm thick porcine tissue, 23% of DOX was still released in the same period, compared to ca. 5% for a nonirradiated control sample. Little photodamage to surrounding tissue was observed. Li et al.52 have also taken advantage of the azobenzene/CD interaction in the development of a NIR light-responsive drug delivery system, however this time exploiting the thermal switching capacity of azobenzenes in combination with the photothermal properties of gold nanorods. Their system consists of a DOX-loaded mesoporous silica−gold nanorod core−shell structure (Au@MSN), with α-CD-threaded azobenzene moieties grafted onto the surface (Figure 4). Upon UV irradiation, the generated Z-azobenzene moieties force the threaded α-CD units close to the surface of the mesoporous silica, blocking its pores and inhibiting drug release. Exposure to NIR irradiation, however, leads to thermal-driven production of E-azobenzene, mediated by the heating effects of gold nanorods. This allows the α-CD molecules to migrate outward and onto the azobenzene moieties, opening the pores and triggering drug release. Precise control of drug release from this system using NIR light was demonstrated both in vitro and in vivo. Angelos et al.56 have shown that azobenzenes grafted on the interior and pore openings of MSNs are able to function as “molecular impellers” when irradiated with light, enhancing the rate of escape of encapsulated small molecules (Figure 5). They used blue light (457 nm) to excite both isomers and produce sequential isomerization reactions, causing a continual “dynamic wag” that was able to shunt guest molecules through the pores and expel them into the surrounding solvent. MSNs with azobenzenes grafted on the pore openings showed a faster release profile than those with azobenzenes on the interiors. Lu et al.57 investigated the effectiveness of this nanocarrier for drug release in vitro. In the absence of light, camptothecin (CPT)loaded MSNs showed no activity toward two cell lines (a pancreatic cancer cell line, PANC-1, and a colon cancer cell line, SW480). After 5 min of irradiation with blue light (412 nm, 200 mW/cm2), however, CPT was released from the

Figure 4. (A) Schematic representation of a photoresponsive Au@ MSN−rotaxane system. (B) Release of DOX indicated by confocal images within embryo heads without and with NIR irradiation.52 Reprinted with permission from ref 52. Copyright 2014 Royal Society of Chemistry.

Figure 5. Schematic representation of photoresponsive MSNs functionalized with azobenzene derivatives as impellers and gatekeepers.56 Reprinted with permission from ref 56. Copyright 2007 American Chemical Society.

MSNs, inducing apoptosis in 60% of the PANC-1 cells and 86% of the SW480 cells. Besides acting as “gatekeepers”, azobenzenes derivatives also can be covalently linked to the polymers or lipids or physically doped into the self-assemblies and, hence, have also been widely incorporated into nanoparticles formed via the selfassembly of polymers or lipids for use as photoactivatable drug delivery systems. Reported azobenzene-functionalized selfassembled nanoparticles include thermotropic liquid crystals,58 liposomes,59 vesicles,60,61 hollow nanotubes,63 and hydrogels.55 The significant change in molecular geometry associated with isomerization of azobenzenes can destabilize and potentially even destroy the structure of these self-assemblies, leading to cargo release. However, no visible or NIR light-responsive nanocarriers of this kind have appeared in the literature as yet. These systems are still of significance for constructing long wavelength light-responsive self-assemblies. Hence, here we summarize several such systems that showed a release of diverse cargoes under UV light (365 nm) irradiation in Table 2 for readers’ interests.

3. SPIROPYRANS Spiropyrans represent another well-known family of photoswitchable molecules. Their photochromism was first reported by Fischer and co-workers in 1952.67 These molecules generally contain a 2H-pyran ring linked via the second carbon atom of the ring to another ring that is usually heterocyclic in nature. In polar solvents, UV irradiation (λmax = 365 nm) leads to conversion of the colorless spiropyran (SP) to the intensely colored merocyanine (MC) form via bond cleavage (Figure 6).68 The closed SP form is recoverable either by heating or by exposure to visible light (λ > 450 nm).68 The MC form has a

Figure 3. Schematic representation of a red light-responsive drug delivery system constructed from MSNs modified with azobenzene (Azo)/β-CD supramolecular caps.51 Reprinted with permission from ref 51. Copyright 2016 American Chemical Society. 2876


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Chemistry of Materials Table 2. Selected UV Light-Responsive Polymeric and Lipid-Based Nanocarrier Systems Incorporating Azobenzenes type of host polymer or lipids

type of nanocarriers

cargoes

reference

positive amphiphilic lipids low molecular weight gelators lipids block copolymers dendrimers amphiphilic guest lipids cross-linked polymers

catanonic vesicles hydrogel hollow nanosphere dendrimers superamolecular bilayer vesicles hydrogel

Nile red, DNA DNA, doxorubicin doxorubicin eosin mitoxant peptide

Liu et al.61 Pianowski et al.62 Zhang et al.63 Puntoriero et al.64 Hu et al.65 Nehls et al.66

Figure 6. Photoinduced isomerization of a “positive” spiropyran.68

planar structure and extended π-conjugation between the indoline and the chromene moieties,68 and it can be zwitterionic or positively charged on the N atom of the indoline ring in solution, depending on the pH of the environment. It is highly distinct from the SP form in terms of its absorption and fluorescence characteristics, dipole moment, dielectric constant, and pKa.68−70 Production of the MC form can be induced by a high polarity environment,71 temperature and pH changes,72 and complexation with metal ions.73 Hence, spiropyrans not only exhibit photochromism but also solvatochromism,74 thermochromism,75 ions,73 and acidichromism.76 A drawback of these compounds is that their isomerization usually does not involve a dramatic change in molecular conformation.68 3.1. Long-Wavelength Light-Responsive Spiropyran Derivatives. The most common strategy to achieve visible light-responsiveness has been to develop “negative” spiropyrans, which display contrary photochromic and thermal behavior to the original spiropyran moiety.77,78 These compounds are thermally stable in their colored MC form77 and can be subsequently converted to the colorless ring-closed SP form via exposure to visible light. The MC form is regenerated through thermal back-reaction. The transition between the MC and the SP forms is accompanied by a pH change. Recently developed negative photochromic spiropyrans are illustrated in Figure 7. The group of Liao has reported SP1 and SP2, featuring propyl sulfonate groups to improve water solubility. The pka of SP1 is 7.8. In aqueous solution, the MC isomer exists in a mixture of protonated (MCH) and deprotonated (MC) forms, with λmax values of 424 and ca. 550 nm. Irradiation with either blue light (419 nm) or yellow light (570 nm) leads to the generation of the SP form from the MCH form. The SP form of SP1 displays complete proton dissociation, corresponding to a drop in pH from 5.5 to 3.3 upon irradiation (conc. 0.588 nM).79 SP2 incorporates an indazole ring in place of the phenol ring.80 Due to the dual weakly acidic and weakly basic nature of the indazole moiety, SP2 shows a pKa of 10.1 and, hence, exists mostly (>99%) in its MCH form at pH 7.4. Irradiation with 470 nm light generates the SP form, which exhibits a very long half-life (48 h). Peng’s group introduced the sulfonated compound SP3, which absorbs within the 500−600 nm region and is consequently able to undergo MC/SP isomerization upon irradiation with white light.81

Figure 7. Examples of red-shifted “negative” spiropyran derivatives featuring alkyl sulfonate (SP179 and SP280), sulfo (SP381), TCF (SP482), and CF3PhTCF (SP583) substitution. The wavelengths of maximum absorbance in the visible light region (within the specified solvents) are shown, together with the wavelengths that have been used to trigger isomerization and the half-lives of the SP forms.

The group of Liao has also explored the introduction of highly conjugated electron-withdrawing groups in order to improve the photochromic and pH-switching properties of spiropyran-type photoswitches. In the first example, SP4, a tricyanofuran (TCF) group was incorporated to promote nucleophilic attack and generation of the SP form.82 The MC form exhibits a red-shifted λmax at 428 nm in DMSO, and photoisomerization can be accomplished using 470 nm light. The cyclized SP form exhibits a long half-life (t1/2 = 102 min); however, SP4 suffers from issues with photodecomposition. Introduction of a stronger electron acceptor, CF3PhTCF, produced SP5,83 whose MC form exhibits a λmax of 474 nm. The SP form displays a very short half-life (t1/2 = 23 s), and, overall, compound SP5 shows excellent fatigue resistance. Khodorkovsky and his group have reported 1,3-indandionederived spirocyclohexadine compounds that show rare “positive” visible light-responsive photochromism (Figure 8).84 These compounds exist mainly in a cyclic SP-like, yellow-colored form in the dark in polar solvents, and photoisomerize in a manner similar to spiropyrans despite their more complicated structure. They display broad absorbance bands in the visible region and are very sensitive 2877


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layer served to hinder release of encapsulated cargo into the surrounding aqueous environment (Figure 10).86 Upon lowpower UV irradiation (365 nm, 2.4 μW/cm2), conversion of the spiropyran to the hydrophilic MC caused wetting of the MSNs surface, leading to a 7-fold increase (∼15% vs ∼2% over 12 h) in the rate of cargo release in vitro. Phototriggered drug release was also demonstrated in the presence of two cancer cell lines (EA hy926 and HeLa), leading to a significant decrease in cell viability (32% for EA hy926 and 51% for HeLa after 5 min irradiation). The low level of UV light itself did not affect cell viability. The UV light-driven change in hydrophobicity of spiropyrans has also been exploited by Lu et al.87 in the development of photoresponsive MSNs (Figure 11). These workers embedded a spiropyran-functionalized amphiphilic copolymer, poly(RBMMAPEG-SPMA)-FA, onto the surface of C18-coated MSNs (the folic acid moiety was incorporated to promote targeting of the system to overexpressed folate receptors commonly found on the surface of tumor cells). UV irradiation (365 nm, 200 mW/cm2) led to shedding of the polymer coating due to conversion of the spiropyran to the hydrophilic MC form, with fluorescence from the appended rhodamine B moiety being quenched in the process. 50% of an encapsulated drug (DOX) could be released from the irradiated system over a 10 h period, while negligible release was observed when the system was kept in the dark. Furthermore, UV irradiation of KB cells incubated with the functionalized NP led to a 50% decrease in cell viability relative to an appropriate control. 3.2.2. Self-Assembled Nanocarriers. Self-assembled nanocarriers incorporating spiropyrans have predominantly been constructed from polymeric materials. Three main differences between the SP and the MC isomers of spiropyrans have been utilized to manipulate the self-assembly/disassembly of the molecular components of such system: degree of protonation, π−π interactions, and zwitterionicity. As noted in Section 3.1, conversion of the MC form of a spiropyran to the SP form leads to an increase in proton concentration. Liao et al.88 have exploited this to trigger disassembly of a nanoparticle system composed of poly(methyl acrylate-co-acrylic acid) (PMA-co-PAA) and poly(4-vinylpyridine) held together by hydrogen bonding between the carboxylic acid and pyridinyl groups (Figure 12). Irradiation of a methanolic suspension of the polymer and the negative spiropyran derivative SP1 with blue LED light (470 nm, 20 mW/cm2) results in protonation of the pyridinyl groups, leading to disruption of the hydrogen bonding and

Figure 8. Visible light-responsive 1,3-indandione-derived spirocyclohexadine compounds.84

to visible light (red and green), with exposure to light of wavelengths between 254 to 532 nm (derivative c) or even up to 642 nm (derivative b) leading to conversion to the MC-like forms. The MC forms are also strongly absorbing in the visible range but are not photosensitive, unlike typical spirocompounds. Discoloration of the MC form happens spontaneously in the dark, the rate of which is temperature- and solvent polarity-dependent. 3.2. Application of Spiropyrans in Light-Responsive Nanocarriers. 3.2.1. Mesoporous Silica Nanoparticles. Spiropyran derivatives have been widely applied in the development of gated MSNs, although few of these systems are responsive to longer wavelengths of light. Visible lightresponsive MSNs incorporating a mesoporous support (MCM41), a negative spiropyran, and a carboxyl-terminated PAMAM dendrimer have been reported by Aznar et al.85 (Figure 9). At pH 7.2, the negatively charged PAMAM dendrimers form electrostatic bonds with the MC isomers grafted onto the surface of the MCM-41. As with azobenzene formulations, these photochromics act as “caps” to block the pores of the MSNs. Visible irradiation induces conversion of the charged MC form to the neutral SP form, allowing release of the entrapped cargo at a rate seven times higher than that observed in the dark or in the presence of UV light. Some of the more interesting low-power UV-responsive spiropyran-functionalized MSNs are worth highlighting to illustrate the ways in which light-dependent cargo release can be achieved from nanocarrier systems. For example, Jiang and co-workers formed a hydrophobic layer on the surface of MSNs using the SP form of a spiropyran and a fluorinated silane. This

Figure 9. Schematic representation of a photoresponsive nanocarrier system consisting of a mesoporous framework (MCM-41), an anchored photoswitchable spiropyran, a dye in the inner pores, and carboxylate-terminated G1.5 PAMAM dendrimers as molecular caps.85 Reprinted with permission from ref 85. Copyright 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 10. Schematic representation of a “dry−wet” light-responsive release system.86 Reprinted with permission from ref 86. Copyright 2014 American Chemical Society. 2878


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1982, Sunamoto and his group reported the photocontrolled transport of phenylalanine (Phe) across liposomal bilayers that contained a positive-type spiropyran derivative.91 Phe formed ionic complexes with the zwitterionic MC form of the spiropyran upon UV irradiation and was effectively “pulled” across the lipidic bilayer. In similar work, Marx-Tibbon et al. have reported the release of tryptophan from spiropranmodified copolymers upon irradiation.92 A recent study by Wang et al.93 presented spiropyranfunctionalized polymersomes based on poly(ethylene oxide)-bPSPA diblock copolymers, containing carbamate linkages (Figure 13). The SP form of the spiropyran moieties that were generated either under visible light irradiation (λ > 450 nm) or spontaneously in the dark rendered the particles impermeable. The UV light-generated MC form was stabilized through hydrogen bonding to the carbamate group, leading to the release of embedded uncharged, charged, and zwitterionic small-molecule species from the polymersomes. Two modes of release were demonstrated in vitro and in cellulo: (i) sustained release upon a short period of UV irradiation and (ii) switchable release under alternating UV−visible light irradiation. Spiropyran derivatives have also been utilized as dopants in LLC self-assemblies to achieve photocontrol over the release rate of encapsulated cargo. Boyd and co-workers demonstrated that UV irradiation of phytantriol-based LLCs doped with spiropyran derivatives featuring long alkyl tails was able to induce a reversible phase transition from a rapid-release mesophase (bicontinuous cubic phase) to a slow-release mesophase (reverse hexagonal phase), due to the disruption of the packing of the self-assembled lipids induced by photoisomerization of the spiropyran groups.94,95

Figure 11. Schematic representation of a spiropyran-functionalized polymersome for DOX delivery that dissembles upon exposure to UV light due to conversion of the spiropyran to its more hydrophilic MC form.87 Reprinted with permission from ref 87. Copyright 2013 Royal Society of Chemistry.

Figure 12. Schematic representation of reversible dissolution of polymer-based nanoparticles triggered by spiropyran photoisomerization.88 Reprinted with permission from ref 88. Copyright 2016 Royal Society of Chemistry.

4. DIARYLETHENES Diarylethenes are photochromic molecules that contain two aryl groups linked via a CC double bond.96−98 Stilbene is the simplest and most well-known example, incorporating two phenyl groups (Figure 14A).98,58 Upon UV irradiation, stilbenes undergo an initial E-to-Z isomerization, followed by a 6π electrocyclization to form ring-closed dihydrophenanthrene, which can then undergo an irreversible hydrogenelimination reaction with oxygen to produce phenanthrene.98

solubilization of the polymers. Upon cessation of irradiation, the spiropyran derivative returns to its protonated MC form, leading to regeneration of a milky suspension. This novel technology was used to induce the release of a fragrant aldehyde molecule.89 The MC spiropyran isomer can form H-type π−π interactions within the sterically crowded environment of polymer brushes. Based on this, Achilleos et al.90 developed polymeric nanoparticles whose assembly can be triggered by UV light irradiation and then disassociate upon exposure to visible light. A spiropyran-containing monomer, SPMA, was randomly copolymerized with 2-(dimethylamino) ethyl methacrylate on the surface of an inorganic core to give well-defined PDMAEMA-co-PSPMA block copolymer brushes. UV irradiation (λ = 365 nm) led to the generation of the MC form, which formed intraparticle MC−MC stacks within the polymeric layers. The polymeric nanoparticles maintained their form upon removal of the inorganic core due to the MC−MC aggregates serving as noncovalent cross-link points within the dense polymer brush. Visible-light irradiation gave rise to the SP form, leading to dissociation of the H-aggregates and disruption of the structure of the nanoparticles. Although triggered drug release was not demonstrated, this system has definite potential for such application. The zwitterionic nature of the MC form of spiropyrans can be exploited to enhance the transport of small molecules, especially amino acids, across bilayers and membranes.91 In

Figure 13. Schematic representation of photoresponsive polymersomes incorporating spiropyran moieties.93 Light-triggered SP−MC isomerization induces a change in membrane permeability, altering the release rate of noncharged, charged, and zwitterionic small-molecule species below critical molar masses. Reprinted with permission from ref 93. Copyright 2015 American Chemical Society. 2879


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Figure 14. (A) Photoinduced isomerization of the simplest diarylethene, stilbene, and its irreversible oxidation to form phenanthrene.58,98(B) Examples of dithienylethenes featuring a range of linkers that improve photofatigue resistance.

Replacing the phenyl rings of stilbene with thiophene rings can largely improve the stability of the photogenerated cyclic product; dithienylethenes are thus the most popular kind of photochromic diarylethenes.97 Modifications of diarylethenes also include replacement of the CC double bond with a fivemembered ring,99,100 such as a maleic anhydride group101 or fluorocyclopentene,102 or a six-membered ring,103−105 such as benzoquinone,104 in order to improve their resistance to photofatigue (Figure 14B).97 Diarylethenes are unique “P-type” photochromic compounds,98 meaning that the reverse isomerization from the ring-closed form to the ring-open form usually cannot happen thermally but can be readily triggered by visible light (λ > 450 nm). This thermal irreversibility is the most unique property of diarylethenes. 4.1. Long-Wavelength Light-Responsive Diarylethene Derivatives. The simplest approach to acquire a bathochromic shift in the absorbance wavelengths of diarylethenes is to extend the π-conjugation length. Tosic et al.106 achieved this by introducing tetraalkenes (Figure 15, DAE1) or unsaturated benzoic acid ester groups (DAE2). Cyclization of these derivatives can be readily triggered by irradiation with blue light (420 nm), accompanied by a shift in the absorption maxima of the corresponding ring-closed form to the red-light region (λmax > 630 nm). Fukaminato et al.107 indirectly elongated the π-conjugation length by attaching a fluorescent dye, N-bis(1-hexylheptyl)perylene-3,4-dicarboxylic monoimide (PMI), to one of the aryl rings of a diarylethene. The open-toclosed or closed-to-open isomerization of compound DAE3 can be readily triggered by irradiation with green light (560 nm) or blue light (405 nm) in 1,4-dioxane. Both isomers have a sharp absorbance in the range of 430 to 600 nm, which is attributed to the PMI moiety. Given that both isomers display strong absorbances within the 450−550 nm wavelength range, it is surprising that both isomers can be generated in very high yields (>90%) upon irradiation. Another strategy to develop visible-light sensitive diarylethenes is to regulate intramolecular photoinduced energy and electron transfer via triplet states. Fredrich and his group incorporated a strong triplet sensitizer, a biacetyl unit, to produce compound DAE4.108 The ring-opened form of DAE4 has a λmax between 300 to 500 nm in acetonitrile, while the ring-closed form has a λmax of 608 nm. Alternating irradiation with blue light (405 nm) and yellow light (579 nm) can quantitatively generate the ring-closed and ring-opened forms, respectively. Moreover, the ring-closure reaction via the triplet manifold does not generate irreversible byproducts, affording improved photofatigue resistance. 4.2. Application of Diarylethenes in Light-Responsive Nanocarriers. Diarylethenes display quite a small geometric

Figure 15. Examples of red-shifted dithienylethenes featuring extended conjunction (DAE1 and DAE2),106 a dye (DAE3),107 and a triplet sensitizer (DAE4).108 The wavelengths of maximum absorbance (within the specified solvents) are shown, together with the wavelengths that have been used to trigger isomerization.

change upon photoisomerization; hence, most of their applications in supramolecular assemblies take advantage of the differing stacking propensities of the two isomers.96 Yagai et al.109 utilized the photoinduced conformational change of the two aryl rings of a diarylethene to induce morphological changes in perylene bisimide (PBI)-based assemblies in toluene (Figure 16A,B). The aryl rings of the ring-opened isomer were stabilized in a parallel conformation by PBI via hydrogen bonds and π−π stacking interactions. The resulting supermolecular diarylthene/PBI complex self-assembled into fiber-like nanostructures. Upon irradiation with UV light, the generated ring-closed form of the diarylethene moiety could not bind with PBI due to its rigid plate structure, leading to the dramatic, reversible formation of granular aggregates. Higashiguchi et al.110 have reported amphiphilic diarylethenes with oligo(ethylene glycol) and alkyl side chains that undergo photoinduced morphological transformation in physiological surroundings (Figure 16C). The ring-opened form of the amphiphilic diarylethenes have a flexible structure and form submicrometer-sized spheres with a diameter of ca. 100 nm in aqueous solution. The ring-closed isomer has a more rigid structure and shows stronger π−π stacking interactions, allowing the formation of fiber-type aggregates. The colored fibers and colorless microspheres can be reversibly generated by alternating exposure to UV and visible light. Similar morphological transformations induced by the photoisomerization of diarylethenes have been reported by other groups.111,112 However, photoinduced release from diarylethene-functionalized delivery systems has not been demonstrated yet.96 2880


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Figure 17. Photoinduced isomerization of HTI, together with isomerization rate for various derivatives: HTI1a,116 HTI1b,116 HIT1c,116 HIT2,116 and HTI3.117

Figure 16. Photoresponsive nanoassemblies incorporating dithienylethenes. AFM height images of (A) fiber coaggregates formed from the ring-opened form of a dithienylethene and PBI and (B) granular aggregates formed from the ring-closed form and PBI.109 Reprinted with permission from ref 109. Copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Photoinduced macroscopic morphological transformation of a supramolecular assembly formed from amphiphilic dithienyethene derivatives.110 Reprinted with permission from ref 110. Copyright 2015 American Chemical Society.

One drawback of HTIs is that some HTI derivatives may undergo irreversible bleaching upon irradiation, potentially limiting their practical application. Tanaka and his group reported that fluoro substitution at the ortho-positions of the stilbene fragment can result in irreversible intramolecular cyclization (Figure 18A).119 HTIs with a cyano group on the stilbene moiety were found to undergo an irreversible intermolecular [2 + 2] cycloaddition of the central double bond, while a HTI derivative with a benzoyl group yielded a [2 + 4] cycloadduct upon irradiation (the Z isomer could be regenerated by heating in this case) (Figure 18B,C)121 Seki et al. reported that when hydrophobic HTI derivatives were incorporated into a bilayer membrane, irreversible bleaching occurred upon irradiation, possibly due to the clustering of the HTIs in the membrane.120 5.1. Application of Hemithioindigos in Light-Responsive Nanocarriers. Although HTIs have been incorporated into amino acids122 and peptides123,124 in order to achieve

5. HEMITHIOINDIGOS Hemithioindigos (HTIs) are a somewhat underexplored class of photoswitchable molecules first introduced by Friedlaender in 1909.113 HTIs consist of thioindigo and stilbene moieties connected via a CC double bond.114 Upon irradiation, HTIs undergo isomerization from the thermally stable Z form to the metastable E form.114 The E form is sufficiently stable to be isolated by chromatography, due to the relatively high-energy barrier between the E and Z forms (typically >27 kcal/ mol).114,115 One of the most attractive properties of HTIs is their absorbance in the visible region, with both isomers displaying λmax > 420 nm. The absorbance of the E isomer shows a moderate bathochromic shift of about 20 nm relative to the Z form, resulting in reversal to the Z form.114 Z-to-E isomerization can also be induced thermally. HTIs have been shown to have very high photofatigue resistance, surviving thousands of cycles of photoswitching.115 Similar to azobenzenes and spiropyrans, substituents on both the thioindigo and the stilbene fragments can strongly affect the photoisomerization characteristics of HTIs (Figure 17).118 Introduction of electron-donating substituents, for example, methoxy (HTI1a) or NH2 groups (HTI1b), to the stilbene fragment leads to red-shifted absorbances and faster isomerization in both directions.116 However, very strong donor substituents (para-dimethylamino (HTI1c) and julolidine (HTI2)) slow down the Z-to-E photoisomerization.116 Cordes and co-workers reported that the introduction of a typical electron-withdrawing group, bromine, to the para-position of the thioindigo fragment (relative to the sulfur atom) leads to a decrease in photoisomerization speed, whereas substitution with a methoxy group, an electron-donating substituent, did not affect the rate of isomerization.117

Figure 18. Irreversible photobleaching of some HTIs. (A) Intramolecular cyclization and dimerization after Z-to-E photoisomerization,119 (B) [2 + 2] cycloaddition,114,120 and (C) [2 + 4] cycloaddition, reversible by heating.121 2881


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Chemistry of Materials photocontrol over the assembly of peptides or enzymes, their application in “smart” nanomaterials is yet to be fully established. Eggers et al.115 synthesized five lipids containing HTI chromophores as part of their hydrophobic tails (Figure 19). These lipids showed the expected photoisomerization behavior in organic solution and when incorporated into vesicle bilayer membranes. Tanaka and his co-workers reported the first application of HTIs in a supramolecular system, based on differing affinities of the E and Z isomers for two porphyrin derivatives (Figure 20).125 The Z form of compound HTI5 was established to have a higher affinity for ureidoporphyrin, while the E form preferentially bound pentafluorobenzamidoporphyrin. Blue light (440 nm) and green light (490 nm) were used to reversibly switch between the E and Z isomers, which showed repeatable movements between the two kinds of porphyrins. Such a system could potentially be exploited in the development of photoresponsive nanocarriers for biomedical applications in the future.

Figure 20. Schematic representation of the photocontrolled repeatable movement of HTI between two kinds of porphyrins. HTI5 in its Z form binds more strongly to the ureidoporphyrin receptor (left), while E isomer binds more strongly to the pentafluorobenzamidoporphyrin receptor (right).125 Adapted with permission from ref 125. Copyright 2008 American Chemical Society.

6. DONOR−ACCEPTOR STENHOUSE ADDUCTS Photochromic donor−acceptor Stenhouse adducts (DASAs) were recently developed by Read de Alaniz and others,126−131 based on the study of Stenhouse salts (Figure 21). These molecules consist of a photoreactive furfural part, an amine moiety, and a parent ring: barbituric acid or Meldrum’s acid. Upon visible light irradiation, DASAs switch from an extended, hydrophobic, and intensely colored triene form to a compact, colorless, and zwitterionic cyclopentenone structure. The reverse isomerization can occur spontaneously in the dark or by gently heating the sample. The proposed mechanism for the photoisomerization is an initial Z-to-E isomerization of an alkene group, followed by a reversible Nazarov-type 4π electrocyclization.132,133 By replacing the aliphatic amine present within the first generation of DASAs with an aniline-based amine, a bathochromic shift in absorbance maxima up to 750 nm has been achieved, together with excellent resistance to photofatigue.134 In addition, second-generation DASAs are capable of photoswitching in polar solvents such as THF and DCM and in solid polymer matrices such as polystyrene and poly(methyl methacrylate), in contrast to first-generation DASAs. 6.1. Application of Donor−Acceptor Stenhouse Adducts in Light-Responsive Nanocarriers. The two isomers of DASAs display significant differences with regards to their physical properties, spectral absorption, solubility, and molecular volume.126,127 This makes DASAs very attractive for developing photoresponsive delivery systems. The group of de Alaniz coupled a DASA derivative to an alkyne-terminated monomethyl PEG chain (Figure 22), which self-assembled into micelles in an aqueous environment.127

Figure 21. Photoinduced isomerization of DASAs. The wavelengths of maximum absorbance for various derivatives are also shown.126,134

Figure 22. Schematic representation of a photoresponsive micelle formed from an amphiphilic DASA-functionalized polymer.127 Visible light irradiation leads to the formation of the more hydrophilic cyclopentenone form of DASA, resulting in micelle disruption and cargo release. Reprinted with permission from ref 127. Copyright 2014 American Chemical Society.

Upon visible light irradiation (570 nm) conversion of the DASA to the more hydrophilic cyclopentenone form was found to promote disassembly of the micelles and release of an encapsulated hydrophobic model cargo molecule, Nile Red. Our group has recently reported that incorporation of an alkylated DASA into a phytantriol-based LLC system permits rapid, reversible switching from a rapid-release bicontinuous cubic phase to a slow-release hexagonal phase using green light (532 nm).135 Although DASAs show great potential, one issue is that isomerization from the triene form to the cyclopentenone form occurs in aqueous solution in the dark.133 It has also been reported that some polar solvents can induce irreversible cyclization with no observed Z-to-E isomerization.136 This may hinder their application as reversible photoswitches in a biomedical setting.

Figure 19. HTI-bearing lipids.115 2882


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Figure 23. Photoinduced isomerization of HABIs. (A) HABIs displaying positive photochromic behavior, featuring [2,2]paracyclophane (HABI1),142 naphthalene (HABI2),143,144 and benzene (HABI3)145 linkers. (B) HABIs displaying negative photochromic behavior (HABI4146 and HABI5147).

7. HEXAARYLBIIMIDAZOLES Hexaarylbiimidazole (HABI) is a photochromic compound that was first reported by Taro Hayashi and Koko Maede in 1960.137,138 Oxidation of 2,4,5-triphenylimidazole with potassium ferricyanide in an aqueous solution of potassium hydroxide yielded a light yellow-colored compound, which rapidly transformed into a reddish purple-colored product upon irradiation with light.138,139 The mechanism behind this lighttriggered color change entails homolytic cleavage of the C−N bond between the imidazole rings, resulting in the formation of the colored triphenylimidazolyl radical (Figure 23).140,141 Recombination of the radical to form the original C−N bond takes place in the dark, but this process takes several minutes due to diffusion effects. Because radical species are highly active and can react with oxygen or active hydrogen, HABI displays poor photo-fatigue resistance.138,139 Different techniques have been utilized in order to avoid oxidation of the colored HABI, revolving around suppressing the diffusion of the radical. Abe and his group have synthesized several UV-light responsive HABI derivatives featuring a [2,2]paracyclophane (HABI1) or naphthalene linker (HABI2) between two triphenylimidazole or benzene units (HABI3) which show much lower discoloration rates.38,143,148,144,145 Compound HABI3 showed the fastest thermal back-reaction, with a half-life of 35 μs in solution at room temperature.145 However, the bridged HABIs can still be oxidized by oxygen in air or solution.144 7.1. Long-Wavelength Light-Responsive Hexaarylbiimidazole Derivatives. Compound HABI4 has a special C−N bond between the nitrogen atom of the imidazole ring and the carbon atom from the linker binaphthyl, instead of the usual C−N bond between the imidazole rings.146 Visible light irradiation of this colorless compound leads to the cleavage of the C−N bond and the generation of imidazolyl radicals, followed by radical coupling to form a colorless isomer with a

C−C bond between the two imidazole rings. The reverse isomerization and resulting coloration occurs thermally in the dark, and can also be rapidly induced by UV light irradiation (355 nm) via the radical path. Compound HABI5 incorporates a phenanthroimidazole moiety and a di-tert-butylphenol ring.147 The isomerization can be triggered by white light, while the coloration reaction only takes 1.9 s, making it the fastest negative photochromic reported so far. Notably, the presence of molecular oxygen does not affect the reverse isomerization. The application of HABIs in drug delivery systems has not been reported yet; however, the extreme changes in conformation and production of radicals accompanying photoisomerization may prove useful for “on-demand” manipulation of smart materials in the future.

8. CONCLUDING REMARKS Recent advances in the design and synthesis of long-wavelength light-responsive photoswitchable molecules and their incorporation into nanocarriers have been summarized in this review. Some UV light-responsive systems have also been highlighted in order to illustrate particular release strategies and outcomes of note. The presented examples represent only a small part of the huge amount of work that has been done in this area. We hope, nevertheless, that by providing a general survey of the different types of designs and strategic approaches being pursued, this review will be of assistance to researchers seeking to develop photoresponsive nanocarriers with improved properties for biomedical applications. The tremendous progress in developing light-responsive nanocarriers has involved a combination of photochemistry, synthesis, and materials science. Computational science has also had a role to play, with methods such as density functional theory (DFT) assisting the design of new photoswitches.116,147 Despite major achievements in the field, challenges still remain. For example, the stability of some newly reported long2883


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(9) Lee, C. C.; MacKay, J. a; Fréchet, J. M. J.; Szoka, F. C. Designing Dendrimers for Biological Applications. Nat. Biotechnol. 2005, 23 (12), 1517−1526. (10) Hamidi, M.; Azadi, A.; Rafiei, P. Hydrogel Nanoparticles in Drug Delivery. Adv. Drug Delivery Rev. 2008, 60 (15), 1638−1649. (11) Ganta, S.; Devalapally, H.; Shahiwala, A.; Amiji, M. A Review of Stimuli-Responsive Nanocarriers for Drug and Gene Delivery. J. Controlled Release 2008, 126 (3), 187−204. (12) Couvreur, P.; Vauthier, C. Nanotechnology: Intelligent Design to Treat Complex Disease. Pharm. Res. 2006, 23, 1417−1450. (13) Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. M. Therapeutic Nanoparticles for Drug Delivery in Cancer. Clin. Cancer Res. 2008, 14 (5), 1310−1316. (14) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an Emerging Platform for Cancer Therapy. Nat. Nanotechnol. 2007, 2 (12), 751−760. (15) Sortino, S. Photoactivated Nanomaterials for Biomedical Release Applications. J. Mater. Chem. 2012, 22 (2), 301−318. (16) Hu, Q.; Katti, P. S.; Gu, Z. Enzyme-Responsive Nanomaterials for Controlled Drug Delivery. Nanoscale 2014, 6 (21), 12273−12286. (17) Liu, J.; Huang, Y.; Kumar, A.; Tan, A.; Jin, S.; Mozhi, A.; Liang, X. J. PH-Sensitive Nano-Systems for Drug Delivery in Cancer Therapy. Biotechnol. Adv. 2014, 32 (4), 693−710. (18) Alimoradi, H.; Matikonda, S. S.; Gamble, A. B.; Giles, G. I.; Greish, K. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy. Curr. Pharm. Des. 2016, 22 (19), 2808−2820. (19) Huo, M.; Yuan, J.; Tao, L.; Wei, Y. Redox-Responsive Polymers for Drug Delivery: From Molecular Design to Applications. Polym. Chem. 2014, 5 (5), 1519−1528. (20) Satarkar, N. S.; Hilt, J. Z. Magnetic Hydrogel Nanocomposites for Remote Controlled Pulsatile Drug Release. J. Controlled Release 2008, 130 (3), 246−251. (21) Brazel, C. S. Magnetothermally-Responsive Nanomaterials: Combining Magnetic Nanostructures and Thermally-Sensitive Polymers for Triggered Drug Release. Pharm. Res. 2009, 26 (3), 644−656. (22) Ge, J.; Neofytou, E.; Cahill, T. J.; Beygui, R. E.; Zare, R. N. Drug Release from Electric-Field-Responsive Nanoparticles. ACS Nano 2012, 6 (1), 227−233. (23) Schroeder, A.; Kost, J.; Barenholz, Y. Ultrasound, Liposomes, and Drug Delivery: Principles for Using Ultrasound to Control the Release of Drugs from Liposomes. Chem. Phys. Lipids 2009, 162 (1− 2), 1−16. (24) Shanmugam, V.; Selvakumar, S.; Yeh, C.-S. Near-Infrared LightResponsive Nanomaterials in Cancer Therapeutics. Chem. Soc. Rev. 2014, 43 (17), 6254−6287. (25) Rwei, A. Y.; Wang, W.; Kohane, D. S. Photoresponsive Nanoparticles for Drug Delivery. Nano Today 2015, 10 (4), 451−467. (26) Olejniczak, J.; Carling, C.-J.; Almutairi, A. Photocontrolled Release Using One-Photon Absorption of Visible or NIR Light. J. Controlled Release 2015, 219, 18−30. (27) Raulin, C.; Karsai, S. Laser and IPL Technology in Dermatology and Aesthetic Medicine. Laser IPL Technol. Dermatology Aesthetic Med. 2011, DOI: 10.1007/978-3-642-03438-1. (28) Bowen, J. The Absorption Spectra and Extinction of Myoglobin. J. Biol. Chem. 1949, 235−245. (29) Cheong, W.-F.; Prahl, S. a.; Welch, A. J. A Review of the Optical Properties of Biological Tissues. IEEE J. Quantum Electron. 1990, 26 (12), 2166−2185. (30) Weissleder, R. A Clearer Vision for in Vivo Imaging Progress Continues in the Development of Smaller, More Penetrable Probes for Biological Imaging. Toward the Phosphoproteome. Nat. Biotechnol. 2001, 19 (4), 316−317. (31) Ntziachristos, V.; Ripoll, J.; Weissleder, R. Would near-Infrared Fluorescence Signals Propagate through Large Human Organs for Clinical Studies? Opt. Lett. 2002, 27 (5), 333−335. (32) Scientific Committee on Emerging and Newly-Identified Health Risks. The Appropriateness of the Risk Assessment Methodology in Accordance with the Technical Guidance Documents for New and Existing

wavelength light-responsive photoswitches in biological environments needs to be improved. The utilization of longwavelength light-responsive photochromics in nanocarriers has not yet been fully explored. Azobenzene and its derivatives have dominated the photoresponsive drug delivery area, presumably due to their excellent biostability and significant geometrical change upon isomerization. This, in turn, shows directions for the development of new photoswitches. There are many technical difficulties that need to be addressed as well, such as the prevention of leakage from nanocarriers and the development of appropriate laser sources for efficient in vivo activation. Even though light as a stimuli has been successfully applied in bioapplication, such as photodynamic therapy for cancer treatment,149 photosensors for diagnoses,150 and photodegradable materials for tissue engineering,151 there are no photoresponsive nanocarriers that have been used in clinical applications to date. Nevertheless, we feel confident that the next decade or so will see the eventual development of photoresponsive nanosystems suitable for in vivo use.

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AUTHOR INFORMATION

Corresponding Author

*Ben J. Boyd. E-mail: [email protected]. ORCID

Wye-Khay Fong: 0000-0002-0437-9332 Ben J. Boyd: 0000-0001-5434-590X Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

S.J. is the recipient of a Chinese Scholarship Council Scholarship. W.-K.F. is the recipient of a Victorian Postdoctoral Research Fellowship. B.J.B. and B.G. are both recipients of an Australian Research Council Future Fellowship.

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