Photoswitchable Molecules in Long-Wavelength Light ...

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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 ABSTRACT: Stimuli-responsive nanocarriers can release their bioactive cargo on demand, potentially improving the selectivity, specicity, and ecacy of therapeutic drugs. Light of wavelengths between 6501100 nm is a unique stimulus with many advantages. It is noninvasive and bio-friendlyand can be manipulated with precision and ease. Many light- responsive 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 one- photon visible and near-infrared light-triggered photoswitch- able compounds in the development of long-wavelength light- responsive nanocarriers. 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 (nano- carriers), including mesoporous silica nanoparticles, 1,2 plas- monic nanoparticles, 3,4 polymeric nanoparticles, 5 liposomes, 6 micelles, 7 dendrimers, 8,9 hydrogels, 10 and other nanoassem- blies. 11 To facilitate their application as drug delivery agents, eorts have focused particularly on the generation of structurally well-dened nanocarriers possessing good bio- compatibility and high loading capacities. 1214 The pharmaco- kinetics 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 demandin response to specic stimuli. Such systems provide a means of improving the selectivity, specicity, and ecacy of therapeutic drug treat- ments, as well as delivering patients benets 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 physio- logical dierences 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 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 princi- pally comprise systems that are responsive to applied magnetic elds, 20,21 electric eld, 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 nely 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 eld. 15,25,26 Nonionizing light can be broadly divided into three wavelength ranges, namely, ultraviolet (UV, 10400 nm), visible (400750 nm), and near-infrared (NIR, 7501100 nm). Both the wavelength and the power of the light used to trigger cargo release directly inuence the eectiveness and safety prole 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. 2831 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 Received: January 24, 2018 Revised: April 9, 2018 Published: April 9, 2018 Review pubs.acs.org/cm Cite This: Chem. Mater. 2018, 30, 2873-2887 © 2018 American Chemical Society 2873 DOI: 10.1021/acs.chemmater.8b00357 Chem. Mater. 2018, 30, 28732887 Downloaded via PURDUE UNIV on October 6, 2018 at 01:38:06 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Transcript of Photoswitchable Molecules in Long-Wavelength Light ...

Photoswitchable Molecules in Long-Wavelength Light-ResponsiveDrug Delivery: From Molecular Design to ApplicationsShiyang 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 Scienceand 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

ABSTRACT: Stimuli-responsive nanocarriers can release theirbioactive cargo “on demand”, potentially improving theselectivity, specificity, and efficacy of therapeutic drugs. Lightof wavelengths between 650−1100 nm is a unique stimuluswith many advantages. It is noninvasive and “bio-friendly” andcan be manipulated with precision and ease. Many light-responsive nanocarriers reported in the literature employphotochromic molecules that undergo reversible isomerizationupon irradiation, thereby functioning as gates or switches forthe release of encapsulated bioactive compounds. This reviewsurveys the design, synthesis, function, and application of one-photon visible and near-infrared light-triggered photoswitch-able compounds in the development of long-wavelength light-responsive nanocarriers.

1. INTRODUCTION

Advances in materials science have seen an increasing range ofnanomaterials employed in the development of nanosystemsfor the transport and release of molecular cargo (“nano-carriers”), including mesoporous silica nanoparticles,1,2 plas-monic nanoparticles,3,4 polymeric nanoparticles,5 liposomes,6

micelles,7 dendrimers,8,9 hydrogels,10 and other nanoassem-blies.11 To facilitate their application as drug delivery agents,efforts have focused particularly on the generation ofstructurally well-defined nanocarriers possessing good bio-compatibility and high loading capacities.12−14 The pharmaco-kinetics and bioavailability of encapsulated drugs are to a largeextent dictated by the physicochemical properties of thenanocarrier, providing an attractive strategy for improving thedistribution of, for example, poorly water-soluble drugs.15

The past few years have witnessed particularly strong interestin the development of stimuli-responsive nanocarriers, designedto release bioactive cargo “on demand” in response to specificstimuli. Such systems provide a means of improving theselectivity, specificity, and efficacy of therapeutic drug treat-ments, as well as delivering patients benefits in reducinginjection 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. Endogenousstimuli-responsive nanocarriers exploit the fact that physio-logical differences often exist between diseased and healthytissue, e.g., the increased metabolic requirements of fastgrowing tumor cells result in changes to the biochemistry of

cancerous tissue. Those stimuli includes enzyme,16 pH,17

hypoxia,18 and redox.19 Endogenously responsive systems arenot the focus of this review but are mentioned here forcompleteness. External stimuli-responsive nanocarriers princi-pally comprise systems that are responsive to applied magneticfields,20,21 electric field,22 ultrasound,23 and light.24 Amongthese stimuli, light has many advantageous features. In additionto being relatively noninvasive and “bio-friendly”, light is easilymanipulated and finely tunable, allowing for precise controlover the site, timing and dosage of released species.Unsurprisingly, therefore, light-responsive nanocarriers haveattracted major interest within the drug delivery field.15,25,26

Nonionizing light can be broadly divided into threewavelength 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 triggercargo release directly influence the effectiveness and safetyprofile of a light-responsive nanocarrier.25,27 The mostimportant parameters that need to be considered are the tissuepenetration depth and phototoxicity of the light employed.Generally speaking, the longer the wavelength of light, thedeeper its penetration through skin, for wavelengths up to 900nm.28−31 For example, the reported penetration depth(attenuation down to 1%) in the skin of light at wavelength360 nm is 190 μm; 700 nm is 400 μm and 1200 nm is 800

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

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pubs.acs.org/cmCite This: Chem. Mater. 2018, 30, 2873−2887

© 2018 American Chemical Society 2873 DOI: 10.1021/acs.chemmater.8b00357Chem. Mater. 2018, 30, 2873−2887

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μm.32 This is predominantly due to the absorbance character-istics of the endogenous chromophores hemoglobin, oxy-hemoglobin, and myoglobin. Another major tissue component,water, has strong absorbance in the NIR and IR regions, leadingto increasingly poor penetration for wavelengths above 900nm.30 The “optical window” or “therapeutic window” refers tothe range of wavelengths from ca. 650 to 1100 nm where lighthas its maximum depth of penetration into tissue.Absorption of large amounts of optical radiation by tissues

can result in photochemical reactions or heating effects, whichmay induce protein denaturation, DNA breakage, or lipidperoxidation, ultimately leading to cell death.27,33 Seriousphototoxicity occurs when the irradiation exceeds themaximum permissible exposure (MPE).32 Light energy isdependent upon the per-photon energy, the distance from thelight source, the duration, and the intensity of irradiation. It istherefore important for these details to be clearly presentedwithin publications. Photon energy has an inverse relationshipwith wavelength of light, meaning that light of longerwavelengths is more biocompatible.27 UV light has a lowMPE due to its high energy-per-photon and high tissueabsorbance, rendering it undesirable for many bioapplications.Visible and NIR light have higher MPEs and are therefore moresuited to in vivo and in cellulo use.26

Many light-responsive nanocarriers reported in the literatureincorporate photochromic molecules that function as “gates” or“switches” for the release of encapsulated bioactive compounds.Photochromic molecules, also known as photoswitchablemolecules, undergo reversible isomerization when exposed toelectromagnetic radiation of a specific wavelength.34,35 Photo-isomerization usually occurs though one of two mainmechanisms, illustrated in Figure 1. The first, exemplified byazobenzenes, is E-to-Z isomerization of a double bond,resulting in significant geometric change. The other is 6πelectrocyclization of a triene system, e.g., spiropyrans anddiarylethenes, which produces a large change in electronicdistribution. The two isomers of a photoswitchable moleculepossess distinct chemical, physical and optical properties (e.g.,absorbance signature, molecular volume, and molecularcharge), which can be utilized to tune the release propertiesof a host material.Most traditional photoswitchable systems require UV light

for excitation; however, recent years have seen a concertedpush to develop long-wavelength light-responsive analogues inorder to improve biocompatibility.35 These molecular design

efforts have often gone hand-in-hand with ones aimed atenhancing isomerization yield, resistance to photodegradation,the degree of shape change upon isomerization, and ease ofincorporation of photoswitchable molecules into host materials.An alternative method that has been utilized to create visible

and NIR light-responsive materials is the introduction ofupconverting moieties, which convert photon energy from longwavelengths of light to UV wavelength on the atomicscale.36−38 This has been achieved by using photosensitivegroups that absorb two photons of visible or NIR light to accesshigher energy excited states or by combining with upconvertingnanoparticles (usually lanthanide-based nanomaterials) thatconvert visible/NIR light to UV light.39,40 Although promising,this approach suffers from issues pertaining to the low quantumyield of upconversion processes25,41 and is not the focus of thisreview (interested readers are directed to ref 41).The design and synthesis of photoswitchable molecules and

their incorporation into “smart” nanomaterials requirescollective cross-disciplinary efforts, especially advanced knowl-edge from chemistry and photochemistry. This review examinesthe state-of-the-art in the design, synthesis, and mechanism ofone-photon visible and NIR light-responsive photoswitchablecompounds, as well as the exploitation of these compounds inthe generation of light-responsive nanocarriers. It is dividedinto four major sections based on the major chemistriesinvolved: (i) azobenzenes, (ii) spiropyrans, (iii) diarylethenes,and (iv) other promising photoswitchable molecules, includinghemithioindigos, donor−acceptor Stenhouse adducts, andhexaarylbiimidazoles (Figure 1). A comprehensive under-standing of the design and preparation of visible/NIR light-responsive photochromic-based nanocarriers is intended in thisreview.

2. AZOBENZENES

Azobenzenes consist of an azo group (NN) withappended aryl groups. These compounds undergo an E-to-Zisomerization upon irradiation. The simplest example,azobenzene, features two unsubstituted phenyl groups.Irradiation with 365 nm UV light transforms of the E isomerto the Z form via excitation of π → π* (Figure 2). The reverseZ-to-E isomerization is induced by 450 nm light (or byheating), but the presence of overlapping n → π* bands forboth isomers in the vicinity of this wavelength preventscomplete photoreversion to the E form.42

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

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2.1. Long-Wavelength Light-Responsive AzobenzeneDerivatives. Recent research has demonstrated that introduc-tion of ring substituents significantly influences the absorbancemaxima of the E and Z isomers of azobenzene (examplesshown in Table 1). The shift in absorbance maxima has beenattributed to three factors: (1) the electron-donating group onthe rings lead to a red-shift of the absorbance of the E isomer,possibly due to raising the relative energy of the highestoccupied molecular orbital (HOMO) in the E-form;43,50 (2)steric interactions reduces the sp2 character of the N atoms, alsoraising the HOMO energy, leading to the red-shiftabsorbance;44 and (3) electron-withdrawing groups such as F

atoms can lower the n-orbital energy of the Z isomer byreducing the electron density in the nearby NN bond.42

With appropriate functionalization, the separation of the n→π* bands of the E and Z isomers of azobenzenes becomessufficiently large that visible light can be exploited to selectivelyisomerize both the E and the Z isomers.Bleger 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 toZ form in 90% yield with green light (λ > 500 nm) and thenback 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 2years. Beharry et al. have similarly developed tetra-ortho-methoxy-substituted azobenzenes that are switchable withgreen/blue light.43 Building on this seminal work, Samanta etal.46 prepared a series of peptides cross-linked with tetra-ortho-methoxy substituted azobenzene derivatives (e.g., AB2) forwhich the n→ π* absorption bands of the E isomers tailed past600 nm. Red light (635 nm, 90 mW/cm2) could be used toaccess the Z isomer of AB2 (ca. 98%), and the E isomerrecovered (ca. 85%) via exposure to blue light (450 nm).Thermal reversion to the E form was slow (hours). This groupsubsequently created a series of thiol-substituted azobenzenederivatives (e.g., AB3) that could also be triggered with 635 nmlight, but which exhibited faster thermal Z-to-E back-reactionrates (t1/2 of the order of minutes).47

Yang et al.48,49 have reported BF2-coordinated azobenzenesthat exhibit visible and NIR light switching properties. Forexample, the E isomers of AB4 and AB5 can be converted tothe Z forms with 570 and 710 nm light, respectively. The Zisomer 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-ResponsiveNanocarriers. Light-responsive cyclodextrin (CD)-basednanocarriers have been developed in which azobenzenes serveas a light-controllable “gatekeepers”. CD, especially β-CD, has ahigher binding affinity for the E isomer of azobenzene than theZ form. When E-azobenzene binds to β-CD, it acts as ananopore-sealing cap. Upon irradiation, E-to-Z isomerizationleads to dissociation from the β-CD, thus opening thenanopore and providing a mechanism for cargo release. Thislight-sensitive host−guest interaction underpins the functioningof a number of mesoporous silica nanoparticle (MSN)-51,52 andhydrogel-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 sequenceof WGEACAREAAAREAACRQ),46 and thiol (AB3)47 substitution, anunusual BF2 bridge (AB4),48 and plus a para-dimethylaminosubstitution (AB5).49 The wavelengths of maximum absorbance inthe visible light region (within the specified solvents) are shown,together with the wavelengths that have been used to trigger E-to-Zisomerization, and the half-lives of the Z forms.

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 H atoms 36445 348 (π → π*), 473 (n → π*)43

methoxyl groups43 methoxyl groups 338 (π → π*), 480 (n → π*) ∼330 (π → π*), 444 (n → π*)piperidine groups44 H atoms 445 N/AF atoms42 F atoms ∼364 (π → π*), 370 (n → π*) ∼314 (π → π*), 450 (n → π*)

aThe 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.

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methoxy-substituted azobenzene and β-CD to control releaseof doxorubicin (DOX) from MSNs (Figure 3).51 Exposure tored light (625 nm, 60 mW/cm2) for 360 min resulted in releaseof ca. 38% of encapsulated DOX. Moreover, when the lightintensity was tempered by passage through 2 mm thick porcinetissue, 23% of DOX was still released in the same period,compared to ca. 5% for a nonirradiated control sample. Littlephotodamage 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 drugdelivery system, however this time exploiting the thermalswitching capacity of azobenzenes in combination with thephotothermal properties of gold nanorods. Their systemconsists of a DOX-loaded mesoporous silica−gold nanorodcore−shell structure (Au@MSN), with α-CD-threaded azo-benzene moieties grafted onto the surface (Figure 4). Upon UVirradiation, the generated Z-azobenzene moieties force thethreaded α-CD units close to the surface of the mesoporoussilica, blocking its pores and inhibiting drug release. Exposure toNIR irradiation, however, leads to thermal-driven production ofE-azobenzene, mediated by the heating effects of goldnanorods. This allows the α-CD molecules to migrate outwardand onto the azobenzene moieties, opening the pores andtriggering drug release. Precise control of drug release from thissystem using NIR light was demonstrated both in vitro and invivo.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 therate of escape of encapsulated small molecules (Figure 5). Theyused blue light (457 nm) to excite both isomers and producesequential isomerization reactions, causing a continual “dynam-ic wag” that was able to shunt guest molecules through thepores and expel them into the surrounding solvent. MSNs withazobenzenes grafted on the pore openings showed a fasterrelease profile than those with azobenzenes on the interiors. Luet al.57 investigated the effectiveness of this nanocarrier for drugrelease in vitro. In the absence of light, camptothecin (CPT)-loaded MSNs showed no activity toward two cell lines (apancreatic cancer cell line, PANC-1, and a colon cancer cellline, SW480). After 5 min of irradiation with blue light (412nm, 200 mW/cm2), however, CPT was released from the

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 physicallydoped into the self-assemblies and, hence, have also beenwidely incorporated into nanoparticles formed via the self-assembly of polymers or lipids for use as photoactivatable drugdelivery systems. Reported azobenzene-functionalized self-assembled nanoparticles include thermotropic liquid crystals,58

liposomes,59 vesicles,60,61 hollow nanotubes,63 and hydrogels.55

The significant change in molecular geometry associated withisomerization of azobenzenes can destabilize and potentiallyeven destroy the structure of these self-assemblies, leading tocargo release. However, no visible or NIR light-responsivenanocarriers of this kind have appeared in the literature as yet.These systems are still of significance for constructing longwavelength light-responsive self-assemblies. Hence, here wesummarize several such systems that showed a release of diversecargoes under UV light (365 nm) irradiation in Table 2 forreaders’ interests.

3. SPIROPYRANSSpiropyrans represent another well-known family of photo-switchable molecules. Their photochromism was first reportedby Fischer and co-workers in 1952.67 These molecules generallycontain a 2H-pyran ring linked via the second carbon atom ofthe ring to another ring that is usually heterocyclic in nature. Inpolar solvents, UV irradiation (λmax = 365 nm) leads toconversion of the colorless spiropyran (SP) to the intenselycolored merocyanine (MC) form via bond cleavage (Figure6).68 The closed SP form is recoverable either by heating or byexposure to visible light (λ > 450 nm).68 The MC form has a

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

Figure 4. (A) Schematic representation of a photoresponsive Au@MSN−rotaxane system. (B) Release of DOX indicated by confocalimages within embryo heads without and with NIR irradiation.52

Reprinted with permission from ref 52. Copyright 2014 Royal Societyof Chemistry.

Figure 5. Schematic representation of photoresponsive MSNsfunctionalized with azobenzene derivatives as impellers and gate-keepers.56 Reprinted with permission from ref 56. Copyright 2007American Chemical Society.

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planar structure and extended π-conjugation between theindoline and the chromene moieties,68 and it can bezwitterionic or positively charged on the N atom of theindoline ring in solution, depending on the pH of theenvironment. It is highly distinct from the SP form in termsof its absorption and fluorescence characteristics, dipolemoment, dielectric constant, and pKa.

68−70 Production of theMC form can be induced by a high polarity environment,71

temperature and pH changes,72 and complexation with metalions.73 Hence, spiropyrans not only exhibit photochromism butalso solvatochromism,74 thermochromism,75 ions,73 and acid-ichromism.76 A drawback of these compounds is that theirisomerization usually does not involve a dramatic change inmolecular conformation.68

3.1. Long-Wavelength Light-Responsive SpiropyranDerivatives. The most common strategy to achieve visiblelight-responsiveness has been to develop “negative” spiropyr-ans, which display contrary photochromic and thermal behaviorto the original spiropyran moiety.77,78 These compounds arethermally stable in their colored MC form77 and can besubsequently converted to the colorless ring-closed SP form viaexposure to visible light. The MC form is regenerated throughthermal back-reaction. The transition between the MC and theSP forms is accompanied by a pH change.Recently developed negative photochromic spiropyrans are

illustrated in Figure 7. The group of Liao has reported SP1 andSP2, featuring propyl sulfonate groups to improve watersolubility. The pka of SP1 is 7.8. In aqueous solution, the MCisomer exists in a mixture of protonated (MCH) anddeprotonated (MC) forms, with λmax values of 424 and ca.550 nm. Irradiation with either blue light (419 nm) or yellowlight (570 nm) leads to the generation of the SP form from theMCH form. The SP form of SP1 displays complete protondissociation, corresponding to a drop in pH from 5.5 to 3.3upon irradiation (conc. 0.588 nM).79 SP2 incorporates anindazole ring in place of the phenol ring.80 Due to the dualweakly acidic and weakly basic nature of the indazole moiety,SP2 shows a pKa of 10.1 and, hence, exists mostly (>99%) in itsMCH form at pH 7.4. Irradiation with 470 nm light generatesthe SP form, which exhibits a very long half-life (48 h). Peng’sgroup introduced the sulfonated compound SP3, which absorbswithin the 500−600 nm region and is consequently able toundergo MC/SP isomerization upon irradiation with whitelight.81

The group of Liao has also explored the introduction ofhighly conjugated electron-withdrawing groups in order toimprove the photochromic and pH-switching properties ofspiropyran-type photoswitches. In the first example, SP4, atricyanofuran (TCF) group was incorporated to promotenucleophilic attack and generation of the SP form.82 The MCform exhibits a red-shifted λmax at 428 nm in DMSO, andphotoisomerization 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-indandione-

derived spirocyclohexadine compounds that show rare“positive” visible light-responsive photochromism (Figure8).84 These compounds exist mainly in a cyclic SP-like,yellow-colored form in the dark in polar solvents, andphotoisomerize in a manner similar to spiropyrans despitetheir more complicated structure. They display broadabsorbance bands in the visible region and are very sensitive

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 catanonic vesicles Nile red, DNA Liu et al.61

low molecular weight gelators lipids hydrogel DNA, doxorubicin Pianowski et al.62

block copolymers hollow nanosphere doxorubicin Zhang et al.63

dendrimers dendrimers eosin Puntoriero et al.64

amphiphilic guest lipids superamolecular bilayer vesicles mitoxant Hu et al.65

cross-linked polymers hydrogel peptide Nehls et al.66

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

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

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to visible light (red and green), with exposure to light ofwavelengths between 254 to 532 nm (derivative c) or even upto 642 nm (derivative b) leading to conversion to the MC-likeforms. The MC forms are also strongly absorbing in the visiblerange but are not photosensitive, unlike typical spiro-compounds. Discoloration of the MC form happens sponta-neously in the dark, the rate of which is temperature- andsolvent polarity-dependent.3.2. Application of Spiropyrans in Light-Responsive

Nanocarriers. 3.2.1. Mesoporous Silica Nanoparticles.Spiropyran derivatives have been widely applied in thedevelopment of gated MSNs, although few of these systemsare responsive to longer wavelengths of light. Visible light-responsive MSNs incorporating a mesoporous support (MCM-41), a negative spiropyran, and a carboxyl-terminated PAMAMdendrimer have been reported by Aznar et al.85 (Figure 9). AtpH 7.2, the negatively charged PAMAM dendrimers formelectrostatic bonds with the MC isomers grafted onto thesurface of the MCM-41. As with azobenzene formulations,these photochromics act as “caps” to block the pores of theMSNs. Visible irradiation induces conversion of the chargedMC form to the neutral SP form, allowing release of theentrapped cargo at a rate seven times higher than that observedin the dark or in the presence of UV light.Some of the more interesting low-power UV-responsive

spiropyran-functionalized MSNs are worth highlighting toillustrate the ways in which light-dependent cargo release canbe achieved from nanocarrier systems. For example, Jiang andco-workers formed a hydrophobic layer on the surface of MSNsusing the SP form of a spiropyran and a fluorinated silane. This

layer served to hinder release of encapsulated cargo into thesurrounding aqueous environment (Figure 10).86 Upon low-power UV irradiation (365 nm, 2.4 μW/cm2), conversion of thespiropyran to the hydrophilic MC caused wetting of the MSNssurface, leading to a 7-fold increase (∼15% vs ∼2% over 12 h)in the rate of cargo release in vitro. Phototriggered drug releasewas also demonstrated in the presence of two cancer cell lines(EA hy926 and HeLa), leading to a significant decrease in cellviability (32% for EA hy926 and 51% for HeLa after 5 minirradiation). The low level of UV light itself did not affect cellviability.The UV light-driven change in hydrophobicity of spiropyrans

has also been exploited by Lu et al.87 in the development ofphotoresponsive MSNs (Figure 11). These workers embeddeda spiropyran-functionalized amphiphilic copolymer, poly(RBM-MAPEG-SPMA)-FA, onto the surface of C18-coated MSNs(the folic acid moiety was incorporated to promote targeting ofthe system to overexpressed folate receptors commonly foundon the surface of tumor cells). UV irradiation (365 nm, 200mW/cm2) led to shedding of the polymer coating due toconversion of the spiropyran to the hydrophilic MC form, withfluorescence from the appended rhodamine B moiety beingquenched 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 keptin the dark. Furthermore, UV irradiation of KB cells incubatedwith the functionalized NP led to a 50% decrease in cellviability relative to an appropriate control.

3.2.2. Self-Assembled Nanocarriers. Self-assembled nano-carriers incorporating spiropyrans have predominantly beenconstructed from polymeric materials. Three main differencesbetween the SP and the MC isomers of spiropyrans have beenutilized to manipulate the self-assembly/disassembly of themolecular 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 protonconcentration. Liao et al.88 have exploited this to triggerdisassembly of a nanoparticle system composed of poly(methylacrylate-co-acrylic acid) (PMA-co-PAA) and poly(4-vinylpyr-idine) held together by hydrogen bonding between thecarboxylic acid and pyridinyl groups (Figure 12). Irradiationof a methanolic suspension of the polymer and the negativespiropyran derivative SP1 with blue LED light (470 nm, 20mW/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 spirocyclo-hexadine compounds.84

Figure 9. Schematic representation of a photoresponsive nanocarriersystem consisting of a mesoporous framework (MCM-41), ananchored photoswitchable spiropyran, a dye in the inner pores, andcarboxylate-terminated G1.5 PAMAM dendrimers as molecular caps.85

Reprinted with permission from ref 85. Copyright 2007 WILEY-VCHVerlag GmbH & Co. KGaA, Weinheim.

Figure 10. Schematic representation of a “dry−wet” light-responsiverelease system.86 Reprinted with permission from ref 86. Copyright2014 American Chemical Society.

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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 noveltechnology was used to induce the release of a fragrantaldehyde molecule.89

The MC spiropyran isomer can form H-type π−πinteractions within the sterically crowded environment ofpolymer brushes. Based on this, Achilleos et al.90 developedpolymeric nanoparticles whose assembly can be triggered byUV light irradiation and then disassociate upon exposure tovisible light. A spiropyran-containing monomer, SPMA, wasrandomly copolymerized with 2-(dimethylamino) ethyl meth-acrylate on the surface of an inorganic core to give well-definedPDMAEMA-co-PSPMA block copolymer brushes. UV irradi-ation (λ = 365 nm) led to the generation of the MC form,which formed intraparticle MC−MC stacks within thepolymeric layers. The polymeric nanoparticles maintainedtheir form upon removal of the inorganic core due to theMC−MC aggregates serving as noncovalent cross-link pointswithin the dense polymer brush. Visible-light irradiation gaverise to the SP form, leading to dissociation of the H-aggregatesand disruption of the structure of the nanoparticles. Althoughtriggered drug release was not demonstrated, this system hasdefinite 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

1982, Sunamoto and his group reported the photocontrolledtransport of phenylalanine (Phe) across liposomal bilayers thatcontained a positive-type spiropyran derivative.91 Phe formedionic complexes with the zwitterionic MC form of thespiropyran 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 spiropran-modified copolymers upon irradiation.92

A recent study by Wang et al.93 presented spiropyran-functionalized polymersomes based on poly(ethylene oxide)-b-PSPA diblock copolymers, containing carbamate linkages(Figure 13). The SP form of the spiropyran moieties thatwere generated either under visible light irradiation (λ > 450nm) or spontaneously in the dark rendered the particlesimpermeable. The UV light-generated MC form was stabilizedthrough hydrogen bonding to the carbamate group, leading tothe release of embedded uncharged, charged, and zwitterionicsmall-molecule species from the polymersomes. Two modes ofrelease were demonstrated in vitro and in cellulo: (i) sustainedrelease upon a short period of UV irradiation and (ii)switchable release under alternating UV−visible light irradi-ation.Spiropyran derivatives have also been utilized as dopants in

LLC self-assemblies to achieve photocontrol over the releaserate of encapsulated cargo. Boyd and co-workers demonstratedthat UV irradiation of phytantriol-based LLCs doped withspiropyran derivatives featuring long alkyl tails was able toinduce a reversible phase transition from a rapid-releasemesophase (bicontinuous cubic phase) to a slow-releasemesophase (reverse hexagonal phase), due to the disruptionof the packing of the self-assembled lipids induced byphotoisomerization of the spiropyran groups.94,95

4. DIARYLETHENES

Diarylethenes are photochromic molecules that contain twoaryl groups linked via a CC double bond.96−98 Stilbene is thesimplest and most well-known example, incorporating twophenyl groups (Figure 14A).98,58 Upon UV irradiation,stilbenes undergo an initial E-to-Z isomerization, followed bya 6π electrocyclization to form ring-closed dihydrophenan-threne, which can then undergo an irreversible hydrogen-elimination reaction with oxygen to produce phenanthrene.98

Figure 11. Schematic representation of a spiropyran-functionalizedpolymersome for DOX delivery that dissembles upon exposure to UVlight due to conversion of the spiropyran to its more hydrophilic MCform.87 Reprinted with permission from ref 87. Copyright 2013 RoyalSociety of Chemistry.

Figure 12. Schematic representation of reversible dissolution ofpolymer-based nanoparticles triggered by spiropyran photoisomeriza-tion.88 Reprinted with permission from ref 88. Copyright 2016 RoyalSociety of Chemistry.

Figure 13. Schematic representation of photoresponsive polymer-somes incorporating spiropyran moieties.93 Light-triggered SP−MCisomerization induces a change in membrane permeability, altering therelease rate of noncharged, charged, and zwitterionic small-moleculespecies below critical molar masses. Reprinted with permission fromref 93. Copyright 2015 American Chemical Society.

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Replacing the phenyl rings of stilbene with thiophene rings canlargely improve the stability of the photogenerated cyclicproduct; dithienylethenes are thus the most popular kind ofphotochromic diarylethenes.97 Modifications of diarylethenesalso include replacement of the CC double bond with a five-membered ring,99,100 such as a maleic anhydride group101 orfluorocyclopentene,102 or a six-membered ring,103−105 such asbenzoquinone,104 in order to improve their resistance tophotofatigue (Figure 14B).97

Diarylethenes are unique “P-type” photochromic com-pounds,98 meaning that the reverse isomerization from thering-closed form to the ring-open form usually cannot happenthermally but can be readily triggered by visible light (λ > 450nm). This thermal irreversibility is the most unique property ofdiarylethenes.4.1. Long-Wavelength Light-Responsive Diarylethene

Derivatives. The simplest approach to acquire a bathochromicshift in the absorbance wavelengths of diarylethenes is toextend the π-conjugation length. Tosic et al.106 achieved this byintroducing tetraalkenes (Figure 15, DAE1) or unsaturatedbenzoic acid ester groups (DAE2). Cyclization of thesederivatives can be readily triggered by irradiation with bluelight (420 nm), accompanied by a shift in the absorptionmaxima of the corresponding ring-closed form to the red-lightregion (λmax > 630 nm). Fukaminato et al.107 indirectlyelongated the π-conjugation length by attaching a fluorescentdye, N-bis(1-hexylheptyl)perylene-3,4-dicarboxylic monoimide(PMI), to one of the aryl rings of a diarylethene. The open-to-closed or closed-to-open isomerization of compound DAE3can be readily triggered by irradiation with green light (560nm) or blue light (405 nm) in 1,4-dioxane. Both isomers have asharp absorbance in the range of 430 to 600 nm, which isattributed to the PMI moiety. Given that both isomers displaystrong absorbances within the 450−550 nm wavelength range,it is surprising that both isomers can be generated in very highyields (>90%) upon irradiation.Another strategy to develop visible-light sensitive diary-

lethenes is to regulate intramolecular photoinduced energy andelectron transfer via triplet states. Fredrich and his groupincorporated a strong triplet sensitizer, a biacetyl unit, toproduce compound DAE4.108 The ring-opened form of DAE4has a λmax between 300 to 500 nm in acetonitrile, while thering-closed form has a λmax of 608 nm. Alternating irradiationwith blue light (405 nm) and yellow light (579 nm) canquantitatively generate the ring-closed and ring-opened forms,respectively. Moreover, the ring-closure reaction via the tripletmanifold does not generate irreversible byproducts, affordingimproved photofatigue resistance.4.2. Application of Diarylethenes in Light-Responsive

Nanocarriers. Diarylethenes display quite a small geometric

change upon photoisomerization; hence, most of theirapplications in supramolecular assemblies take advantage ofthe differing stacking propensities of the two isomers.96

Yagai et al.109 utilized the photoinduced conformationalchange of the two aryl rings of a diarylethene to inducemorphological changes in perylene bisimide (PBI)-basedassemblies in toluene (Figure 16A,B). The aryl rings of thering-opened isomer were stabilized in a parallel conformationby PBI via hydrogen bonds and π−π stacking interactions. Theresulting supermolecular diarylthene/PBI complex self-as-sembled into fiber-like nanostructures. Upon irradiation withUV light, the generated ring-closed form of the diarylethenemoiety could not bind with PBI due to its rigid plate structure,leading to the dramatic, reversible formation of granularaggregates.Higashiguchi et al.110 have reported amphiphilic diary-

lethenes with oligo(ethylene glycol) and alkyl side chains thatundergo photoinduced morphological transformation inphysiological surroundings (Figure 16C). The ring-openedform of the amphiphilic diarylethenes have a flexible structureand form submicrometer-sized spheres with a diameter of ca.100 nm in aqueous solution. The ring-closed isomer has a morerigid structure and shows stronger π−π stacking interactions,allowing the formation of fiber-type aggregates. The coloredfibers and colorless microspheres can be reversibly generated byalternating exposure to UV and visible light. Similarmorphological transformations induced by the photoisomeriza-tion of diarylethenes have been reported by other groups.111,112

However, photoinduced release from diarylethene-function-alized delivery systems has not been demonstrated yet.96

Figure 14. (A) Photoinduced isomerization of the simplest diary-lethene, stilbene, and its irreversible oxidation to formphenanthrene.58,98(B) Examples of dithienylethenes featuring a rangeof linkers that improve photofatigue resistance.

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

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5. HEMITHIOINDIGOSHemithioindigos (HTIs) are a somewhat underexplored classof photoswitchable molecules first introduced by Friedlaenderin 1909.113 HTIs consist of thioindigo and stilbene moietiesconnected via a CC double bond.114 Upon irradiation, HTIsundergo isomerization from the thermally stable Z form to themetastable E form.114 The E form is sufficiently stable to beisolated by chromatography, due to the relatively high-energybarrier between the E and Z forms (typically >27 kcal/mol).114,115 One of the most attractive properties of HTIs istheir absorbance in the visible region, with both isomersdisplaying λmax > 420 nm. The absorbance of the E isomershows a moderate bathochromic shift of about 20 nm relativeto the Z form, resulting in reversal to the Z form.114 Z-to-Eisomerization can also be induced thermally. HTIs have beenshown to have very high photofatigue resistance, survivingthousands of cycles of photoswitching.115

Similar to azobenzenes and spiropyrans, substituents on boththe thioindigo and the stilbene fragments can strongly affect thephotoisomerization characteristics of HTIs (Figure 17).118

Introduction of electron-donating substituents, for example,methoxy (HTI1a) or NH2 groups (HTI1b), to the stilbenefragment leads to red-shifted absorbances and faster isomer-ization in both directions.116

However, very strong donor substituents (para-dimethyla-mino (HTI1c) and julolidine (HTI2)) slow down the Z-to-Ephotoisomerization.116 Cordes and co-workers reported thatthe 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 inphotoisomerization speed, whereas substitution with a methoxygroup, an electron-donating substituent, did not affect the rateof isomerization.117

One drawback of HTIs is that some HTI derivatives mayundergo irreversible bleaching upon irradiation, potentiallylimiting their practical application. Tanaka and his groupreported that fluoro substitution at the ortho-positions of thestilbene fragment can result in irreversible intramolecularcyclization (Figure 18A).119 HTIs with a cyano group on thestilbene moiety were found to undergo an irreversibleintermolecular [2 + 2] cycloaddition of the central doublebond, while a HTI derivative with a benzoyl group yielded a [2+ 4] cycloadduct upon irradiation (the Z isomer could beregenerated by heating in this case) (Figure 18B,C)121 Seki etal. reported that when hydrophobic HTI derivatives wereincorporated into a bilayer membrane, irreversible bleachingoccurred upon irradiation, possibly due to the clustering of theHTIs in the membrane.120

5.1. Application of Hemithioindigos in Light-Respon-sive Nanocarriers. Although HTIs have been incorporatedinto amino acids122 and peptides123,124 in order to achieve

Figure 16. Photoresponsive nanoassemblies incorporating dithienyle-thenes. AFM height images of (A) fiber coaggregates formed from thering-opened form of a dithienylethene and PBI and (B) granularaggregates formed from the ring-closed form and PBI.109 Reprintedwith permission from ref 109. Copyright 2014 WILEY-VCH VerlagGmbH & Co. KGaA, Weinheim. (C) Photoinduced macroscopicmorphological transformation of a supramolecular assembly formedfrom amphiphilic dithienyethene derivatives.110 Reprinted withpermission from ref 110. Copyright 2015 American Chemical Society.

Figure 17. Photoinduced isomerization of HTI, together withisomerization rate for various derivatives: HTI1a,116 HTI1b,116

HIT1c,116 HIT2,116 and HTI3.117

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

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photocontrol over the assembly of peptides or enzymes, theirapplication in “smart” nanomaterials is yet to be fullyestablished.Eggers et al.115 synthesized five lipids containing HTI

chromophores as part of their hydrophobic tails (Figure 19).These lipids showed the expected photoisomerization behaviorin organic solution and when incorporated into vesicle bilayermembranes.Tanaka and his co-workers reported the first application of

HTIs in a supramolecular system, based on differing affinities ofthe E and Z isomers for two porphyrin derivatives (Figure20).125 The Z form of compound HTI5 was established to havea higher affinity for ureidoporphyrin, while the E formpreferentially bound pentafluorobenzamidoporphyrin. Bluelight (440 nm) and green light (490 nm) were used toreversibly switch between the E and Z isomers, which showedrepeatable movements between the two kinds of porphyrins.Such a system could potentially be exploited in the develop-ment of photoresponsive nanocarriers for biomedical applica-tions in the future.

6. DONOR−ACCEPTOR STENHOUSE ADDUCTSPhotochromic 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). Thesemolecules consist of a photoreactive furfural part, an aminemoiety, 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. Thereverse isomerization can occur spontaneously in the dark orby gently heating the sample. The proposed mechanism for thephotoisomerization is an initial Z-to-E isomerization of analkene group, followed by a reversible Nazarov-type 4πelectrocyclization.132,133

By replacing the aliphatic amine present within the firstgeneration of DASAs with an aniline-based amine, a bath-ochromic shift in absorbance maxima up to 750 nm has beenachieved, together with excellent resistance to photofatigue.134

In addition, second-generation DASAs are capable of photo-switching in polar solvents such as THF and DCM and in solidpolymer matrices such as polystyrene and poly(methylmethacrylate), in contrast to first-generation DASAs.6.1. Application of Donor−Acceptor Stenhouse

Adducts in Light-Responsive Nanocarriers. The twoisomers of DASAs display significant differences with regardsto their physical properties, spectral absorption, solubility, andmolecular volume.126,127 This makes DASAs very attractive fordeveloping photoresponsive delivery systems.The group of de Alaniz coupled a DASA derivative to an

alkyne-terminated monomethyl PEG chain (Figure 22), whichself-assembled into micelles in an aqueous environment.127

Upon visible light irradiation (570 nm) conversion of theDASA to the more hydrophilic cyclopentenone form was foundto promote disassembly of the micelles and release of anencapsulated hydrophobic model cargo molecule, Nile Red.Our group has recently reported that incorporation of an

alkylated DASA into a phytantriol-based LLC system permitsrapid, reversible switching from a rapid-release bicontinuouscubic phase to a slow-release hexagonal phase using green light(532 nm).135

Although DASAs show great potential, one issue is thatisomerization from the triene form to the cyclopentenone formoccurs in aqueous solution in the dark.133 It has also beenreported that some polar solvents can induce irreversiblecyclization with no observed Z-to-E isomerization.136 This mayhinder their application as reversible photoswitches in abiomedical setting.Figure 19. HTI-bearing lipids.115

Figure 20. Schematic representation of the photocontrolled repeatablemovement of HTI between two kinds of porphyrins. HTI5 in its Zform binds more strongly to the ureidoporphyrin receptor (left), whileE isomer binds more strongly to the pentafluorobenzamidoporphyrinreceptor (right).125 Adapted with permission from ref 125. Copyright2008 American Chemical Society.

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

Figure 22. Schematic representation of a photoresponsive micelleformed from an amphiphilic DASA-functionalized polymer.127 Visiblelight irradiation leads to the formation of the more hydrophiliccyclopentenone form of DASA, resulting in micelle disruption andcargo release. Reprinted with permission from ref 127. Copyright 2014American Chemical Society.

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7. HEXAARYLBIIMIDAZOLES

Hexaarylbiimidazole (HABI) is a photochromic compound thatwas first reported by Taro Hayashi and Koko Maede in1960.137,138 Oxidation of 2,4,5-triphenylimidazole with potas-sium ferricyanide in an aqueous solution of potassiumhydroxide yielded a light yellow-colored compound, whichrapidly transformed into a reddish purple-colored product uponirradiation with light.138,139 The mechanism behind this light-triggered color change entails homolytic cleavage of the C−Nbond between the imidazole rings, resulting in the formation ofthe colored triphenylimidazolyl radical (Figure 23).140,141

Recombination of the radical to form the original C−N bondtakes place in the dark, but this process takes several minutesdue to diffusion effects.Because radical species are highly active and can react with

oxygen or active hydrogen, HABI displays poor photo-fatigueresistance.138,139 Different techniques have been utilized inorder to avoid oxidation of the colored HABI, revolving aroundsuppressing the diffusion of the radical. Abe and his group havesynthesized several UV-light responsive HABI derivativesfeaturing a [2,2]paracyclophane (HABI1) or naphthalenelinker (HABI2) between two triphenylimidazole or benzeneunits (HABI3) which show much lower discolorationrates.38,143,148,144,145 Compound HABI3 showed the fastestthermal back-reaction, with a half-life of 35 μs in solution atroom temperature.145 However, the bridged HABIs can still beoxidized by oxygen in air or solution.144

7.1. Long-Wavelength Light-Responsive Hexaarylbii-midazole Derivatives. Compound HABI4 has a special C−Nbond between the nitrogen atom of the imidazole ring and thecarbon atom from the linker binaphthyl, instead of the usualC−N bond between the imidazole rings.146 Visible lightirradiation of this colorless compound leads to the cleavageof 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 reverseisomerization and resulting coloration occurs thermally in thedark, and can also be rapidly induced by UV light irradiation(355 nm) via the radical path. Compound HABI5 incorporatesa phenanthroimidazole moiety and a di-tert-butylphenol ring.147

The isomerization can be triggered by white light, while thecoloration reaction only takes 1.9 s, making it the fastestnegative photochromic reported so far. Notably, the presenceof 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 inconformation and production of radicals accompanying photo-isomerization may prove useful for “on-demand” manipulationof smart materials in the future.

8. CONCLUDING REMARKS

Recent advances in the design and synthesis of long-wavelengthlight-responsive photoswitchable molecules and their incorpo-ration into nanocarriers have been summarized in this review.Some UV light-responsive systems have also been highlightedin order to illustrate particular release strategies and outcomesof note. The presented examples represent only a small part ofthe huge amount of work that has been done in this area. Wehope, nevertheless, that by providing a general survey of thedifferent types of designs and strategic approaches beingpursued, this review will be of assistance to researchers seekingto develop photoresponsive nanocarriers with improvedproperties for biomedical applications.The tremendous progress in developing light-responsive

nanocarriers has involved a combination of photochemistry,synthesis, and materials science. Computational science has alsohad a role to play, with methods such as density functionaltheory (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 long-

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 andHABI5147).

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wavelength light-responsive photoswitches in biological envi-ronments needs to be improved. The utilization of long-wavelength light-responsive photochromics in nanocarriers hasnot yet been fully explored. Azobenzene and its derivatives havedominated the photoresponsive drug delivery area, presumablydue to their excellent biostability and significant geometricalchange upon isomerization. This, in turn, shows directions forthe development of new photoswitches. There are manytechnical difficulties that need to be addressed as well, such asthe prevention of leakage from nanocarriers and the develop-ment of appropriate laser sources for efficient in vivo activation.Even though light as a stimuli has been successfully applied inbioapplication, such as photodynamic therapy for cancertreatment,149 photosensors for diagnoses,150 and photodegrad-able materials for tissue engineering,151 there are no photo-responsive nanocarriers that have been used in clinicalapplications to date. Nevertheless, we feel confident that thenext decade or so will see the eventual development ofphotoresponsive nanosystems suitable for in vivo use.

■ AUTHOR INFORMATION

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

ORCIDWye-Khay Fong: 0000-0002-0437-9332Ben J. Boyd: 0000-0001-5434-590XAuthor ContributionsThe manuscript was written through contributions of allauthors. All authors have given approval to the final version ofthe manuscript.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

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

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