Photoswitchable Molecules in Long-Wavelength Light-Responsive

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Photoswitchable molecules in long-wavelength lightresponsive drug delivery: from molecular design to applications Shiyang Jia, Wye-Khay Fong, Bim Graham, and Ben J. Boyd Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b00357 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 15, 2018

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Photoswitchable molecules in long-wavelength light-responsive drug delivery: from molecular design to applications Shiyang Jia,a Wye-Khay Fong,b,d Bim Graham,a and Ben J. Boyd*b,c a Medicinal Chemistry, b Drug Delivery, Disposition and Dynamics, and c 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. d ETH Zurich, Department of Health Science & Technology, Schmelzbergstrasse 9, LFO E23, 8092 Zurich, Switzerland. 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 non-invasive, “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 one-photon visible and near-infrared light-triggered photoswitchable 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 (“nanocarriers”), including mesoporous silica nanoparticles1,2 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 focussed particularly on the generation of structurally well-defined nanocarriers possessing good biocompatibility and high loading capacities.12,13,14 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 reduce 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 cancerous tissue. Those stimuli includes enzyme,16 pH,17 hypoxia,18 redox19. Endogenously

responsive systems are not the focus of this review, but are mentioned here for completeness.External stimuliresponsive nanocarriers principally comprise systems that are responsive to applied magnetic fields,20,21 electric field,22 ultrasound,23 and light24. Among these stimuli, light has many advantageous features. In addition to being relatively non-invasive and “bio-friendly” (, light is easily manipulated and finely tuneable, 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 Non-ionizing light can be broadly divided into three wavelength ranges, namely ultraviolet (UV, 10–400 nm), visible (400–750 nm), near-infrared (NIR, 750–1100 nm). Both the wavelength and 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 wave lengths up to 900 nm.28,29,30,31 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 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


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

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 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, re-

sistance 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.36,37,38 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 light39,40. 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 light-responsive 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∗



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Table 1. Various visible light-responsive azobenzene derivatives reported in the literature. (The λmax of Z isomer of the first 43 43,44 42 example was obtained from calculation using the TDDFT (B3LYP/6-31G*) methods. ) Adapted from refs. and

R1

R2

H atoms

H atoms

λmax of Z isomer (nm) *

348 (π→π∗) , 473 (n→π∗)43

Methoxyl groups

338 (π→π∗), 480 (n→π∗)

~330 (π→π∗), 444 (n→π∗)

44

H atoms

445

N/A

F atoms

~364 (π→π∗), 370 (n→π∗)

Piperidine groups F atoms

364

45

43

Methoxyl groups 42

λmax of E isomer (nm)

bands for both isomers in the vicinity of this wavelength prevents complete photoreversion to the E form.42 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-

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.

*

~314 (π→π∗), 450 (n→π∗)

43,50

(2) steric interactions reduces the sp2 character form; of the N atoms, also raising the HOMO energy, leading to the red-shift absorbance;44 (3) electron-withdrawing groups such as F 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 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-ortho-methoxy-substituted azobenzenes that are switchable with green/blue light.43 Building on this seminal work, Samanta et al.46 prepared a series of peptides crosslinked with tetra-ortho-methoxy 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 sec), 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


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

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-based53,54,55 light-responsive drug delivery systems. A notable recent example reports the construction of a red light-responsive “supramolecular valve” using tetraortho-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 non-irradiated 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 lightresponsive 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 outwards and onto the azobenzene moieties,

(B)

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

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 towards 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 MSNs, inducing apoptosis in 60% of PANC-1 cell 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, hence have also been widely incorporated into nanoparticles fo rmed via the self-assembly of polymers or lipids for use as photoactivatable drug delivery systems. Reported azobenzene-functionalized self-assembled nanoparticles include thermotropic liquid crystals,58 liposomes,59 vesicles,60,61

Figure 5. Schematic representation of photoresponsive MSNs functionalized with azobenzene derivatives as impel-



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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, Yu Chuan et al.

Low molecular weight gelators lipids

Hydrogel

DNA, Doxorubicin

Pianowski, Zbigniew L et al.

Block copolymers

Hollow nanosphere

Doxorubicin

Zhang, Haitao et al.

Dendrimers

Dendrimers

Eosin

Puntoriero, Fausto et al et al.

Amphiphilic guest lipids

Superamolecular bilayer vesicles

Mitoxant

Hu, Xiao-yu et al.

Crosslinked polymers

Hydrogel

Peptide

Nehls, Eric M et al.

61 62

63 64

65 66

56

lers and gatekeepers. Reprinted with permission from ref. 56 . Copyright 2007 American Chemical Society.

hollow nanotubes63 and hydrogels55. 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 selfassemblies. 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 Fisher and coworkers 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 exposure to visible light (λ > 450 nm).68 The MC form has a 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, dielec tric constant and pKa.68,69,70 Production of the MC form can be induced by a high polarity environment,71 tempera ture and pH changes,72 and complexation with metal ions73. Hence, spiropyrans not only exhibit photochromism, but also solvatochromism,74 thermochromism,75 andions73. Hence, spiropyrans not only exhibit photochromism, but also solvatochromism,74 thermochromism,75 and acidichromism.76 A drawback of these compounds is that their isomerization usually does not involve a dramatic

Figure 6. The photo-induced isomerization of a “positive” 68 spiropyran.

change in molecular conformation.68 3.1 Long-wavelength light-responsive spiropyran derivatives The most common strategy to achieve visible lightresponsiveness 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 form,77 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 SP forms is accompanied by a pH change. Recently developed negative photochromic spiropyrans are illustrated in Figure 7. The group of Liao have 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, 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 The group of Liao have 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


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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

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

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 light-responsive MSNs incorporating a mesoporous support (MCM-41), a negative spiropyran, and a carboxylterminated PAMAM dendrimer have been reported by Aznar et al. 85 (Figure 9). At pH 7.2, the negativelycharged 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.

Figure 7. Examples of red-shifted “negative” spiropyran de79 80 rivatives featuring alkyl sulfonate (SP1 and SP2 ), sulfo 81 82 83 (SP3 ), TCF (SP4 ) and CF3PhTCF (SP5 ) substitution. The wavelengths of maximum absorbance in 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.

displays a very short half-life (t1/2 = 23 s) and, overall, compound SP5 shows excellent fatigue resistance. Khodorkovsky and his group have reported 1,3indandione-derived 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 to visible light (red and green), with exposure to light of wavelengths between 254 nm 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 spiro-compounds. Discoloration of the MC form happens spontaneously in the dark, the rate of which is temperature- and solvent polaritydependent.

Some of the more interesting low-power UV-responsive spiropyran-functionalised MSNs are worth highlighting to illustrate the ways in which light-dependent cargo release can be achieved from nanocarrier systems. For example, Jiang and coworkers formed a hydrophobic layer on the surface of MSNs using the SP form of a spiropyran and a fluorinated silane. This layer served to hinder release of encapsulated cargo into the surrounding aqueous environment (Figure 10).86 Upon low-power 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 seven-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.

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 85 dendrimers as molecular caps. Reprinted with permission


Chemistry of Materials 85

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from ref. . Copyright 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

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Figure 11. Schematic representation of a spiropyranfunctionalized polymersome for DOX delivery that dissembles upon exposure to UV light due to conversion of the spi87 ropyran to its more hydrophilic MC form. Reprinted with 87 permission from ref. . Copyright 2013 Royal Society of Chemistry.

Figure 10. Schematic representation of a “dry-wet” light86 responsive release system. Reprinted with permission from 86 ref. . Copyright 2014 American Chemical Society.

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-(RBM-MAPEG-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 dark. Furthermore, UV irradiation of KB cells incubated with the functionalised 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 MC isomers of spiropyrans have been utilised to manipulate the self-assembly/disassembly of the molecular components of such system: degree of protonation, π−π interactions and zwitterionicity.

Figure 12. Schematic representation of reversible dissolution of polymer-based nanoparticles triggered by spiropyran pho88 88 toisomerization. Reprinted with permission from refs. . Copyright 2016 Royal Society of Chemistry.

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-vinyl pyridine) 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 hydrogenbonding and 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, 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 crosslink 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.


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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 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 spiropran-modified copolymers upon irradiation. 92 A recent study by Wang et al.93 presented spiropyranfunctionalized polymersomes based on poly(ethylene oxide)-b-PSPA 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 coworkers 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 selfassembled lipids induced by photoisomerization of the spiropyran groups.94,95 4. Diarylethenes Diarylethenes are photochromic molecules that contain two aryl groups linked via a C=C double bond.96,97,98 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-

triggered SP-MC isomerization induces a change in membrane permeability, altering the release rate of non-charged, charged, and zwitterionic small-molecule species below criti93 cal molar masses. Reprinted with permission from ref. . Copyright 2015 American Chemical Society.

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

closed dihydrophenanthrene, which can then undergo an irreversible hydrogen-elimination reaction with oxygen to produce phenanthrene.98 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 five-membered ring,99,100 such as a maleic anhydride group101 or fluorocyclopentene102, or a six-membered ring103,104,105, 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)perylene3,4-dicarboxylic monoimide (PMI), to one of the aryl rings of a diarylethene. The open-to-closed or closed-toopen 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 wave-

Figure 13. Schematic representation of photoresponsive pol93 ymersomes incorporating spiropyran moieties. Light-



length 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

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

biacetyl unit, to produce compound DAE4.108 The ringopened form of DAE4 has a λmax between 300 to 500 nm in acetonitrile, whilst 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 by-products, affording improved photofatigue resistance. 4.2 Application of diarylethenes in light-responsive nanocarriers Diarylethenes display quite a small geometric change upon photoisomerization, hence most of its 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, 16B). The aryl rings of the ring-opened isomer were stabilized in a parallel conformation by PBI via hydrogen bonds and π-π stacking

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interactions. The resulting supermolecular diarylthene/PBI complex self-assembled into fibre-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.

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

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 fibre-type aggregates. The colored fibres 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 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


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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

Figure 18. Irreversible photo-bleaching of some HTIs. (A) Intramolecular cyclization and dimerization after Z-to-E photoisomerization,119 (B) [2+2] cycloaddition114,120, (C) [2+4] cycloaddition, reversible by heating121.

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

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 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 (paradimethylamino (HTI1c)and julolidine (HTI2)) slow down the Z-to-E photoisomerization.116 Cordes and coworkers reported that the introduction of a typical electronwithdrawing group, bromine, to the para-position of the

115

Figure 19. HTI-bearing lipids.

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 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 orthopositions 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 and 21C)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 responsive nanocarriers

in

light-

Although HTIs have been incorporated into amino acids122 and peptides123,124 in order to achieve 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



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19). These lipids showed the expected photoisomerization behavior in organic solution and when incorporated into vesicle bilayer membranes. Tanaka and his coworkers 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, whilst 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 125 125 (right). Adapted with permission from ref. . Copyright 2008 American Chemical Society.

6. Donor-acceptor Stenhouse adducts Photochromic donor-acceptor Stenhouse adducts (DASAs) were recently developed by de Alaniz and others, 126,127,128,129,130,131 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 firstgeneration DASAs.

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

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

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 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 have 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. 7. Hexaarylbiimidazoles


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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 light-triggered colour 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.

hv N

N

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Hexaarylbiimidazole

(A) Positive HABIs

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HABI4

Figure 23. Photoinduced isomerization of HABIs. (A) HABIs displaying positive photochromic behaviour, featuring 142 143,144 145 [2,2]paracyclophane (HABI1) , naphthalene (HABI2) and benzene (HABI3) linkers. (B) HABIs displaying negative pho146 147 tochromic behaviour (HABI4 and HABI5 ).

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 hex-

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-tertbutylphenol 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.

Compound HABI4 has a special C-N bond between the nitrogen atom of the imidazole ring and the carbon atom

The application of HABIs in drug delivery systems has not been reported yet, however the extreme changes in conformation and production of radicals accompanying

7.1 Long-wavelength light-responsive aarylbiimidazole derivatives



photoisomerization may prove useful for “on-demand” manipulation of smart materials in the future.

REFERENCES (1)

Concluding remarks Recent advances in the design and synthesis of longwavelength 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 lightresponsive 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 long-wavelength light-responsive photoswitches in biological environments need to be improved. The utilization of long wavelength-light-responsive photochromics in nanocarriers has not yet been fully explored. Azobenzene and its derivatives has 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 treatment149, photosensors for diagnose150, photodegradable materials for tissue engineering,151 there is no photoresponsive nanocarriers that have been used in clinical 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

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* Ben J. Boyd [email protected]

Author Contributions

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

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ACKNOWLEDGMENT 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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Photoswitchable Molecules in Long-Wavelength Light-Responsive

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