Applications of Light-Responsive Systems for Cancer Theranostics

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Applications of Light-Responsive Systems for Cancer Theranostics Hongzhong Chen, and Yanli Zhao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b01114 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

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ACS Applied Materials & Interfaces

Applications of Light-Responsive Systems for Cancer Theranostics Hongzhong Chen† and Yanli Zhao*,†,‡ †

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical

Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 ‡

School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang

Avenue, Singapore 639798

ABSTRACT. Achieving controlled and targeted delivery of chemotherapeutic drugs and other therapeutic agents to tumor sites is challenging. Among many stimulus strategies, light as a mode of action shows various advantages such as high spatiotemporal selectivity, minimal invasiveness and easy operation. Thus, drug delivery systems (DDSs) have been designed with the incorporation of various functionalities responsive to light as an exogenous stimulus. Early development has focused on guiding chemotherapeutic drugs to designated location, followed by the utilization of UV irradiation for controlled drug release. Because of the disadvantages of UV light such as phototoxicity and limited tissue penetration depth, scientists have moved the research focus onto developing nanoparticle systems responsive to light in the visible region (400 nm to 700 nm), aiming to reduce the phototoxicity. In order to enhance the tissue penetration depth, near-infrared light triggered DDSs become increasingly important. In addition, light-based advanced systems for fluorescent and photoacoustic imaging, as well as photodynamic and photothermal therapy have also been reported. Herein, we highlight some of recent developments by applying light-responsive systems in cancer theranostics, including light activated drug release, photodynamic and photothermal therapy, and bioimaging techniques such as fluorescent and photoacoustic imaging. Future prospect of light-mediated cancer treatment is discussed at the

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end of the review. This Spotlights on Applications article aims to provide up-to-date information about rapidly developing field of light-based cancer theranostics.

KEYWORDS: cancer theranostics, fluorescence imaging, light activated therapy, photoacoustic imaging, photodynamic therapy, photothermal therapy

Introduction Cancer is a group of diseases characterized by rapidly proliferating cells that can spread to other tissues in a process called metastasis. Complete resection of tumor tissues by surgery is difficult. Chemotherapy is required for the removal of remaining cancer tissues. However, serious side effects in patients are often inevitable when chemotherapy drugs are administrated intravenously, mainly due to their hydrophobic and non-targeting nature. Therefore, there is an urgent need to develop safe and effective techniques that increase the therapeutic efficacy and reduce the drug dosage. Due to the leaky vasculature and poor lymphatic drainage of growing tumors, enhanced permeability and retention (EPR) effects could endow better accumulation of nanoparticles.1,2 For effective treatment of cancer, the development of such nanoparticles as drug delivery systems (DDSs) with the incorporation of simultaneous cancer diagnostics and therapeutics (so called theranostics) is required.3–5 DDSs are sophisticatedly designed systems that deliver drugs to targeted location when triggered through various means. Different stimuli could be used in these DDSs to trigger the release of drugs in order to enable on-demand drug release at designated area and time.6–9 In general, stimuli in DDSs could be classified as endogenous and exogenous approaches. Endogenous stimuli include acidic pH,10 reducing environment,11 reactive oxygen species (ROS),12 and overly expressed enzymes13,14 found intrinsically in cancer cells. Exogenous


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stimuli include the use of electromagnetic radiations such as UV light,15 visible light,16 nearinfrared (NIR) light,17 and γ-ray irradiation,18 as well as the application of ultrasound and magnetic field19 externally to trigger the release of drugs. Among these methods, light mediated therapy has been regarded as the powerful modality to achieve on-demand drug release in the target tissues. Light displays dual wave-particle properties, which consists of photons having packs of energy inversely related to its wavelength. It is the narrow spectral region of electromagnetic radiation perceived by human vision (400 to 700 nm) and is often extended to ultraviolet region (200 to 400 nm) and NIR region (700 to 100 nm) in photochemistry and photobiology. Upon the interaction with a tissue, the reflection, scattering, transmission and absorption of light can occur, which largely depend on several optical features of the tissue such as the tissue heterogeneity, and absorbance by water and endogenous dyes. The maximum skin permeability to light occurs in the NIR light window from 650–900 nm with the penetration depth of up to 2 cm. Therefore, the use of NIR light has significant advantages for phototherapy and optical imaging within deep tissues over UV and visible light. Particularly for oncology, light as a mode of stimulus has its high potential on account of its various advantages such as excellent temporal and spatial accuracy, minimal invasiveness, tunability in the wavelength of light used, increased reliability, and its orthogonality to intracellular environment.20 Absorption of light by molecules could lead to (1) photochemical reactions of molecules themselves (such as the photolysis of prodrugs to drugs and the photoisomerization) or with other molecules (such as the interaction of photosensitizers with oxygen to generate singlet oxygen), (2) emission of light due to radiative relaxation of molecules (such as fluorescence), and (3) transfer of light energy to other forms due to nonradiative relaxation of molecules (such as thermal energy for photothermal therapy (PTT) and acoustic energy for photoacoustic (PA) imaging). Light could also be employed for the release of chemotherapeutic drugs or the



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excitation of photosensitive materials in other types of cancer treatment. In general, two strategies are proposed in the design of light stimulus DDSs for chemotherapeutic drugs to be delivered in the cancer treatment: (1) Absorption of light to dissociate prodrug into their active forms, and (2) absorption of light by photosensitive molecules, triggering physical changes and thus releasing the encapsulated drugs. The former usually involves the functionalization of available chemotherapeutic drugs to afford prodrugs with reduced cytotoxicity. Upon the illumination at the targeted sites, the photolysis of these prodrugs results in the release of chemotherapeutic drugs.21 The latter normally employs numerous photo-isomerizable organic molecules such as azobenzene derivatives22 and diaryethene derivatives23 grafted on the surface of functional nanoparticles. The isomerization (e.g., trans-cis isomerization) of these photo-responsive groups upon the light illumination leads to the conformation or molecular changes, releasing encapsulated drugs. Apart from designing of light responsive DDSs for the cancer chemotherapy, light sensitive inorganic and organic nanomaterials have been employed for other forms of cancer theranostics including photodynamic therapy (PDT), PTT, and PA imaging. Examples of such inorganic nanomaterials frequently used include gold nanoparticles (AuNPs),24 two-dimensional (2D) nanomaterials

(e.g.,

graphene,25

black

phosphorous,26

and metal

oxide/sulfide

nanostructures27), upconversion nanoparticles (UCNPs),28 and carbon dots.29 Moreover, various organic dyes such as derivatives of porphyrin and phthalocyanine molecules have been designed to show high photothermal conversion efficacy or singlet oxygen generation capability upon the light irradiation for the cancer treatment through PTT or PDT.30–33 In this article, we discussed recent advancements in the applications of light-responsive systems for cancer theranostics (Scheme 1). Some representative light-responsive systems including the light activated prodrugs and light triggered DDSs are highlighted. DDSs designed for light-mediated cancer therapy including PTT and PDT are also covered. Furthermore, light-


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assisted imaging techniques such as fluorescent and PA imaging are also briefly reviewed. Finally, prospects and challenges in the research field of light-mediated cancer theranostics are presented.

Scheme 1. Schematic illustration for the applications of light-responsive systems in the cancer theranostics, including 1) light activated prodrugs, 2) light triggered DDSs, 3) PDT, 4) PTT, 5) fluorescence imaging theranostics, and 6) PA imaging.

Light activated prodrug systems Due to promising application potential and inherent advantages including precisely controlled release, non-contact mode of action, high spatiotemporal resolution and stoichiometric cleavage under the light irradiation, light-triggered prodrug systems have drawn great attention in the field of drug delivery and bioimaging. Photolytic cleavage has been regarded as a powerful approach to control the drug release at specific area because of the excellent temporal and spatial accuracy



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under the light irradiation. Many research efforts have been made to introduce photolytic functional groups into the prodrug design. A general strategy to synthesize light-active prodrugs is to decrease or minimize drug activities by blocking the active site of anticancer drugs using light-removable functional groups. Upon the light irradiation at a specific wavelength, the removal of such photocages leads to the release of the drug in its active form. Among several types of developed photolytic functional groups, one of commonly employed functional groups is o-nitrobenzyl derivatives.34–36 O-nitrobenzyl derivatives have received considerable attentions on account of their facile synthesis and efficient photolysis under the irradiation of UV light. Numerous o-nitrobenzyl derivatives blocking prodrugs have been reported, especially in polymer prodrugs.36,37

Using

camptothecin

(CPT)

derivatives

with

two

active

sites

(10-

hydroxycamptothecin and 9-aminocamptothecin) as monomers to polymerize with o-nitrobenzyl derivatives, Cheng et al. developed polymeric prodrugs with UV controllable drug release property (Figure 1).38 The polymeric prodrugs were only composed of two moieties, including a trigger linker and a CPT unit. The polymeric prodrugs could form nanoparticles (150 nm in diameter) with poly(ethylene glycol)-block-poly(L-lactide) polymer, exhibiting high drug loading efficacy. The prodrug nanoparticles showed fast response to UV light as a stimulus, as indicated by the release of 59% drug upon the irradiation of the UV light with a power of 40 mW/cm2 in 10 min, while negligible drug release was observed in dark. 3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay demonstrate that the half maximal inhibitory concentration (IC50) value of the polymer prodrugs in HeLa cells under the UV light irradiation was 20 times lower than that without the UV treatment under the same conditions.


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Figure 1: Chemical structures of two polymeric prodrugs and their drug release process under the UV light irradiation.

Other than o-nitrobenzyl derivatives, efforts were made to increase the light wavelength using arylmethyl groups. In our recent research (Figure 2a), a type of organic nanoparticles (Acr-Cbl) was synthesized with acridin-9 methanol and chlorambucil.39 Three important functions were achieved in this system, including cancer cell-targeting, regulated drug release, and fluorescent chromophore for cell imaging. The nanoparticles with small size of 60 nm in diameter were efficient in delivering anticancer drug chlorambucil into the target nucleus, killing the cancer cells upon the light irradiation with a wavelength of >400 nm. In a similar study (Figure 2b), a perylene-derived prodrug (Pe(Cbl)4) with four chlorambucil units attached displays an interesting photophysical property, allowing the drug release to be monitored through fluorescence.40 However, these common light-responsive molecules such as o-nitrobenzyl derivatives and arylmethyl groups utilizing UV and visible light for the photolysis often suffer from several drawbacks, since the usage of UV and visible light often endows poor tissue penetration depth as well as phototoxicity.



Figure 2: Chemical structures of the prodrugs (a) Acr-Cbl and (b) Pe(Cbl)4, and their drug release process under the light irradiation.

In order to achieve deeper tissue penetration and better therapeutic performance, lightcleavable systems based on two-photon active molecules or prodrugs activated by NIR light were developed. Due to deeper tissue penetration and low phototoxicity of NIR light, NIR is an ideal light source to induce the photolysis. On the other hand, on account of inherent low energy of NIR light, it is challenging to design suitable linkers to construct NIR-responsive prodrugs. Twophoton excitation technique was developed for photobiological applications under the NIR light irradiation. In general, a molecule is excited from the ground state to higher energy state by the absorption of one photon with energy equivalent to the energy difference of the two states. With the development of two-photon excitation technique, photoactive agents that absorbed light of wavelength in the UV and visible region could be activated using higher intensity pulsed NIR


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laser light, meaning that a single molecule could absorb two photons of lower energy (i.e., longer wavelength) to be excited to the same higher energy state. This absorption of two photons concurrently in a single transition is termed as two-photon absorption. Two-photon absorption has drawn a lot of applications in bioimaging, PDT and photolysis of two-photon active agents.41,42

Figure 3: Chemical structure of prodrug and its functionalization onto the surface of MSNs (CDMSN). The drug release from CD-MSN was achieved by the photolysis under one- or twophoton excitation. Reproduced with permission.46 Copyright 2010, American Chemical Society.



In particular, numerous fluorophores with high two-photon cross-sections have been well employed as photocages for chemotherapeutic drugs.43,44 One example of such fluorophores is coumarin. Coumarin is a natural dye molecule found in plants, and various derivatives have been developed due to its ease of modifications. Coumarin derivatives are considered outstanding candidates as fluorophore probes with excellent fluorescence properties such as high quantum yield, large Stokes shift, and high photostability. Most importantly, coumarin has large twophoton absorption cross section, making it suitable for two-photon excitation.45 Zhu and coworkers reported a theranostic platform with two-photon triggered prodrug using coumarin as the fluorophore.46 As shown in Figure 3, anticancer drug chlorambucil was conjugated with the coumarin derivative via an ester bond, followed by the conjugation with silane to afford the silane precursor. Then, the precursor was grafted on the surface of mesoporous silica nanoparticles (MSNs) to give prodrug-functionalized nanoparticles. After the uptake by HeLa cells, active drug chlorambucil was observed to exhibit a controlled release in 40% within 2 h upon the irradiation with 800 nm NIR light, and the maximum release was up to almost 100% when the irradiation time was extended to 3 h at the power intensity of 10 mW/cm2. The MTT assay also showed the reduction of cell viability upon increasing light irradiation time. Even though two-photon excitation triggered drug release from prodrugs show promising advantages, several disadvantages such as complicated hardware and small focal beam result in difficulties for clinical applications. The selection of fluorophores also requires stringent conditions that can undergo two-photon irradiation. Thus, the use of continuous pulsed laser with the wavelength in the NIR region is highly appreciated for its simple administration and less complicated hardware. Ideally, NIR light should be employed to trigger the drug release from its prodrug form. In the work by Schnermann et al., a prodrug based on C4′-dialkylaminesubstituted heptamethine cyanine that was cleavable with NIR light was fabricated. A phenol-


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containing small molecule was uncaged through a sequential release of C4′-amine and intramolecular cyclization (Figure 4a).47 The sequential release of the drug was initiated by exploiting a photochemical reaction of the cyanine fluorophore scaffold. Low intensity light at 690 nm was used for the photocleavage with minimized photocytotoxicity. Apart from the photocleavage of covalent bonds directly, other strategies were also employed, which include the use of ROS sensitive linkers. In a study by You et. al., an NIR triggered paclitaxel (PTX) prodrug was designed. The prodrug was composed of three moieties, a silicon phthalocyanine (SiPc), an aminoacrylate linker, and an anticancer drug PTX.48 SiPc was introduced into the system as the photosensitizer, which could generate singlet oxygen under the irradiation of NIR light. The toxicity of PTX was effectively reduced because its active site was blocked after the modification. As shown in Figure 4b, when employing the light irradiation at 690 nm, aminoacrylate linker was cleaved by the singlet oxygen produced by SiPc, releasing a carbon dioxide molecule and the active drug. This PTX prodrug is different from conventional photocleavable prodrug since it requires the NIR light activation for combinational PDT and chemotherapy.



Figure 4: (a) Chemical structure and uncaging reactions of C4′-dialkylamine-substituted heptamethine cyanine. Reproduced with permission.47 Copyright 2014, American Chemical Society. (b) Chemical structure of singlet oxygen-cleavable PTX prodrug and its application for combining PDT and site-specific PTX chemotherapy. Reproduced with permission.48 Copyright 2016, American Chemical Society.

Light triggered drug delivery systems Light triggered DDSs could be divided into two types: (1) “reversible” light triggered DDSs in which the release process is mediated by the photoisomerization of specific units, and (2) “irreversible” light activated DDSs in which the release of encapsulated drugs is based on the cleavage and subsequent removal of capping agents. Similar to abovementioned photocleavable prodrug systems, light responsive DDSs also exhibit obvious advantages such as controlled release of drug molecules at target locations. Molecules with light-induced isomerization properties have been introduced into the design of light-controlled DDSs. We recently fabricated some light-mediated DDSs based on functional MSNs. Using azobenzene as a photo-responsive functional group, we synthesized azobenzene-containing rotaxanes functionalized on MSNs to achieve remote-controlled drug release in vivo.49 In this work, a light-responsive azobenzene axle was synthesized with a stopper group at one end, followed by reacting with alkyne modified MSNs through the click reaction in the presence of the α-cyclodextrin (α-CD) to afford the [2]rotaxane-functionalized MSNs (Figure 5a). Initially, the α-CD ring is located at the transazobenzene, allowing cargoes such as chemotherapeutic drugs to be loaded into the nanopores of the MSNs. Upon the UV light irradiation with a wavelength of 365 nm, the α-CD ring moves to the triazole/ethylene glycol site because of trans-to-cis photoisomerization of azobenzene, preventing the loaded cargoes from the release out of the MSNs. The nanoparticles could undergo


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repeated photoisomerization under the alternating irradiation of UV and visible lights, showing high photostability and reversibility. After loading curcumin as the therapeutic drug, the drug release was carried out. Negligible fluorescence of the curcumin was detected in the dark over 120 min, indicating minimal drug release. Interestingly, a gradual enhancement of the fluorescence intensity was observed in the presence of visible light, indicating controlled drug release. After injected in zebrafish larvae, a fluorescence intensity decrease of 11.5% was recorded in the dark, while an obvious decrease of 34.9% was observed under continuous visible light illumination over 1 h, meaning successful light-triggered drug release in zebrafish larvae. Not only was such system responsive to UV and visible light, it also exhibited thermal responsive property. We further modified this system to improve its therapeutic performance (Figure 5b).50 By encapsulating gold nanorods (AuNRs) with mesoporous silica, an NIR triggered drug delivery system was achieved. The surface of the obtained core–shell hybrid (Au@MSN) was first grafted with azobenzene-based rotaxane. In this case, doxorubicin (DOX) was loaded within the nanopores of the core-shell hybrid under the irradiation of the UV light. The diffusion of loaded DOX from the nanopores was prevented by the α-CD ring. Upon laser irradiation with a wavelength at 808 nm, the heat generated by AuNRs led to cis-to-trans isomerization of the azobenzene unit, resulting in the movement of α-CD to render the drug release from the pores. Drug release efficacy of DOX loaded hybrid was detected by injecting into zebrafish embryo, and the fluorescence was recorded by confocal laser microscopy. As compared with the group without the NIR laser irradiation, wider DOX distribution and higher fluorescence intensity were observed for the group with the irradiation of the NIR laser.



Figure 5: (a) Schematic presentation of drug-loaded and rotaxane-functionalized MSNs for controlled drug delivery in zebrafish larvae, triggered by temperature or visible light irradiation. Reproduced with permission.49 Copyright 2012, Wiley-VCH. (b) Schematic illustration of rotaxane-functionalized Au@MSN (Au@MSN–Rotaxane) for NIR light triggered drug release in zebrafish embryo model. Reproduced with permission.50 Copyright 2014, Royal Society of Chemistry.

In addition to “reversible” light-responsive triggers, we also introduced photolytic groups into light-triggered DDSs as “irreversible” light activated DDSs. O-nitrobenzyl derivatives were used to not only fabricate prodrug systems, but also serve as responsive linkers in the design of lighttriggered DDSs. We recently developed pH, reduction, and UV light triple responsive drug delivery platform based on hollow MSNs (HMSNs).51 In this work, disulfide linker was modified onto the surface of the HMSNs, followed by the conjugation with o-nitrobenzyl bearing atom transfer radical polymerization (ATRP) initiation group (Figure 6). After grafting pH-sensitive polymer on the surface via ATRP, triple responsive HMSNs were successfully obtained. The onitrobenzyl linker could be cleaved by UV light, and thus the grafted polymer was removed for


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the cargo release. Upon the UV light irradiation twice with 10 min irradiation each time, 40% of the loaded DOX was released over 24 h. Results obtained from in vitro cell viability experiments indicate that the polymer grafted HMSNs exhibit low cell viability under the irradiation of the UV light on account of higher amount of DOX release. With the introduction of light-responsive linkers onto the surface of nanoparticles, controlled release of therapeutic cargoes was made possible.

Figure 6: Schematic representation of polymer grafted HMSNs for pH, reduction, and UV light triple responsive drug release. PDEAEMA stands for poly(2-(diethylamino)ethyl methacrylate). Reproduced with permission.51 Copyright 2015, American Chemical Society.

Photodynamic therapy Some organic molecules and inorganic materials are light sensitive and can be used as therapeutic agents directly. One type of such therapy is PDT, which uses photosensitizers as main



therapeutic agents. PDT is a form of treatment that involves the administration of photosensitizer on the tumor site, followed by the light irradiation to produce cytotoxic singlet oxygen from endogenous oxygen. Some of key features that a photodynamic agent should possess includes: (1) low or no dark toxicity, (2) strong absorption of NIR light, (3) high singlet oxygen quantum yield, (4) good biocompatibility and biodegradability, and (5) excellent photostability. Photofrin remains one of the most widely used photosensitizers in clinical PDT. Because of long-lasting skin phototoxicity of Photofrin, several new photosensitizers have been developed for clinical trials.31,52,53 Some examples of organic photosensitizers include derivatives of phthalocyanine, boron-dipyrromethene (BODIPY) and chlorin, and some examples of inorganic photosensitizers include black phosphorus and some metal oxide nanomaterials. The accumulation of photosensitizers at the tumor site is important for precise and effective cancer treatment. Thus, there is an urgent need to develop carrier systems for the delivery of photosensitizers. We successfully employed functional MSNs as carriers to deliver photosensitizers into cancer cells for PDT (Figure 7a).54,55 To maintain good dispersity in water for long term circulation in biological systems, the surface of MSNs was decorated with hydrophilic functional groups. In contrast, almost all photosensitizers are hydrophobic, leading to poor drug loading efficacy into MSNs. To enhance the loading capability of hydrophobic photosensitizers in MSNs, we modified hydrophobic MSNs with the adamantane group attached on the surface as well as in the pore well to achieve higher zinc(II) phthalocyanine (ZnPC) loading amount than MSNs without such modification. In addition, the adamantane group could serve as a spacer to prevent the aggregation of ZnPC inside MSNs. The water dispersity of nanoparticles was significantly enhanced by introducing amino-substituted-CD (CD-2NH2) through the host-guest interaction strategy. β-CD not only served as the hydrophilic domain, but also was employed as a gatekeeper to prevent the leakage of the loaded photosensitizers.


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Furthermore, the conjugation of targeting ligand folic acid with this hybrid was to achieve selective endocytosis by cancer cells. This novel hybrid exhibited tumor-targeting capability and significant photodynamic performance under the irradiation of a suitable light. To overcome low loading efficacy of photosensitizers, we also developed another strategy by delivering hydrophilic photosensitizer precursors that could be converted to photosensitizers in biological conditions (Figure 7b).56 In this case, 5-aminolevulinic acid (5-ALA), a precursor for the formation of strong photosensitizer protoporphyrin IX (PphIX), was loaded into functional HMSNs. Not only was targeted delivery achieved through the functionalization of folic acid onto the nanoparticle surface, the delivered 5-ALA could form PphIX photosensitizer in tumor cells, rendering effective PDT upon the light irradiation.

Figure 7: (a) Schematic Illustration for the preparation of ZnPc-loaded MSNs and their complexation with CD-2NH2 (MSNP-Ad+ZnPc+CD-2NH2) for PDT. Reproduced with permission.54 Copyright 2013, American Chemical Society. (b) Schematic illustration of 5-ALA loaded HMSNs for targeted PDT of skin cancer. Reproduced with permission.56 Copyright 2015, American Chemical Society.



Some new strategies for the fabrication of photosensitizers have been developed, involving the incorporation of heavy atoms such as iridium. On account of the heavy atom effect, iridium could relax the spin rule, resulting in high phosphorescence quantum yield and subsequently endowing the photosensitizer to produce singlet oxygen when interacted with triplet oxygen for PDT. We recently reported a conjugated polymer containing phosphorescent iridium for ratiometric oxygen sensing and photodynamic cancer therapy (Figure 8).57 Originally, the conjugated polymer was prepared as a sensor to detect oxygen. To our surprise, it was found that this conjugated polymer exhibited good photodynamic effect. This polymer could self-assemble in aqueous condition to form ultrasmall nanoparticles with the diameter size less than 10 nm. The conjugated polymer exhibited strong red emission at 630 nm with weak blue emission at 450 nm due to highly efficient Förster resonance energy transfer (FRET) from the polyfluorene unit to cyclometalated iridium. The red emission of the polymer dots was sharply decreased upon increasing the oxygen content, and quenched in the presence of pure oxygen, accompanied with solution color change from red to blue upon UV lamp irradiation at 365 nm. Controlled experiments indicate that Ir(III) complex played a dominant role in the oxygen sensing. On account of the energy transfer between the Ir(III) complex in polymer dots and oxygen through triplet-triplet annihilation process, the singlet oxygen was generated from polymer dots upon light irradiation. In the cell studies, polymer dots exhibited obvious PDT-induced apoptosis and remarkable cell death. To overcome PDT resistance or chemotherapy resistance, the combination therapy with different therapeutic techniques has drawn a lot of attention. In another work, cyclometalated iridium was conjugated with a chemotherapeutic drug through glutathione (GSH) responsive disulfide linker.58 In this work, a CPT-containing ligand was coordinated with two different kinds of Ir(III) compounds to afford two types of GSH-activatable Ir(III) complexes. Ir(III) complexes were encapsulated with folic acid modified Pluronic F127 polymer to give nanosized micelles.


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MTT assay was employed to examine anticancer efficacy of the Ir(III) complex encapsulated micelles in HeLa cell line and MCF cell line. Obvious cell viability reduction was observed when cancer cells were incubated with micelles, attributing to GSH-activated chemotherapy in the dark. Much higher cell death rate was recorded when micelle-treated cancer cells were illuminated with visible light for the generation of singlet oxygen. Thus, the combination therapy was achieved from this platform to exhibit enhanced therapeutic performance. Even though iridium complexes could be used as candidates for PDT applications, the cytotoxicity of such heavy atoms remains questionable and requires more extensive studies on their pharmacokinetics and pharmacodynamics in living systems.

Figure 8: (a) Chemical structures of phosphorescent conjugated polymers with Ir(III) complexes. (b) TEM image of polymer dots in aqueous solution. (c) Mechanism illustrating the oxygen



sensing and PDT by using polymer dots. Reproduced with permission.57 Copyright 2014, WileyVCH.

Photothermal therapy PTT is another compelling therapeutic method that has attracted attention for the treatment of cancer. In general, photothermal agents that can convert NIR light into heat are administered to a specific location for thermal ablation of cancer cells. Thermal energy generated locally from light irradiation could damage these tissues, resulting in the death of these tissues. The development of highly efficient photothermal agents is critical to ensure effective treatment and the maximum efficacy. Criteria for achieving qualified photothermal agents includes: (1) absorption in the NIR region, (2) excellent photothermal conversion efficiency, (3) good biocompatibility and biodegradability, and (4) facile synthesis. The amount of heat produced should also be > 42 oC to incur the cell death. Some of photothermal materials that could be used for PTT applications include organic materials such as indocyanine green (ICG), cypate, IR780 and IR825, as well as inorganic materials such as gold nanoparticles, copper sulfide crystals, carbon nanomaterials, and black phosphorus.59 Organic photothermal dyes possess excellent biodegradability and photothermal conversion capability. However, they are often hydrophobic and have a poor stability when administrated into biological systems. Thus, DDSs have been fabricated for the delivery of organic photothermal dyes. While we discussed some photothermal examples in the section of lighttriggered drug release systems, more studies about photothermal induced therapy are highlighted in this section. In our recent work, functional HMSNs were loaded with photothermal dye (IR825) in order to enhance the dye delivery into tumor sites (Figure 9a).60 After coating acid responsive DOX grafted polymer on the HMSNs, combinational therapeutic system (HMSNs-


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DOX/IR825) was achieved. The polymer coating could also prevent premature release of loaded photothermal dye. HeLa and A2780 (DOX resistance cell line) cells were chosen as in vitro cell models for cell viability studies. For HeLa cells treated with HMSNs-DOX/IR825, the IC50 value was 8.4 µg mL−1 without the laser irradiation, and 2.8 µg mL−1 in the presence of the laser irradiation. For A2780 cells treated with HMSNs-DOX/IR825, the IC50 value could not be obtained in the absence of laser irradiation due to their high DOX resistance. Interestingly, an IC50 value of 2 µg mL−1 was recorded in the presence of the laser irradiation.

Figure 9: (a) Schematic illustration of polymeric prodrug coated NIR-absorbing dye loaded HMSNs for combined photothermal-chemotherapy. Reproduced with permission.60 Copyright 2016, American Chemical Society. (b) Schematic illustration for the synthesis of HPSN through the self-assembly between triblock copolymer F108 and silica precursor. Reproduced with permission.62 Copyright 2017, Wiley-VCH. (c) Illustration for the preparation of TixTa1-xSyOz nanosheets from layered bulk crystals. Reproduced with permission.64 Copyright 2017, WileyVCH. (d) Schematic illustration showing the structure and action mechanism of NIR-absorptive



DOX-loaded stealth liposome. Reproduced with permission.63 Copyright 2015, Wiley-VCH. (e) Schematic illustration for the formation of AuNR-Si-ZnPc-HA toward combinational PTT and PDT. Reproduced with permission.65 Copyright 2016, Royal Society of Chemistry.

Using inorganic materials as carriers likely leads to renal clearance issue. In order to address this issue, we fabricated hollow structured polymer–silica nanohybrid (HPSN) that exhibited fast recurrence property in mouse models, because of its ultrasmall size and suitable surface modification.61 In this work, we employed this HPSN to deliver both anticancer drug PTX and photothermal agent palladium phthalocyanine for combinational photothermal and chemotherapy (Figure 9b).62 One of the advantages from this system is that most of the off-targeted HPSN nanocarriers could be excreted through a hepatobiliary pathway in about 10 days. Serology results showed that the fast-clearable HPSN could significantly reduce side effect arising from chemotherapeutic drug PTX. To further enhance the biocompatibility of photothermal dyes, an alternative approach is to incorporate them into organic nanoparticle systems. In another work from us, IR825 was incorporated into the hydrophobic portion of liposomes in replace of conventional cholesterol (Figure 9c).63 This method led to a light-responsive liposomal system. Upon the light irradiation at 808 nm, the liposomes were disrupted and DOX loaded within the cavities were sequentially released for cancer chemotherapy. Without the laser irradiation, negligible DOX release was observed, while 80% DOX release within 30 min was recorded upon the irradiation with an NIR laser. The liposomes exhibited excellent therapeutic efficacy with obvious tumor size regression upon NIR laser irradiation using zebrafish embryo models. Some newly developed inorganic materials were also used for PTT applications. Just recently, we developed an ultrathin TixTa1-xSyOz (x = 0.71, 0.49, and 0.30) nanosheets in high yields for photothermal applications (Figure 9d).64 These nanosheets exhibited strong absorbance in the


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near-infrared region, giving a large extinction coefficient of 54.1 Lg-1 cm-1 at 808 nm, and a high photothermal conversion efficiency of 39.2%. The modification of these nanosheets with lipoic acid-conjugated polyethylene glycol rendered them suitable photothermal agents for the treatment of cancer cells. AuNRs are also excellent photothermal agents on account of their high surface plasmon resonance. We made research efforts to achieve synergetic PDT and PTT based on functional AuNRs by using single excitation light source (Figure 9e).65 In this work, we optimized AuNRs with different longitudinal length to allow the absorption overlapping of AuNRs with tetraamino ZnPc (ZnPc-4NH2). After the functionalization of ZnPC-4NH2 on the surface, AuNRs were further decorated with hyaluronic acid (HA) to improve water dispersibility and endow cancer-targeting ability. Under the excitation of 730 nm laser light, the obtained hybrid (AuNR-Si-ZnPc-HA) showed high photothermal conversion ability with the temperature increase of 21 °C and remarkable PDT effect. AuNR-Si-ZnPc-HA presented lower cell viability in HeLa cells as compared with other AuNRs upon the irradiation with 730 nm laser. The results successfully demonstrated the application of functional AuNRs for synergetic PTT and PDT under single excitation source.

Fluorescence imaging guided therapy Diagnostics is important in the detection and tracing of cancer. Various bioimaging techniques as diagnostic tools have been employed to monitor the condition and treatment processes of tumor. These bioimaging techniques normally include positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), optical fluorescence imaging, and PA imaging. Fluorescence imaging involves detecting the light emission of fluorophores promoted by the light excitation at a specific wavelength. Fluorescence imaging has its



advantages such as simple operation, noninvasiveness and cost-effective.66,67 Some examples of fluorescence materials for bioimaging include organic dyes, quantum dots and carbon dots. Some DDSs were designed to deliver therapeutic agents, coupled with bioimaging capability. In such systems, the drug release process could be monitored by fluorescent bioimaging. For example, we prepared self-assembled prodrug nanoparticles consisting of D-mannose as the targeting ligand and naphthalimide unit for fluorescent imaging connected to an anticancer drug chlorambucil through a disulfide bond (Figure 10a).68 Upon the cleavage of the disulfide bond under the tumor reducing environment with intracellular GSH, free chlorambucil drug could be released with the fluorescence receptor having its fluorescence maximum red-shifted from blue to green. Confocal laser scanning microscopy and flow cytometry results provide the evidence of selective uptake of nanoparticles in mannose receptor-overexpressed cancer cells. Obvious fluorescence red-shift enabled the nanoparticles for intracellular imaging and imaging-guided drug delivery. Thus, the nanoparticles exhibited selective cytotoxicity in mannose receptoroverexpressed cancer cells and decreased cell viability as compared to the original chlorambucil drug. On account of its excellent imaging-guided drug delivery, this system shows a great application potential in precise cancer treatment. In addition, naphthalimide was used for monitoring the release of CPT prodrug in a selfassembled supramolecular system that can co-deliver siRNA and CPT to cancer cells for achieving synergetic treatment (Figure 10b).69 By taking advantage of the supramolecular strategy, the construction of the prodrug assembly was much easier in comparison to conventional synthetic approaches. The fluorophore unit of the prodrug underwent a significant red-shift after disulfide bond cleavage followed by an intramolecular cyclization, which was used to image the drug release in cancer cells real-time. In vitro experiments indicate that the supramolecular prodrug vesicles exhibited excellent water solubility and stability. When


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incubated with the vesicles we fabricated, lower cell viability was measured as compared to that of the original anticancer drug by MTT assay. Benefited from abundant free amine groups at terminal sites of the dendrimer unit as binding sites, the supramolecular amphiphilic vesicles were also employed as an siRNA delivery vector for chemo/gene combination therapy. siRNA could be loaded by the amphiphilic vesicles efficiently. Cell studies demonstrated that the loaded siRNA was transported into cancer cells to enable synergistic cancer treatment. Herein, we directly developed prodrug-based supramolecular amphiphiles via the host-guest interaction, and utilized the amphiphilic vesicles to achieve synergetic therapy. This work would provide a new strategy to simultaneously deliver prodrug and gene, showing promising applications in the combination cancer therapy. Although these studies indicate the feasibility of their applications in cancer theranostics, further investigations of these systems using animal models could be conducted to evaluate their effectiveness in vivo toward future uses. We recently synthesized charge-convertible platinum prodrug-loaded carbon dots for imagingguided cancer therapy (Figure 10c).70,71 The initial anionic polymer that was fabricated from dimethylmaleic acid could undergo interesting charge conversion to a cationic polymer in mildly acidic tumor extracellular microenvironment of pH 6.8. Under normal pH environments, negligible functionalized carbon dots were endocytosed by cancer cells because of negative surface charge of the carbon dots. Obvious fluorescence enhancement was observed under the condition of pH 6.8 on account of the surface charge conversion to positive. The functionalized carbon dots exhibited significant inhibition of the solid tumor growth in animal models. By using tumor microenvironment-induced charge conversion strategy, a pH-triggered platform based on carbon dots was employed for imaging-guided cancer theranostics.



Figure 10: (a) Schematic illustration of vesicles to be selectively internalized by MCF-7 cells through D-mannose receptor-mediated endocytosis. Its disassembly by GSH leads to a red shift of fluorescence along with the drug release. Reproduced with permission.68 Copyright 2016, American Chemical Society. (b) Schematic illustration of the prodrug-based supramolecular vesicles for the co-delivery of therapeutic agents with the fluorescence turn-on mechanism. Reproduced with permission.71 Copyright 2017, American Chemical Society. (c) Schematic illustration for the drug delivery of platinum prodrug-loaded carbon dots. Reproduced with permission.69 Copyright 2016, American Chemical Society.


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Photoacoustic imaging Optical imaging plays a crucial role in clinical diagnosis. However, optical imaging has its limitation, where the scattering of the light limits its spatial resolution for deep tissue imaging. As such, PA imaging has shown its immense potential to overcome the constraint. PA imaging is based on PA effects, whereby the absorbed optical energy is converted into acoustic energy. More specifically, the energy absorbed is converted into heat energy, leading to transient thermoelastic expansion and wideband (i.e., MHz) ultrasonic emission. The generated ultrasonic waves are detected by ultrasonic transducers and then analyzed to produce PA images. Due to much lesser scattering of acoustic waves in tissues, PA technique could produce high-resolution images. Furthermore, non-ionising radiation source is often used for the irradiation. Since the signals are arisen from optical absorption, PA imaging readily takes advantage of rich endogenous and exogenous optical contrasts. PA imaging is also more time- and cost-effective as compared to other imaging techniques.32,33 UCNPs have been widely employed as powerful materials for deep tissue optical imaging particularly due to their long NIR excitation wavelength and upconversion property where the absorption of light with higher wavelength could lead to the emission of light with lower wavelength. UCNPs normally show serious fluorescence quenching in aqueous solution, and exhibit photothermal property. We employed a supramolecular strategy to enhance aqueous dispersibility of UCNPs and significantly improve their photothermal efficacy to generate strong PA signals for in vivo PA imaging (Figure 11a).72 In this work, UCNPs were transferred from the oil phase to water phase by introducing α-CD as a phase transfer agent. Hydrophobic surfactants on the surface of UCNPs were complexed by α-CD. The obtained UCNPs (UC-α-CD) exhibited considerable fluorescence quenching over 60 % and generated strong PA signals in aqueous solution, while negligible PA signals were observed in cyclohexane solution. Under the



excitation of 980 nm laser, strong PA signals were observed in mouse models, proving that this platform could serve as efficient PA contrast agents for PA imaging. Addition to UCNPs, some organic photothermal dyes possessing excellent photothermal conversion efficacy reviewed in previous section were also utilized as PA contrast agents. PA tomography imaging could be combined with fluorescence imaging for noninvasive visualization of biological structures. We designed some interesting nanosystems for such bimodal imaging using NIR-absorbing squaraine dyes.73 In this case, a squaraine dye was encapsulated inside pluronic F-127 micelles to obtain squaraine-encapsulated micelles in aqueous conditions (Figure 11b). The squaraine-encapsulated micelles exhibited high photostability and low cytotoxicity in biological conditions, while retaining photophysical properties of the squaraine dye. Imaging using this micelle system was demonstrated by fluorescence and PA tomography experiments in live mice, showing contrast-enhanced deep tissue imaging capability in the 800 – 900 nm window. Preclinical experiments in rodents revealed its outstanding potential for NIR fluorescence and PA bimodal imaging.

Figure 11: (a) Schematic illustration of luminescence quenching effect and subsequent PA signal enhancement from α-CD-covered UCNPs (UC-α-CD) in water. Reproduced with permission.72


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Copyright 2014, Wiley-VCH. (b) Schematic preparation of squaraine-encapsulated micelles (D1micelle) for NIR fluorescence and PA bimodal imaging in vivo. Reproduced with permission.73 Copyright 2015, American Chemical Society.

Conclusion and future prospects DDSs with light as a stimulus in the cancer treatment has been designed and developed. In this Spotlights on Applications article, we have highlighted some recent developments on lightresponsive systems for cancer theranostics. These systems such as light-activated prodrugs, light activated drug release, and using photosensitizers and photothermal agents in PDT and PTT have their unique advantages, proving to be effective in the treatment of certain cancers. NIR light is often chosen as the mode of stimulus because of its deeper tissue penetration and the fact that it lies in the optical transparent window of tissues in our body. Despite various advantages of light, its further development has been restricted to a certain extent, especially in the treatment of solid tumor. This is possibly due to the uncertainty involved including the penetration depth, effective area, power intensity, and irradiation time. The lack of large scale clinical trials validating the benefits of light-responsive systems further hinders their translational applications in clinical settings. Furthermore, many of the developed photosensitizers and photothermal agents have inherent toxicity. The utilization of some inorganic materials as light-responsive platforms in biological systems remains a concern about their metabolism and possible harmful accumulation in various organs. Thus, the biocompatibility, biodistribution and long-term toxicity of light-responsive systems need to be carefully assessed before their practical applications. Since theranostic systems combining bioimaging and therapy show enhanced complexity, their efficacy and dosage as well as the imaging capability and modality have to be weighed and balanced for achieving the optimized



performance. Nevertheless, current research using light-responsive systems for the cancer theranostics has paved a way for future clinical applications.

AUTHOR INFORMATION Corresponding Author *[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding No competing financial interests have been declared. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Y. L. Z. thanks the ACS Applied Materials & Interfaces and the ACS Division of Colloid & Surface Chemistry for providing him the 2017 ACS Applied Materials & Interfaces Young Investigator Award. This research was financially supported by the Singapore National Research Foundation Investigatorship (No. NRF-NRFI2018-03) and the Singapore Academic Research Fund (No. RG121/16, RG11/17, and RG114/17).

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Table of Contents Figure


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Applications of Light-Responsive Systems for Cancer Theranostics

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