Photo-controlled Drug Release Research Articles

Photo-controllable drug releasing bulk polyacrylic intraocular lens material for safer posterior capsular opacification prevention

Posterior capsular opacification (PCO) is the most common complication that occurs after intraocular lens (IOL) implantation in cataract therapy. In recent years, IOLs have been developed as drug delivery platforms, but concerns over the safety of uncontrolled proliferative drug release have arisen. Therefore, a controlled drug release strategy is needed for safer PCO prevention. In this study, a new monomer contained coumarin group was introduced in material preparation, and poly(ethylene glycol phenyl ether methacrylate-co-2-(2-ethoxyethoxy) ethyl acrylate-co-7-(2-methacryloyloxyethoxy)-4-methylcoumarin) (PEEC) acrylic IOL materials were synthesized. The antiproliferative drug 5-fluorouracil (5-FU) could be chemically grafted to the PEEC IOL materials easily via a light induced [2 + 2] cycloaddition reaction with the coumarin group, getting drug-loaded IOL (PEEC@5-FU IOL). The PEEC@5-FU IOL exhibited excellent optical and mechanical properties and biocompatibility. More importantly, the loaded 5-FU could be easily controlled from release by light irradiation via photo-dissociation of the cyclobutane ring that was obtained by the [2 + 2] cycloaddition reaction of 5-FU and coumarin. The in vitro and in vivo experiments demonstrated that such photo-controllable drug release IOL could effectively prevent PCO after implantation in a safe way.

Near-infrared-responsive GE11-CuS@Gal nanoparticles as an intelligent drug release system for targeting therapy against oral squamous cell carcinoma

Galangin (Gal) is a natural plant flavonoid. More and more evidence shows that Gal can achieve anti-tumor effects by regulating various mechanisms. However, its poor water solubility, low bioavailability, and insufficient lesion targeting limit its clinical application. To overcome these shortcomings, we designed and developed a mesoporous nanosystem (GE11-CuS) that actively located the target area and photo-controlled drug release, which promoted the rapid accumulation of drugs in tumor tissues under NIR irradiation, thus achieving positive effects against cancer. In this study, we explored the application of the Gal-loaded nanometer system (GE11-CuS@Gal) in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. The results exhibited that GE11-CuS@Gal had excellent targeting ability and could accumulate efficiently in tumor cells (HSC-3). Meanwhile, the temperature of GE11-CuS@Gal increasing rapidly under NIR illumination damaged the integrity of the carrier and allowed Gal molecules to escape from the pores of the nanoparticles. When the accumulation of Gal in the nidus reached a certain level, the intracellular ROS level could be significantly increased and the antioxidative stress pathway mediated by Nrf2/OH-1 was effectively blocked, to inhibit the growth and migration of tumors. In conclusion, the GE11-CuS improved the antitumor activity of Gal in the body, which laid a foundation for the treatment of OSCC with traditional Chinese medicine ingredients.

Preparation and optimization of agarose or polyacrylamide/amino acid-based double network hydrogels for photocontrolled drug release

The high water content and biocompatibility of amino-acid-based supramolecular hydrogels have generated growing interest in drug delivery research. Nevertheless, the existing dominant approach of constructing such hydrogels, the exploitation of a single amino acid type, typically comes with several drawbacks such as weak mechanical properties and long gelation times, hindering their applications. Here, we design a near-infrared (NIR) light-responsive double network (DN) structure, containing amino acids and different synthetic or natural polymers, i.e., polyacrylamide, poly(N-isopropylacrylamide), agarose, or low-gelling agarose. The hydrogels displayed high mechanical strength and high drug-loading capacity. Adjusting the ratio of Fmoc-Tyr-OH/Fmoc-Tyr(Bzl)-OH or Fmoc-Phe-OH/Fmoc-Tyr(Bzl)-OH, we could drastically shorten the gelation time of the DN hydrogels at room and body temperatures. Moreover, introducing photothermal agents (graphene oxide, carbon nanotubes, molybdenum disulfide nanosheets, or indocyanine green), we equipped the hydrogels with NIR responsivity. We demonstrated the light-triggered release of the drug baclofen, which is used in severe spasticity treatment. Rheology and stability tests confirmed the positive impact of the polymers on the mechanical strength of the hydrogels, while maintaining good stability under physiological conditions. Overall, our study contributed a novel hydrogel formulation with high mechanical resistance, rapid gel formation, and efficient NIR-controlled drug release, offering new opportunities for biomedical applications.

Precision Nanocluster-Based Toroidal and Supertoroidal Frameworks Using Photocycloaddition-Assisted Dynamic Covalent Chemistry.

Atomically precise nanoclusters (NCs) have recently emerged as ideal building blocks for constructing self-assembled multifunctional superstructures. The existing structures are based on various non-covalent interactions of the ligands on the NC surface, resulting in inter-NC interactions. Despite recent demonstrations on light-induced reversible self-assembly, long-range reversible self-assembly based on dynamic covalent chemistry on the NC surface has yet to be investigated. Here, it is shown that Au25 NCs containing thiolated umbelliferone (7-hydroxycoumarin) ligands allow [2+2] photocycloaddition reaction-induced self-assembly into colloidal-level toroids. The toroids upon further irradiation undergo inter-toroidal reaction resulting in macroscopic supertoroidal honey-comb frameworks. Systematic investigation using electron microscopy, atomic force microscopy (AFM), and electron tomography (ET) suggest that the NCs initially form spherical aggregates. The spherical structures further undergo fusion resulting in toroid formation. Finally, the toroids fuse into macroscopic honeycomb frameworks. As a proof-of-concept, a cross-photocycloaddition reaction between coumarin-tethered NCs and an anticancer drug (5-fluorouracil) is demonstrated as a model photo-controlled drug release system. The model system allows systematic loading and unloading of the drug during the assembly and disassembly under two different wavelengths. The results suggest that the dynamic covalent chemistry on the NC surface offers a facile route for hierarchical multifunctional frameworks and photocontrolled drug release.

Aromatic Dipeptide Homologue-Based Hydrogels for Photocontrolled Drug Release.

Peptide-based hydrogels are considered of special importance due to their biocompatibility and biodegradability. They have a wide range of applications in the biomedical field, such as drug delivery, tissue engineering, wound healing, cell culture media, and biosensing. Nevertheless, peptide-based hydrogels composed of natural α-amino acids are limited for in vivo applications because of the possible degradation by proteolytic enzymes. To circumvent this issue, the incorporation of extra methylene groups within the peptide sequence and the protection of the terminal amino group can increase the enzymatic stability. In this context, we investigated the self-assembly capacity of aromatic dipeptides (Boc-α-diphenylalanine and Boc-α-dityrosine) and their β- and γ-homologues and developed stable hydrogels. Surprisingly, only the Boc-diphenylalanine analogues were able to self-assemble and form hydrogels. A model drug, l-ascorbic acid, and oxidized carbon nanotubes (CNTs) or graphene oxide were then incorporated into the hydrogels. Under near-infrared light irradiation, the photothermal effect of the carbon nanomaterials induced the destabilization of the gel structure, which caused the release of a high amount of drug, thus providing opportunities for photocontrolled on-demand drug release.

A Platelet Intelligent Vehicle with Navigation for Cancer Photothermal-Chemotherapy.

Controllable and visible delivery of therapeutic agents is critical for tumor precise therapy. Tumor targeting and deep penetration of therapeutic agents are still challenging issues for controllable delivery. Visible drug delivery with imaging navigation can optimize the treatment window for personalized medicine. Herein, a biomimetic platelet intelligent vehicle with navigation (IRDNP-PLT) was developed to achieve controllable and visible delivery with a navigation system, a driving system, and a loading system. The platelets acted as engines and drug repositories to exert the target driving and delivery functions. The fluorescent photothermal agent IR-820 was introduced in the platform to offer an imaging navigation for the intelligent platelet vehicle in addition to photothermal therapy. The nanodrug-loaded platelets enabled efficient drug loading and controlled release of the therapeutic payload by encapsulating photothermal-/pH-sensitive chemotherapeutic nanoparticles (PDA@Dox NPs). In in vivo experiments on 4T1 tumor-bearing mice models, IRDNP-PLT performed well in tumor targeting and showed excellent therapeutic efficacy and tumor recurrence prevention ability. The intelligent platelet vehicle achieved the functions of tumor targeting and deep penetration, fluorescence imaging guidance, photocontrolled drug release, and chemo-photothermal combination therapy, suggesting the advancement for tumor precise delivery and efficient therapy.

Photo-responsive intraocular lens with on demand drug release for posterior capsule opacification prevention and improved biosafety

Posterior capsular opacification (PCO) is the most common complication after cataract surgery, which is caused by the adhesion, proliferation, migration and epithelial-mesenchymal transformation of the residual lens epithelial cells (LECs) in lens capsule. The drug eluting coating modification provides a powerful way to inhibit PCO incidence after IOL implantation. However, the uncontrolled proliferative drug brings intraocular biosafety issues when application. Therefore, developing new strategies with controlled drug release for PCO prevention is of great significance. In this investigation, a hydrophilic photo-responsive drug release coating was successfully constructed on IOL surface, which was verified through 1H•NMR, UV–Vis, FTIR and XPS. In vitro assay indicated that the IOL coating exhibited excellent anti-adhesion and anti-proliferation effects on LECs under irradiation. The photo-controlled drug release in vitro can be achieved by simply adjusting the intensity and time of irradiation. Finally, the surface-modified IOL was implanted in rabbit eyes and in vivo evaluation was carried out. In vivo assay demonstrated that the implantation of the modified IOL into eyes can significantly reduce the occurrence of PCO. Moreover, the modified IOL exhibited good biocompatibility and biosafety. We believe that this work will provide a synergistic strategy for effective prevention of PCO through a photo-controllable drug release coating on IOL surface.

UVA-Triggered Drug Release and Photo-Protection of Skin.

Light has attracted special attention as a stimulus for triggered drug delivery systems (DDS) due to its intrinsic features of being spatially and temporally tunable. Ultraviolet A (UVA) radiation has recently been used as a source of external light stimuli to control the release of drugs using a “switch on- switch off” procedure. This review discusses the promising potential of UVA radiation as the light source of choice for photo-controlled drug release from a range of photo-responsive and photolabile nanostructures via photo-isomerization, photo-cleavage, photo-crosslinking, and photo-induced rearrangement. In addition to its clinical use, we will also provide here an overview of the recent UVA-responsive drug release approaches that are developed for phototherapy and skin photoprotection.

A multiphysics model of photo-sensitive hydrogels in response to light-thermo-pH-salt coupled stimuli for biomedical applications

This paper aims to unveil the fundamental response mechanism of photo-sensitive hydrogels subject to light-thermo-pH-salt coupled stimuli, for their potential biomedical uses such as cell scaffolds and extracellular matrices, where biological activity largely depends on internal electrochemical changes. To mimic the microenvironment of biomolecules or cells, we focus on a spirobenzopyran-modified N-isopropylacrylamide hydrogel incorporating acrylic acid as a proton generator and develop a multiphysics model to characterize its behaviour within aqueous solution in response to light intensity, temperature, buffer pH, and salt concentration. The model allows for concurrent chemical reactions, ionic diffusion, electrostatic effects and large mechanical deformation, as well as interaction with the solution domain. Validation was performed by comparison with the published experimental results and showed good agreement. It is demonstrated by the simulation results that the photo-sensitive hydrogel exhibits a varied sensitivity to the external stimuli if incorporated with different molar ratios of acrylic acid. The electrical and pH response characteristics of the hydrogel, especially those in neutral solution, may inspire some potential biomedical applications, such as photo-controlled drug release and cell growth.

Rod-based urchin-like hollow microspheres of Bi2S3: Facile synthesis, photo-controlled drug release for photoacoustic imaging and chemo-photothermal therapy of tumor ablation

Hollow nanostructures have been evoked considerable attention owing to their intriguing hollow interior for important and potential applications in drug delivery, lithium battery, catalysis and etc. Herein, Bi2S3 hollow microspheres with rod-based urchin-like nanostructures (denoted as U-BSHM) were synthesized through a facile and rapid ion exchanging method using a particular hard template. The growth mechanism of the U-BSHM has been investigated and illustrated by the morphological evolution of the different samples at early stages. The obtained U-BSHM exhibited strong and wide UV–vis–NIR absorption ability and outstanding photothermal conversion efficiency. Thus, the U-BSHM can be used as spatio-temporal precisely controlled carrier by loading the mixture of 1-tetradecanol (phase change material, PCM) with melting point around 38 °C and hydrophilic chemotherapeutic doxorubicin hydrochloride (denoted as DOX) into the hollow interior to form (PCM + DOX)@Bi2S3 nanocomposites (denoted as PD@BS) for photoacoustic (PA) imaging and chemo-photothermal therapy of the tumors. When exposed to 808 nm near infrared light (NIR) laser irradiation, this nanocomposites could elevate the temperature of the surroundings by absorption and conversion of the NIR photons into heat energy, which inducing the triggered release of DOX from the hollow interior once the temperature reach up to the melting point of PCM. The killing efficiency of the chemo-photothermal therapy was systematically validated both in vitro and in vivo. In the meanwhile, the implanted tumor was completely restrained through PA imaging and combined therapies. Therefore, this kind of urchin-like hollow nanostructures would be used as important candidates for the multimodal bioimaging and therapy of tumors.

Preparation of injectable hydrogel with near-infrared light response and photo-controlled drug release

Photo-controlled release hydrogel provides a new strategy for treating tumours. Under the stimulation of external light sources, the ability to release the entrapped drug on time and space on demand has outstanding advantages in improving drug utilisation, optimising treatment, and reducing toxicity and side effects. In this study, a photo-controlled drug delivery system for disulphide cross-linked polyaspartic acid (PASP-SS) hydrogels encapsulating proteinase K (ProK) adsorbed with platinum nanoparticles (PtNPs) was designed. The injectable cysteamine-modified polyaspartic acid (PASP-SH) sol and PtNPs adsorbed by ProK (ProK-PtNPs) as regulatory factors were prepared. Then, ProK-PtNPs and lentinan were dissolved in the sol, and the oxidant was added to the matrix to form the gel in situ quickly after injection. Finally, the degradation of PASP-SS hydrogel by ProK and the controllability of drug release under near-infrared (NIR) light irradiation were elucidated. In vitro degradation of hydrogels and drug release experiments showed that the degradation rate of PASP-SS hydrogel significantly increased and the drug release rate increased significantly under near-infrared radiation. The results of cytotoxicity test showed that PASP-SS, ProK-PtNPs, and lentinan all had more than 90% cell survival rate on NIH3T3, and the lentinan released from the carrier obviously inhibited the proliferation of MCF7. PASP hydrogel has the potential to respond to on-demand light control.

Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging-Guided On-Demand Drug Release.

NIR light responsive nanoplatforms hold great promise for on-demand drug release in precision cancer medicine. However, currently available systems utilize "always-on" photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H2 S-mediated in situ production of NIR photothermal agents for imaging-guided and photocontrolled drug release. The system targets H2 S-rich cancers. This nanoplatform shows H2 S-activatable NIR-II emission and NIR light controllable release of the drug Camptothecin-11. Upon administering the system to HCT116 tumor-bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer-specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR-II imaging.

Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging‐Guided On‐Demand Drug Release

AbstractNIR light responsive nanoplatforms hold great promise for on‐demand drug release in precision cancer medicine. However, currently available systems utilize “always‐on” photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H2S‐mediated in situ production of NIR photothermal agents for imaging‐guided and photocontrolled drug release. The system targets H2S‐rich cancers. This nanoplatform shows H2S‐activatable NIR‐II emission and NIR light controllable release of the drug Camptothecin‐11. Upon administering the system to HCT116 tumor‐bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer‐specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR‐II imaging.

Synthesis and application of photo-responsive polymers

Stimulus-responsive polymers, especially photo-responsive polymers have aroused great interest in recent years. Since light is an environment-friendly and remotely controllable stimulus, which affords photo-responsive polymers with great advantages. This review summarized the recent progress on the synthesis of photo-responsive polymers via post-polymerization modification, radical polymerization and polycondensation, the response mechanism of photo-responsive polymers, and their applications in photo-controlled drug release, photoelectric devices and biosensors.

New Acylhydrazone Photoswitches with Quantitative Conversion and High Quantum Yield but without Hydrogen Bond Stabilizing ( Z)-Isomer.

Hydrazones are recently attracting increasing interest because of their facile synthesis and high addressability, fatigue resistance, and modifiability as molecular switches. However, this new class of switches generally suffers from low conversion from E- to Z-configuration. Here, novel benzoylhydrazones were synthesized by condensation of 2-methoxynaphthaldhyde and benzoylhydrazine. In this hydrazone system, both sides of the imine double bond had large steric hindrance, so that the ( E)-isomer of the benzoylhydrazones was less stable and easily converted into the ( Z)-isomer even without an intramolecular hydrogen bond. Up to 99% conversion efficiency and 89% quantum yield were obtained, in addition to excellent addressability and high fatigue resistance. Outstandingly, the crystal structure of one ( Z)-isomer disclosed no intermolecular hydrogen bonds between the molecules of the ( Z)-isomer but strong and sequential hydrogen bonds between those of the ( E)-isomer. Therefore, the ( E)-isomer was less soluble in solvents than the ( Z)-isomer. This molecular switch system could be easily modified by both hydrophilic pentaethylene glycol chains and hydrophobic octyl chains. Under light irradiation, the resultant amphiphilic acylhydrazone could be transferred from ( E)-isomer to ( Z)-isomer in more than 90% yield even in water after light irradiation. Meanwhile, the self-assembled big nanospheres could rearrange into much smaller vesicles because of the solubility difference of ( Z)- and ( E)-isomers. After the anticancer drug procarbazine was loaded by this kind of acylhydrazone in water, it could be released by light irradiation, showing potential application in photocontrollable drug release.

Chemiluminescence-initiated and in situ-enhanced photoisomerization for tissue-depth-independent photo-controlled drug release.

Tissue-penetration-depth-independent self-luminescence is highly expected to perform photoisomerization-related bioapplications in vivo to overcome the limitation of shallow tissue-penetration from external photoexcitation. However, it remains extremely challenging because of lacking a target-specific high-intensity self-luminescence to precisely and effectively drive the photoisomerization. Here, we first report a target-specific tissue-depth-independent photoisomerization in vivo by developing a target-specific initiated and in situ-enhanced chemiluminescence (one of self-luminescence) strategy that overcomes the limitation of lacking target-specific high-intensity self-luminescence. Considering that photoisomerization shows boundless glamour in drug-controlled release for disease-specific chemotherapy, we demonstrated applicability of our strategy to apply it in tumor-specific self-luminescence-controlled drug chemotherapy. Specifically, a chemiluminescence substrate and chemiluminescence fluorophore (antitumor drug, CPT) were co-encapsulated in host-guest carriers composed of cyclodextrin and the photoisomerization molecule azobenzene. Tumor-specific H2O2-induced chemiluminescence preliminarily isomerizes azobenzene, triggering the partial dissociation of host-guest carriers and CPT release. Particularly, the initially released CPT again functions as a chemiluminescence enhancer to achieve in situ enhanced chemiluminescence, assuring target-specific enhanced isomerization and CPT release. With high tumor-inhibition-rate (73%) and no obvious therapy-side-effect in vivo indicates the good efficiency and target-specificity of our chemiluminescence-driven photoisomerization. Although we only demonstrated one example of a photoisomerization-related bioapplication, namely photoisomerization-controlled drug chemotherapy, our work provides guidelines to design various target-specific tissue-depth-independent photoisomerization for bioapplications.

Near-infrared light-responsive, diselenide containing core-cross-linked micelles prepared by the Diels–Alder click reaction for photocontrollable drug release application

We report a facile and efficient preparation of a NIR-triggered micelle system for a drug vehicle.

Expanding Anti-Stokes Shifting in Triplet-Triplet Annihilation Upconversion for In Vivo Anticancer Prodrug Activation.

A strategy to expand anti-Stokes shifting from the far-red to deep-blue region in metal-free triplet-triplet annihilation upconversion (TTA-UC) is presented. The method is demonstrated by in vivo titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti-Stokes shift of any reported TTA system. TTA core-shell-structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low-power density far-red light-emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far-red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications.

Expanding Anti‐Stokes Shifting in Triplet–Triplet Annihilation Upconversion for In Vivo Anticancer Prodrug Activation

AbstractA strategy to expand anti‐Stokes shifting from the far‐red to deep‐blue region in metal‐free triplet–triplet annihilation upconversion (TTA‐UC) is presented. The method is demonstrated by in vivo titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti‐Stokes shift of any reported TTA system. TTA core–shell‐structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low‐power density far‐red light‐emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far‐red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications.

A Smart, Photocontrollable Drug Release Nanosystem for Multifunctional Synergistic Cancer Therapy.

Multifunctional synergistic therapy holds promise in biomedical studies and clinical practice. However, strategies aimed at easily integrating the components of such multimodal therapies are needed. Therefore, we herein report a smart drug release nanosystem able to perform photodynamic therapy, photothermal therapy and chemotherapy in a photocontrollable manner. Doxorubicin (DOX), a chemotherapy drug, and 5, 10, 15, 20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4), a photosensitizer, were physically intercalated into a DNA assembly immobilized on gold nanorods. The drugs were efficiently delivered to target cells and released under light irradiation, resulting in a synergism that combined phototherapy and chemotherapy for cancer treatment. This smart, photocontrollable drug release nanosystem promises precisely controlled drug release for multifunctional synergistic cancer therapy.