Light-responsive Drug Delivery Research Articles

Light-Responsive Polymers: Developments in Drug Delivery Systems

Abstract: Photoresponsive polymers have emerged as innovative tools in the domain of drug delivery, presenting advanced solutions for controlled and targeted release of therapeutic agents. This review explores recent advances in the design and application of photoresponsive polymers, focusing on their pivotal role in lighttriggered drug delivery systems. It also encompasses organic synthesis methodologies, key advancements in polymer design, and the integration of photoresponsive elements into drug carriers. Moreover, this review also focuses on the applications, challenges, and future prospects, providing a comprehensive overview of the evolving landscape of light-responsive drug delivery technologies. The information about the synthesis presented herein aims to contribute to the understanding and advancement of this dynamic field, offering insights for researchers and practitioners engaged in the development of next-generation drug delivery systems.

Visible light degradable micelles for intraocular corticosteroid delivery.

Visible light responsive micellar drug delivery formulations are of notable interest for the treatment of ocular diseases, as their successful development would enable controlled drug release at the back of the eye, improving efficacy and reducing side-effects when compared to existing approaches. In this work, an aliphatic polycarbonate-based visible light responsive micelle formulation based on mPEG-b-poly(5-hydroxy-trimethylene carbonate) (PHTMC) was prepared wherein the pendant hydroxyl groups of the PHTMC repeating units were protected by blue light-labile [7-(diethylamino)coumarin-4-yl]methyl (DEACM). The photo-labile DEACM provided a photo-triggered release profile, as, upon the removal of these protecting groups by photo-irradiation, the micelles underwent structural disruption, leading to the release of the payload. The removal of DEACM also deprotected the pendant hydroxyl groups of PHTMC, leading to PHTMC backbone degradation via intramolecular cyclization.

Hyaluronic acid hydrogel for controlled release of heterobifunctional photocleavable linker-modified epidermal growth factor in wound healing

Peptide and protein drugs, such as epidermal growth factor (EGF), face challenges related to stability and bioavailability. Recently, hydrogels have emerged as promising carriers for these drugs. This study focuses on a light-responsive hydrogel-based drug delivery system for the controlled release of EGF in wound healing. A photocleavable (PC) linker was designed to bind EGF to the hydrogel matrix, enabling UV light-triggered release of EGF. Hydrogels have evolved from drug reservoirs to controlled release systems, and the o-nitrobenzyl-based PC linkers offer selective cleavage under UV irradiation. We used a thiol-ene crosslinked hyaluronic acid (HA) hydrogel matrix modified with the PC-linked EGF. The release of EGF from the HA hydrogel under UV irradiation was evaluated, along with in vitro and in vivo experiments to assess the controlled effect of EGF on wound healing. Our results indicate that the successful development of a light-responsive hydrogel-based system for precise temporal release of EGF enhances the therapeutic potential in wound healing. This study highlights the importance of incorporating stimulus-responsive functionalities into hydrogel-based drug delivery systems to optimize protein drugs in clinical applications.

In situ forming mesoporous polydopamine nanocomposite thermogel for combined chemo-photothermal therapy of intraocular cancer

Intraocular cancers such as retinoblastoma and uveal melanoma will induce severe vision loss or even death. Herein, a versatile nanocomposite thermogel based on hexanoyl glycol chitosan (HGC) and mesoporous polydopamine nanoparticles (MPDA NPs) was designed for potential use as an intraocular “drug depot” for the treatment of intraocular tumors. The integrated HGC-MPDA thermogel showed reversible sol-gel transition property as well as injectable and in-situ gelation abilities. The incorporated MPDA NPs endowed the thermogel with outstanding NIR laser-based photothermal conversion ability and enabled NIR light-controlled drug release. Moreover, in vitro study revealed that drug-loaded thermogel (HGC-MPDA@DOX) with the aid of 808 nm laser irradiation possessed superior anticancer effect than any single treatment via synergistic chemo-photothermal therapy. The present study demonstrated that HGC-MPDA could serve as a multifunctional platform for sustained and NIR light-responsive intravitreal drug delivery, avoiding repetitive injection, and the localized chemo-photothermal therapy provides a promising strategy against intraocular tumors.

Preparation and evaluation of controllable drug delivery system: A light responsive nanosphere based on β-cyclodextrin/mesoporous silica

A novel light responsive nanosphere was constructed, and it was used as a drug carrier to investigate the loading and release properties of the Quercetin (QU). In this paper, mesoporous silica nanoparticles (MSN) were used as a substrate, and 3-aminopropyl triethyoxysilane was used as a surface modification agent to introduce —NH2, and the azobenzene-4,4′-dicarboxylic acid (AZO) was used as light responsive agent to introduce the group of —N = N—, and then β-cyclodextrin (β-CD) was combined with AZO through host–guest interaction to construct light responsive nanoparticles (MSN@β-CD). The structure and properties of the carrier were analyzed by FTIR, BET, XPS, TGA, XRD, SEM and TEM. In vitro drug release studies showed the release rate of QU@MSN@β-CD (dark) was 12.19% within 72 h, but the release rate of QU@MSN@β-CD (light 10 min) was 26.09%, exhibiting a light-responsive property. The CCK8 tests demonstrated that MSN@β-CD could significantly decrease the toxicity of QU. Therefore, the controllable light-responsive drug delivery system has great application prospects.

Light responsive hydrogels for controlled drug delivery.

Light is an easy acquired, effective and non-invasive external stimulus with great flexibility and focusability. Thus, light responsive hydrogels are of particular interests to researchers in developing accurate and controlled drug delivery systems. Light responsive hydrogels are obtained by incorporating photosensitive moieties into their polymeric structures. Drug release can be realized through three major mechanisms: photoisomerization, photochemical reaction and photothermal reaction. Recent advances in material science have resulted in great development of photosensitizers, such as rare metal nanostructures and black phosphorus nanoparticles, in order to respond to a variety of light sources. Hydrogels incorporated with photosensitizers are crucial for clinical applications, and the use of ultraviolet and near-infrared light as well as up-conversion nanoparticles has greatly increased the therapeutic effects. Existing light responsive drug delivery systems have been utilized in delivering drugs, proteins and genes for chemotherapy, immunotherapy, photodynamic therapy, gene therapy, wound healing and other applications. Principles associated with site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient compliance and convenience. In view of the importance of this field, we review current development, challenges and future perspectives of light responsive hydrogels for controlled drug delivery.

All-In-One Second Near-Infrared Light-Responsive Drug Delivery System for Synergistic Chemo-Photothermal Therapy.

Light-responsive nanocarrier-based drug delivery systems (NDDSs), due to their unique advantages such as safety, minimal cross-reaction, and spatiotemporal precision, have received wide attention. Notably, second near-infrared (NIR-II) light, which has a high penetration depth for manipulating NDDSs to release drugs, is in high demand. Herein, polyethylene glycol (PEG)-modified hollow CuxS nanoparticles (NPs) are developed as an all-in-one NIR-II light-responsive NDDS for synergistic chemo-photothermal therapy. First, CuxS-PEG NPs were prepared under mild conditions by using Cu2O NPs as sacrificial templates. The morphology, photothermal effect, drug loading/releasing abilities, and synergistic chemo-photothermal therapy of CuxS-PEG NPs have been investigated. The CuxS-PEG NPs with hollow structures showed a high drug loading capacity (∼255 μg Dox per mg of CuxS NPs) and stimuli-responsive drug release triggered by NIR-II laser irradiation. The synergistic chemo-photothermal therapy based on the Dox/CuxS-PEG NPs showed 98.5% tumor elimination. Our study emphasizes the great potential of CuxS-PEG NPs as an all-in-one NIR-II light-responsive NDDS for applications in biomedicine.

Black phosphorus-incorporated titanium dioxide nanotube arrays for near-infrared–triggered drug delivery

Inflammatory reaction after implantation is a serve complication of medical implants. Here, we propose a near-infrared (NIR) light stimulus-responsive drug-eluting platform based on titanium dioxide nanotube (TNT) arrays. Nano-sized black phosphorus (BP) prepared using a liquid exfoliation method served as a photothermal agent and were incorporated with TNTs, imparting TNTs NIR stimulus-responsive activity. The combination of BP and TNTs exhibited excellent photothermal conversion performance. Ibuprofen, a commonly used anti-inflammatory drug, was selected as the model drug and loaded on the NIR-responsive functional TNTs. A coating of 1-tetradecanol (TD) was used as a thermosensitive gatekeeper to prevent drug release at normal body temperature. Upon exposure to NIR light, the NIR-responsive drug delivery system transformed light energy to thermal energy that melted the TD layer and led to drug release from the reservoir. Furthermore, the combination of BP and TNTs showed enhanced biomineralization performance because of the degradation of BP into phosphate. Moreover, BP-modified TNTs showed no obvious cytotoxicity to MC3T3-E1 cells. Thus, this NIR light-responsive drug delivery system shows potential for controlled drug delivery in Ti-based orthopedic implants to overcome the challenges of tissue inflammation after implantation.

Tumor acidity and near-infrared light responsive drug delivery MoS2-based nanoparticles for chemo-photothermal therapy

The rational design of tumor microenvironment (TME)- multifunctional stimuli-responsive nanocomposites is appealing for effective cancer treatment. However, multidrug resistance remains an obstacle to construct responsive oncotherapy. Herein, a novel MoS2/PDA-TPP nanocomposite loaded with chemotherapy drug of doxorubicin (DOX) is designed for TME dual-response and synergistically enhanced anti-tumor therapy based on the tumor-specific mitochondria accumulation ability and photothermal (PTT) therapy. In detail, the designed MoS2/PDA-TPP nanoplatform can act as a pH-responsive dissociation to endow fast release of DOX under an acidic TME and simultaneously improve the efficiency of PTT. Moreover, the mechanism shows that MoS2/PDA-TPP trigger mitochondrial-dependent apoptosis by producing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP). Most importantly, during PTT procedure, hyperthermia up to 50 °C can effectively induce tumor cell death without causing severe inflammation to adjacent tissues. Tumor targeting double stimulation response of nanocomposites is a novel idea to overcome drug resistance, which will provide a more effective strategy for solving practical problems.

Photocleavage-based Photoresponsive Drug Delivery.

Targeted drug delivery has been extensively studied in the last decade, whereas both passive and active targeting strategies still face many challenges, such as off-target drug release. Light-responsive drug delivery systems have been developed with high controllability and spatio-temporal resolution to improve drug efficacy and reduce off-target drug release. Photoremovable protecting groups are light-responsive moieties that undergo irreversible photocleavage reactions upon light irradiation. They can be covalently linked to the molecule of interest to control its structure and function with light. In this review, we will summarize recent applications of photocleavage technologies in nanoparticle-based drug delivery for precise targeting and controlled drug release, with a highlight of strategies to achieve long-wavelength light excitation. A greater understanding of these mechanisms and emerging studies will help design more efficient photocleavage-based nanosystems to advance photoresponsive drug delivery.

NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy

NIR-activated therapies based on light-responsive drug delivery systems are emerging as a remote-controlled method for cancer precise therapy. In this work, fluorescent dye indocyanine green (ICG)-conjugated and bioactive compound gambogic acid (GA)-loaded polymeric micelles (GA@PEG-TK-ICG PMs) were smoothly fabricated via the self-assembly of the reactive oxygen species (ROS)-responsive thioketal (TK)-linked amphiphilic polymer poly(ethyleneglycol)-thioketal-(indocyanine green) (PEG-TK-ICG). The resultant micelles demonstrated increased resistance to photobleaching, enhanced photothermal conversion efficiency, NIR-controlled drug release behavior, preferable biocompatibility, and excellent tumor accumulation performance. Moreover, upon an 808 nm laser irradiation, the micellar photoactive chromophore ICG converted the absorbed optical energy to both hyperthermia for photothermal therapy (PTT) and ROS as the feedback trigger to the micelles for the tumor-specific release of GA, which could serve as not only a chemotherapeutic drug to directly kill tumor cells but also a heat shock protein 90 (HSP90) inhibitor to realize the photothermal sensitization. As a result, an extremely high tumor inhibition rate (97.9%) of mouse 4 T1 breast cancer models was achieved with negligible side effects after the chemo-photothermal synergistic therapy. This NIR-activated nanosystem with photothermal self-sensitization function may provide a feasible option for the effective treatment of aggressive breast cancers.

Polymer-Functionalized Upconversion Nanoparticles for Light/Imaging-Guided Drug Delivery.

The strong upconversion luminescence (UCL) of upconversion nanoparticles (UCNPs) endows the nanoparticles with attractive features for combined imaging and drug delivery. UCNPs convert near-infrared (NIR) light into light of shorter wavelengths such as light in the ultraviolet (UV) and visible regions, which can be used for light-guided drug delivery. Although light-responsive drug delivery systems as such have been known for many years, their application in medicine is limited, as strong UV-light can be damaging to tissue; moreover, UV light will not penetrate deeply into the skin, an issue that UCNPs can now address. However, UCNPs, as obtained after synthesis, are usually hydrophobic and require further surface functionalization to be stable in plasma. Polymers can serve as versatile surface coatings, as they can provide good colloidal stability, prevent the formation of a protein corona, provide a matrix for drugs, and be stimuli-responsive. In this Review, we provide a brief overview of the most recent progress in the synthesis of UCNPs with different shapes/sizes. We will then discuss the purpose of polymer coating for drug delivery before summarizing the strategies to coat UCNPs with various polymers. We will introduce the different polymers that have so far been used to coat UCNPs with the purpose to create a drug delivery system, focusing in detail on light-responsive polymers. To expand the application of UCNPs to allow photothermal therapy or magnetic resonance imaging (MRI) or to simply enhance the loading capacity of drugs, UCNPs were often combined with other materials to generate multifunctional nanoparticles such as carbon-based NPs and nanoMOFs. We then conclude with a discussion on drug loading and release and summarize the current knowledge on the toxicity of these polymer-coated UCNPs.

Tumor Acidity and Near‐Infrared Light Responsive Dual Drug Delivery Polydopamine‐Based Nanoparticles for Chemo‐Photothermal Therapy

AbstractPhotothermal therapy (PTT) combined with chemotherapy, a promising strategy for breast cancer treatment, has a high potential to control drug release, reduce multidrug resistance, and improve therapeutic efficacy. The challenge is how to realize tumor ablation in deeper tissue and NIR‐controlled drug delivery. Herein, tumor acidity and near‐infrared light (NIR) responsive folic acid (FA) functionalized polydopamine (DPA) nanoparticles (NPs) are developed for doxorubicin (DOX) and epigallocatechin‐3‐gallate (EGCG) dual delivery. With the assistance of NIR, the cellular uptake of DOX‐EGCG/DPA‐FA NPs is about three‐ to sixfold higher when compared with the free DOX group and the control group without NIR irradiation. Moreover, biodistribution study in vivo indicates that DPA‐FA NPs can enhance tumoral accumulation, penetration, retention of drugs, and display a ≈4‐ and 19‐fold higher intra‐tumoral distribution than that of the DPA NPs and free drug groups at 24 h postinjection. Furthermore, 60% of breast cancer‐bearing mice survive over 70 days in the DOX‐EGCG/DPA‐FA NPs group. Additionally, DOX‐EGCG/DPA‐FA NPs can effectively boost therapeutic efficacy by inducing significant suppression of tumor growth and angiogenesis, and enhancement of apoptosis and necrosis of breast cancer cells. Taken together, DOX‐EGCG/DPA‐FA NPs may have potential applications as a useful nanoscale vector for enhanced cancer therapy.

3D-Bioprinted Constructs that Breathe

3D-Bioprinted Constructs that Breathe

Visible Light-Responsive Drug Delivery Nanoparticle via Donor-Acceptor Stenhouse Adducts (DASA).

Stimuli-responsive drug release from a nanocarrier triggered by light enables the control of the amount of drug locally. Here, block copolymer micelles based on poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) as the hydrophilic block and a polymer with pendant donor-acceptor Stenhouse adducts (DASA) are used as a means to trigger the release of drugs under green light. The micelles are loaded with ellipticine to yield light-responsive nanoparticles with sizes of around 35nm according to transmission electron microscopy (TEM) analysis. Two micelles with a drug loading content of 4.75 and 7.4wt% are prepared, but the micelle with the higher drug loading content leads to substantial protein adsorption. The release of ellipticine from the micelle, which is monitored using the polarity-sensitive fluorescence of ellipticine, can be switched on by light and off by thermal recovery of DASA in the dark. The micelles are readily taken up by Michigan Cancer Foundation-7 breast cancer cells. Subsequent light irradiation leads to enhanced drug release inside the cell as seen by the enhanced fluorescence.

Core-Shell PVA/PVP-FeOOH Nanofibers as a Potential Visible Light Responsive Drug Delivery System

The high surface area per unit volume and core-shell configuration of electrospun nanofiber mat has a potential for drug delivery applications. Co-axial electrospinning technique resolves the limitation in the traditional transdermal drug delivery materials allowing to load a larger concentration of therapeutic agents per unit mass of the polymer. Encapsulating the drug in the fiber core provides protection and prolonged drug release. In the present study mats of core-shell PVA/PVP-FeOOH nanofibers were successfully formed by the coaxial electrospinning process for the first time. The visible light responsive FeOOH drug carrier material was incorporated in fiber core to provide non-invasive drug release on demand. The prepared materials posses visible light triggered release of organic methylene blue molecules.

Carbon quantum dots-stabilized Pickering emulsion to prepare NIR light-responsive PLGA drug delivery system

A new strategy to prepare NIR light-responsive Poly-lactide-co-glycolide (PLGA) drug delivery systems via carbon quantum dots-stabilized Pickering emulsion polymerization was developed. We successfully fabricated oil-in-water single emulsion and water-in-oil-in-water double emulsion for loading hydrophobic and hydrophilic drugs, respectively.

Emerging NIR light-responsive delivery systems based on lanthanide-doped upconverting nanoparticles.

Together with the development of nanoscience, lanthanide (Ln)-doped upconversion nanoparticles (UCNPs), which can emit UV/VIS light upon irradiation by near-infrared laser sources, is emerging as one of the most favorable materials in the field of nanomedicines. Light-responsive drug delivery is known as an efficient strategy to achieve temporal and spatial controlled drug release. Compared to conventional light-sensitive drug delivery systems, UCNPs are endowed with many advantages, such as deeper tissue penetration and low toxicity. With their unique properties, UCNPs not only serve as potential optical probes for bioimaging but also perform a critical role in therapeutic applications through photon-triggered mechanisms. In particular, UCNPs in combination with different materials and delivery strategies could overcome therapy resistance and enhance therapeutic effectiveness. This article focuses on the current achievements in the last decade of modification methods, diagnostics, and designs of UCNP-based nanoplatforms for successful phototherapy, chemotherapy, and bioimaging.

NIR light-assisted phototherapies for bone-related diseases and bone tissue regeneration: A systematic review.

Recently, the rapid development of biomaterials has induced great interest in the precisely targeted treatment of bone-related diseases, including bone cancers, infections, and inflammation. Realizing noninvasive therapeutic effects, as well as improving bone tissue regeneration, is essential for the success of bone‑related disease therapies. In recent years, researchers have focused on the development of stimuli-responsive strategies to treat bone-related diseases and to realize bone regeneration. Among the various external stimuli for targeted therapy, near infrared (NIR) light has attracted considerable interests due to its high tissue penetration capacity, minimal damage toward normal tissues, and easy remote control properties. The main objective of this systematic review was to reveal the current applications of NIR light-assisted phototherapy for bone-related disease treatment and bone tissue regeneration. Database collection was completed by June 1, 2020, and a total of 81 relevant studies were finally included. We outlined the various therapeutic applications of photothermal, photodynamic and photobiomodulation effects under NIR light irradiation for bone‑related disease treatment and bone regeneration, based on the retrieved literatures. In addition, the advantages and promising applications of NIR light-responsive drug delivery systems for spatiotemporal-controlled therapy were summarized. These findings have revealed that NIR light-assisted phototherapy plays an important role in bone-related disease treatment and bone tissue regeneration, with significant promise for further biomedical and clinical applications.

Dl-Menthol Loaded Polypyrrole Nanoparticles as a Controlled Diclofenac Delivery Platform for Sensitizing Cancer Cells to Photothermal Therapy.

Cancer cells with up-regulated intracellular heat shock proteins (HSPs) expression under adverse heat environment during photothermal therapy (PTT) always resulted in inefficient oncotherapy. As the expression of HSPs is an energy-dependent manner, inhibiting the aerobic glycolysis pathway to realize tumor starvation and therefore consequently reducing the production of intratumoral adenosine 5'-triphosphate (ATP) would offer an efficient way for sensitizing cancer cells to PTT. DLM@PPy NPs, a polypyrrole (PPy)-based platform complexing with dl-menthol (DLM), was well-designed and successfully developed here as a near-infrared (NIR) light and thermo responsive drug delivery system. Benefiting from the volatile property of DLM and high photothermal conversion ability of PPy, the as-prepared DLM@PPy NPs could continuously generate bubbles under NIR light illumination, which is good for precisely controlling the release of encapsulated drug and monitoring the whole therapeutic process by ultrasound imaging. By encapsulating diclofenac (DC, an inhibitor of glucose transporter 1 to realizing tumor starvation) to form DC/DLM@PPy NPs, on-demand DC release could be easily achieved by selectively turning on/off the NIR light irradiation. After releasing DC in tumor lesion to reduce the generation of intratumoral ATP, a significant intensified cell-killing efficiency of PTT was observed. Thus, our study has demonstrated the good potential of DLM/PPy NPs as a stimuli-responsive DC delivery system for intensified PTT through inhibiting the aerobic glycolysis of cancer cells.