Light-controlled Drug Research Articles

Near-infrared light-controllable MXene hydrogel for tunable on-demand release of therapeutic proteins

Precise delivery of therapeutic protein drugs that specifically modulate desired cellular responses is critical in clinical practice. However, the spatiotemporal regulation of protein drugs release to manipulate the target cell population in vivo remains a huge challenge. Herein, we have rationally developed an injectable and Near-infrared (NIR) light-responsive MXene-hydrogel composed of Ti3C2, agarose, and protein that enables flexibly and precisely control the release profile of protein drugs to modulate cellular behaviors with high spatiotemporal precision remotely. As a proof-of-concept study, we preloaded hepatic growth factor (HGF) into the MXene@hydrogel (MXene@agarose/HGF) to activate the c-Met-mediated signaling by NIR light. We demonstrated NIR light-instructed cell diffusion, migration, and proliferation at the user-defined localization, further promoting angiogenesis and wound healing in vivo. Our approach's versatility was validated by preloading tumor necrotic factor-α (TNF-α) into the composite hydrogel (MXene@agarose/TNF-α) to promote the pro-apoptotic signaling pathway, achieving the NIR light-induced programmed cell deaths (PCD) of tumor spheroids. Taking advantage of the deep-tissue penetrative NIR light, we could eradicate the deep-seated tumors in a xenograft model exogenously. Therefore, the proposed MXene-hydrogel provides the impetus for developing therapeutic synthetic materials for light-controlled drug release under thick tissue, which will find promising applications in regenerative medicine and tumor therapy. Statement of significanceCurrent stimuli-responsive hydrogels for therapeutic proteins delivery mainly depend on self-degradation, passive diffusion, or the responsiveness to cues relevant to diseases. However, it remains challenging to spatiotemporally deliver protein-based drugs to manipulate the target cell population in vivo in an “on-demand” manner. Therefore, we have rationally constructed an injectable and Near-infrared (NIR) light-responsive composite hydrogel by embedding Ti3C2 MXene and protein drugs within an agarose hydrogel to enable the remote control of protein drugs delivery with high spatiotemporal precision. The NIR light-controlled release of the growth factor or cytokine has been carried out to regulate receptor-mediated cellular behaviors under deep tissue for skin wound healing or cancer therapy. This system will provide the potential for precision medicine through the development of intelligent drug delivery systems.

Stimuli‐Responsive Nanotheranostics

Stimuli‐Responsive Nanotheranostics

A light-controlled multi-step drug release nanosystem targeting tumor hypoxia for synergistic cancer therapy.

Hypoxia is a major obstacle for cancer therapy due to its association with cell proliferation, tumor distant metastasis, and treatment resistance. In this study, a hypoxia-activated bifunctional prodrug (CC5) was designed, synthesized and encapsulated by a photo-responsive ruthenium complex-derived polymer to yield a light-controlled multi-step drug release system (CC5-RuCa) for synergistic therapy against tumor hypoxia. Under NIR irradiation, CC5-RuCa not only generated ROS to kill the cancer cells in the exterior of the tumor but also released the prodrug CC5 with enhanced intratumoral penetration in the severe hypoxia region inside the tumor tissue. In vivo studies on MDA-MB-231 xenograft models revealed that CC5-RuCa with preferential accumulation in the tumor exhibited highly efficient tumor regression through the synergistic effect of photodynamic therapy and hypoxia-activated chemotherapy.

Multifunctional Platform Based on Electrospun Nanofibers and Plasmonic Hydrogel: A Smart Nanostructured Pillow for Near-Infrared Light-Driven Biomedical Applications.

Multifunctional nanomaterials with the ability to respond to near-infrared (NIR) light stimulation are vital for the development of highly efficient biomedical nanoplatforms with a polytherapeutic approach. Inspired by the mesoglea structure of jellyfish bells, a biomimetic multifunctional nanostructured pillow with fast photothermal responsiveness for NIR light-controlled on-demand drug delivery is developed. We fabricate a nanoplatform with several hierarchical levels designed to generate a series of controlled, rapid, and reversible cascade-like structural changes upon NIR light irradiation. The mechanical contraction of the nanostructured platform, resulting from the increase of temperature to 42 °C due to plasmonic hydrogel-light interaction, causes a rapid expulsion of water from the inner structure, passing through an electrospun membrane anchored onto the hydrogel core. The mutual effects of the rise in temperature and water flow stimulate the release of molecules from the nanofibers. To expand the potential applications of the biomimetic platform, the photothermal responsiveness to reach the typical temperature level for performing photothermal therapy (PTT) is designed. The on-demand drug model penetration into pig tissue demonstrates the efficiency of the nanostructured platform in the rapid and controlled release of molecules, while the high biocompatibility confirms the pillow potential for biomedical applications based on the NIR light-driven multitherapy strategy.

Construction of bifunctional living red blood cells for combined photothermal-chemotherapy

Modifying living cells using in-situ synthesized nanomaterials to endow them with new functions is highly desirable. Herein we report intra- and extra-cellular dual-modified red blood cells (RBCs) with intracellular CaCO3 nanoparticles (NPs) and extracellular polypyrrole-folic acid (PPy-FA) coating, which are exploited as a bifunctional drug carrier. The functionalized living cells (CaCO3@RBC@PPy-FA) are fabricated through first the intracellular in situ reaction of exogenous Ca2+ and CO32− ions to generate CaCO3 NPs, then polymerization of pyrrole and finally modification of folic acid (FA) on the membrane of individual cells, forming a CaCO3@RBC@PPy-FA structure. As a result, such dual-modified RBCs not only preserve the original performances of the cells but also possess the desirable properties as a drug carrier, such as high loading capacity due to the action of CaCO3 NPs, targeting and light-controlled drug release due to the action of PPy-FA. Under NIR laser stimulation, these bifunctional RBCs (DOX-CaCO3@RBC@PPy-FA) present an instant release profile of doxorubicin (DOX) and have high targeting-ability toward cancer cells, achieving a marked synergistic combined photothermal–chemotherapy effect.

Glutathione transmembrane transmission gated by light-switches

Photoresponsive azobenzene-cyclodextrin light-switches fabricated artificial film which can be used to regulate the transmission of glutathione (GSH) across the membrane will gain much significance due to the important role of GSH in various biological process. In this work, we used azobenzene-cyclodextrin complex as switchable unit to manipulate gating transport. Under the control of ultraviolet (UV 365 nm) and visible (Vis 430 nm) light, two states of “ON” and “OFF” transport of GSH can be realized by the switches. This study achieved controlled molecule transport through channels by taking GSH as the research object, providing a new theoretical model for biological research and hold promise for future applications such as light-controlled drug transmission.

Light: A Magical Tool for Controlled Drug Delivery.

Light is a particularly appealing tool for on-demand drug delivery due to its noninvasive nature, ease of application and exquisite temporal and spatial control. Great progress has been achieved in the development of novel light-driven drug delivery strategies with both breadth and depth. Light-controlled drug delivery platforms can be generally categorized into three groups: photochemical, photothermal, and photoisomerization-mediated therapies. Various advanced materials, such as metal nanoparticles, metal sulfides and oxides, metal-organic frameworks, carbon nanomaterials, upconversion nanoparticles, semiconductor nanoparticles, stimuli-responsive micelles, polymer- and liposome-based nanoparticles have been applied for light-stimulated drug delivery. In view of the increasing interest in on-demand targeted drug delivery, we review the development of light-responsive systems with a focus on recent advances, key limitations, and future directions.

Spiropyrans for light-controlled drug delivery.

The supramolecular assembly of acetylsalicylic acid to a merocyanine-Zn complex translates into a photo-controllable drug delivery system. Herein, we present the synthesis and spectroscopic analysis of a three-component assembly combining a spiropyran derivative, a zinc(ii) cation, and acetylsalicylic acid. The ON/OFF system can be modulated by safe and easily affordable stimuli, for the specific delivery of more than one active compound. Our results confirm the formation of a ternary system in solution, where the behaviour is dominated by photo-induced responses, and pave the way for the use of such smart platforms for medicinal chemistry purposes.

Multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness for precise cancer therapy.

Near-infrared (NIR) light-induced photothermal agent-based stimuli-responsive materials have attracted great interest from researchers. However, the highly smart release with precise control by NIR light is not yet well established because of the lack or inadequacy of intelligent release systems, such as premature release of drug and/or photothermal agent. Herein, we put forward a novel and convenient strategy to synthesize cyanine dye-functionalized polymeric materials, where cyanine dye was schemed to attach to polymeric materials by copolymerization, endowing the polymeric materials with NIR light-responsive photothermal property and fluorescent nature for real-time imaging of endocytosis and intracellular trafficking of nanovehicles. Meanwhile, the chemotherapy drug DOX was introduced into the cyanine-containing polymeric materials via formation of dynamic covalent hydrazone bond to circumvent the blood circulation barrier. The nanovehicles displayed fine pH/NIR light-controlled drug release and excellent tumor intracellular drug transposition, which were ulteriorly combined with photo-triggered hyperthermia for enhanced antitumor effect. Therefore, this multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness provides a novel strategy to attain highly smart drug delivery for precise cancer therapy.

NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy

Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808 nm continuous laser illumination, significant heating generated from light-absorbable PPy results in DOX prodrug cleavage and considerable size swelling (∼125-fold), which in turn promotes simultaneous dual drug release, and thus triggering the combined therapeutic activation of PTT and chemotherapy. When laser is switched off, the discontinued photothermal generation makes the nanoparticle shrink back, thereby avoiding the leakage of CPT and DOX. In vivo experiments demonstrate the favorable tumor accumulation and prolonged tumor retention (>24 h) for long-term PA imaging-guided combination therapy. Current multifunctional nanoparticles integrated with light-controlled swelling/shrinking and synergistic therapeutic activation/silence represent a promising platform for precision cancer theranostics.

Dual stimuli-responsive supramolecular polymeric nanoparticles based on poly(α-cyclodextrin) and acetal-modified β-cyclodextrin-azobenzene

To aim at pH environment in tumor tissue and light-controlled drug release, UV and pH dual-responsive supramolecular polymeric nanoparticles mediated by host-guest interactions of poly(α-cyclodextrin) and acetal-modified β-cyclodextrin-azobenzene were developed in this work. The host molecule was poly(α-cyclodextrin) and the guest molecule was composed of acetal-modified β-cyclodextrin with one azobenzene linked. The inclusion of α-cyclodextrin and azobenzene leaded to amphiphilic supramolecular polymer, which further self-assembled to form supramolecular polymeric nanoparticles in aqueous medium. UV and pH responsiveness of supramolecular polymeric nanoparticles attributed to azobenzene and acetal, respectively. Supramolecular polymeric nanoparticles based on poly(α-cyclodextrin) and acetal-modified β-cyclodextrin-azobenzene with the average diameter of sub-100 nm were controllable to release the drugs regulated by pH and UV.

Near-Infrared-Light-Induced Morphology Transition of Poly(ether amine) Nanoparticles for Supersensitive Drug Release.

Near-infrared (NIR)-light-controlled drug release has aroused great interest because of its advantages in spatiotemporal control. Herein, a photothermally induced morphology transition of the nanoparticles (NPs) for supersensitive drug release has been demonstrated. Doxorubicin (DOX)- and cyanine (Cy)-coloaded thermosensitive poly(ether amine) NPs (DOX&Cy@PEA81) were developed. Because of the photothermal activity of Cy upon irradiation, increase in temperature at the tumor site results, which would be used not only for photothermal therapy but also to spur the release of DOX from the NPs for tunable chemotherapy. The NIR-laser-driven DOX release was validated by a series of intracellular and in vivo experiments on animals. Meanwhile, the chemo-photothermal combinatorial therapy results in optimal cytotoxicity and tumor inhibition. This article provides a promising approach to realizing supersensitive drug release and synergistic chemo-photothermal therapy for cancer.

Photo-triggered destabilization of nanoscopic vehicles by dihydroindolizine for enhanced anticancer drug delivery in cervical carcinoma

The efficacy and toxicity of drugs depend not only on their potency but also on their ability to reach the target sites in preference to non-target sites. In this regards destabilization of delivery vehicles induced by light can be an effective strategy for enhancing drug delivery with spatial and temporal control. Herein we demonstrate that the photoinduced isomerization from closed (hydrophobic) to open isomeric form (hydrophilic) of a novel DHI encapsulated in liposome leads to potential light-controlled drug delivery vehicles. We have used steady state and picosecond resolved dynamics of a drug 8-anilino-1-naphthalenesulfonic acid ammonium salt (ANS) incorporated in liposome to monitor the efficacy of destabilization of liposome in absence and presence UVA irradiation. Steady state and picosecond resolved polarization gated spectroscopy including the well-known strategy of solvation dynamics and Förster resonance energy transfer; reveal the possible mechanism out of various phenomena involved in destabilization of liposome. We have also investigated the therapeutic efficacy of doxorubicin (DOX) delivery from liposome to cervical cancer cell line HeLa. The FACS, confocal fluorescence microscopic and MTT assay studies reveal an enhanced cellular uptake of DOX leading to significant reduction in cell viability (∼40%) of HeLa followed by photoresponsive destabilization of liposome. Our studies successfully demonstrate that these DHI encapsulated liposomes have potential application as a smart photosensitive drug delivery system.

Light-controlled drug release from singlet-oxygen sensitive nanoscale coordination polymers enabling cancer combination therapy.

The development of smart drug delivery systems to realize controlled drug release for highly specific cancer treatment has attracted tremendous attention. Herein, nanoscale coordination polymers (NCPs) constructed from hafnium ions and bis-(alkylthio) alkene (BATA), a singlet-oxygen responsive linker, are fabricated and applied as nanocarriers to realize light-controlled drug release under a rather low optical power density. In this system, NCPs synthesized through a solvothermal method are sequentially loaded with chlorin e6 (Ce6), a photosensitizer, and doxorubicin (DOX), a chemotherapeutic drug, and then coated with lipid bilayer to allow modification with polyethylene glycol (PEG) to acquire excellent colloidal stability. The singlet oxygen produced by such NCP-Ce6-DOX-PEG nanocomposite can be used not only for photodynamic therapy, but also to induce the break of BATA linker and thus the destruction of nanoparticle structures under light exposure, thereby triggering effective drug release. Notably, with efficient tumor accumulation after intravenous injection as revealed by CT imaging, those NCP-Ce6-DOX-PEG nanoparticles could be utilized for combined chemo-photodynamic therapy with great antitumor efficacy. Thus, this work presents a unique type of NCP-based drug delivery system with biodegradability, sensitive responses to light, as well as highly efficient tumor retention for effective cancer combinational treatment.

Photoresponsive lipid-polymer hybrid nanoparticles for controlled doxorubicin release

Currently, photoresponsive nanomaterials are particularly attractive due to their spatial and temporal controlled drug release abilities. In this work, we report a photoresponsive lipid-polymer hybrid nanoparticle for remote controlled delivery of anticancer drugs. This hybrid nanoparticle comprises three distinct functional components: (i) a poly(D,L-lactide-co-glycolide) (PLGA) core to encapsulate doxorubicin; (ii) a soybean lecithin monolayer at the interface of the core and shell to act as a molecular fence to prevent drug leakage; (iii) a photoresponsive polymeric shell with anti-biofouling properties to enhance nanoparticle stability, which could be detached from the nanoparticle to trigger the drug release via a decrease in the nanoparticle’s stability under light irradiation. In vitro results revealed that this core–shell nanoparticle had excellent light-controlled drug release behavior (76% release with light irradiation versus 10% release without light irradiation). The confocal microscopy and flow cytometry results also further demonstrated the light-controlled drug release behavior inside the cancer cells. Furthermore, a CCK8 assay demonstrated that light irradiation could significantly improve the efficiency of killing cancer cells. Meanwhile, whole-animal fluorescence imaging of a tumor-bearing mouse also confirmed that light irradiation could trigger drug release in vivo. Taken together, our data suggested that a hybrid nanoparticle could be a novel light controlled drug delivery system for cancer therapy.

Dual-Targeted Multifunctional Nanoparticles for Magnetic Resonance Imaging Guided Cancer Diagnosis and Therapy

Hybrid nanostructures with combined functionalities can be rationally designed to achieve synergistic effects for efficient cancer treatment. Herein, a multifunctional nanoplatform is constructed, containing an inner core of an anticancer drug MTX surrounding by a nanometer-thin layer of gold as the shell with Fe3O4 magnetic nanoparticles (NPs) evenly distributed in the gold layer, and the outermost hybrid LA-PEG-MTX molecules as surface coating agent (denoted as MFG-LPM NPs). This nanocomposite possesses very high drug loading capacity as the entire core is MTX and integrates magnetic- and active- targeting drug delivery, light-controlled drug release, magnetic resonance imaging (MRI), as well as photothermal and chemotherapy. With a strong near-infrared (NIR) absorbance at 808 nm, the nanocomposite enables temperature elevation and light-triggered MTX release. In vitro cytotoxicity studies indicate that the strategy of combining therapy leads to a synergistic effect with high cancer cell killing efficacy. In consistency with this, due to the high accumulation of MFG-LPM NPs at tumor site and their combinatorial chemo-photothermal effects, 100% in vivo tumor elimination can be achieved. Additionally, in vivo MRI of tumor-bearing mice demonstrates an impressive performance of MFG-LPM NPs as a T2 contrast agent. Therefore, such multifunctional nanocomposite has the potential to serve as an excellent theranostic agent that collectively integrates multiple functions for efficient MRI guided cancer diagnosis and treatment.

Nanostructures for NIR light-controlled therapies.

In general, effective clinical treatment demands precision medicine, which requires specific perturbation to disease cells with no damage to normal tissue. Thus far, guaranteeing that selective therapeutic effects occur only at targeted disease areas remains a technical challenge. Among the various endeavors to achieve such an outcome, strategies based on light-controlled therapies have received special attention, mostly due to their unique advantages, including the low-invasive property and the capability to obtain spatial and temporal precision at the targeted sites via specific wavelength light irradiation. However, most conventional light-mediated therapies, especially those based on short-wavelength UV or visible light irradiation, have potential issues including limited penetration depth and harmful photo damage to healthy tissue. Therefore, the implemention of near-infrared (NIR) light illumination, which can travel into deeper tissues without causing obvious photo-induced cytotoxcity, has been suggested as a preferable option for precise phototherapeutic applications in vitro and in vivo. In this article, an overview is presented of existing therapeutic applications through NIR light-absorbed nanostructures, such as NIR light-controlled drug delivery, NIR light-mediated photothermal and photodynamic therapies. Potential challenges and relevant future prospects are also discussed.

Light-Controlled Ion Transport through Biomimetic DNA-Based Channels.

Light-controlled nanochannels are fabricated through self-assembling azobenzene-incorporated DNA (Azo-DNA) strands to regulate ion transport. By switching between collapsed and relaxed states using visible and ultraviolet light alternately, the Azo-DNA channels can be opened and closed because the conformation of Azo-DNA changes, that is, Azo-DNA is used as switchable controlling unit. In addition to sharing short response time and reversibility with other photoresponsive apparatuses, the Azo-DNA-based nanochannel system has advantages in good biocompatibility and versatile design, which could potentially be applied in light-controlled drug release, optical information storage, and logic networks.

Bioelectronically Initiated Cyt P450s Catalysis without NADPH

The catalytic cycle of cytochrome P450s (cyt P450s) features delivery of electrons from NADPH to cyt P450 reductase (CPR) for subsequent delivery to cyt P450 heme. Attempts at bioelectronic initiation of cyt P450s catalysis have been made by replacing the electron donation from expensive NADPH by other electron donnors. 1 To this aim, an electrode-driven drug metabolism biosensors were constructed with a mixed film containing ITO nanoparticles and CYP2C9/CPR-microsomes encapsulated by chitosan (CS) on a GC electrode. The electrochemical response of the enzyme modified electrode to 4-hydroxylation of tolbutamide has been validated, which allowed rapid determination of the affinity parameter Km appat 202.84 μM. The inhibition effect of sulfaphenazole on the CYP2C9-dependent 4-hydroxylation of tolbutamide was also investigated. Quantum dots (QDs), a kind of semiconductor materials, can also act as electron donnors. Based on the photo-induced electron transfer (PET) from QDs to the hemoproteins, a photoelectrochemical biosensor for the light-controlled drug metabolism by cyt P450s was then constructed. As shown in scheme 1, the photosensitized QDs offer electrons demanded in the cyt P450 catalytic process while the electrode at appropriate bias potentials acts as an electron supplier to QDs for neutralizing the VB holes and monitors the occurrence of the light-induced catalytic process. This novel biosensor can be applied in drug discovery and development by monitoring substrate metabolism and enzyme inhibition.

Remotely controlled red blood cell carriers for cancer targeting and near-infrared light-triggered drug release in combined photothermal chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus-responsive, RBC-based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.