Light-controlled Drug Release Research Articles

Tumor Microenvironment-Regulating Two-Photon Probe Based on Bimetallic Post-Coordinated MOF Facilitating the Dual-Modal and Deep Imaging-Guided Synergistic Therapies.

The intricate tumor microenvironment (TME) always brings about unsatisfactory therapeutic effects for treatments, although nanomedicines have been demonstrated to be highly beneficial for synergistic therapies to avoid the side effects caused by the complexity and heterogeneity of cancer. Developing nanotheranostics with the functionalities of both synergistic therapies and TME regulation is a good strategy but is still in its infancy. Herein, an "all-in-one" nanoplatform for integrated diagnosis and treatment, namely, Carrier@ICG@DOX@FA (CIDF), is constructed. Benefiting from the bimetallic coordination of Eu3+-HTHA (4,4,4-trifluoro-1-(9-hexylcarbazol-3-yl)-1,3-butanedione) and Fe3+ with the ligands in UiO-67, CIDF can simultaneously achieve two-photon fluorescence imaging, fluorescent lifetime imaging in deep tumors, and regulation of TME. Owing to its porosity, CIDF can encapsulate indocyanine green as photosensitizers and doxorubicin as chemotherapeutic agent, further realizing light-controlled drug release. Moreover, CIDF exhibited good biocompatibility and tumor targeting by coating with folic-acid-modified polymers. Both in vitro and in vivo experiments demonstrate the excellent therapeutic efficacy of CIDF through dual-modal-imaging-guided synergistic photothermal-, photodynamic-, and chemotherapy. CIDF provides a new paradigm for the construction of TME-regulated synergistic nanotheranostics and realizes the complete elimination of tumors without recurrence.

Surface-modified gold-coated superparamagnetic iron oxide nanoparticles promoting light-controlled drug release

Surface-modified gold-coated superparamagnetic iron oxide nanoparticles promoting light-controlled drug release

Optical Bioimaging and Therapy

Optical Bioimaging and Therapy

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.

Engineering near-infrared laser-activated gold nanorod vesicles with upper critical solution temperature for photothermal therapy and chemotherapy

Multimodal synergistic therapy based on nanomedicine drug delivery systems can achieve accurate cancer treatment. The anisotropy of gold nanorods (AuNRs) allows the adjustment of the longitudinal localized surface plasmon resonance absorption to the near-infrared band, which shows potential application in the field of photothermal therapy of cancer. Here, we report a new type of thermal-sensitive gold nanorod drug-loaded vesicles (UGRV-DOX) via the self-assembly of AuNRs modified with the amphiphilic polymer (PEG45-b-PS150) and upper critical solution temperature (UCST) polymer (P(AAm-co-AN)). The hollow structure of the vesicle can increase the drug loading capacity, and the polymers on its surface are intertwined to reduce drug leakage. As-prepared UGRV-DOX vesicles exhibits excellent photothermal conversion efficiency and can achieve light-controlled drug release. In vivo anti-tumor experiments showed that UGRV-DOX could ablate HepG2 transplanted tumors significantly under 808 nm laser irradiation, and the inhibition rate was as high as 99.3 %. These tumor-specific nanovesicles prefigure great potentials for high-precision cancer treatment.

Turning Red without Feeling Embarrassed─Xanthenium-Based Photocages for Red-Light-Activated Phototherapeutics.

Herein, we present high-yielding, concise access to a set of xanthenium-derived, water-soluble, low-molecular-weight photocages allowing light-controlled cargo release in the green to red region. Very importantly, these new photocages allow installation of various payloads through ester, carbamate, or carbonate linkages even at the last stage of the synthesis. Payloads were uncaged with high efficiency upon green, orange, or red light irradiation, leading to the release of carboxylic acids, phenols, and amines. The near-ideal properties of a carboxanthenium derivative were further evaluated in the context of light-controlled drug release using a camptothecin-derived chemotherapeutic drug, SN38. Notably, the caged drug showed orders of magnitude lower efficiency in cellulo, which was reinstated after red light irradiation. The presented photocages offer properties that facilitate the translation of photoactivated chemotherapy toward clinical applications.

A DNA-based nanodevice for near-infrared light-controlled drug release and bioimaging

DNA-based nanostructures have shown curative potential in drug delivery and anti-tumor therapy. However, the applications of such systems are limited by the lack of precise control over the space and duration of drug release. Here, we report a near-infrared (NIR) light-guided DNA nanodevice that enables controlled drug release for precise tumor imaging and therapy. The DNA nanodevice is constructed by engineering GC-rich DNA duplexes with an ultraviolet (UV) light labile moiety and further modification onto the surface of upconversion nanoparticles (UCNPs). The chemotherapeutic drug (doxorubicin, Dox) is intercalated into the GC motif of DNA duplexes, where the fluorescence signal of Dox is markedly quenched. Upon NIR light irradiation, the UCNPs acting as energy transducers emit UV light that can break the photolabile moiety in DNA duplexes, resulting in the controlled release of Dox and recovery of their fluorescence signal. We present that this DNA nanodevice is not only able to selectively induce tumor cells apoptosis via NIR light-mediated activation, but also enables in situ imaging and monitoring of drug release. Therefore, this modular strategy opens a window for remotely controlled drug delivery.

Co‐delivery CPT and PTX prodrug with a photo/thermo‐responsive nanoplatform for triple‐negative breast cancer therapy

AbstractTriple‐negative breast cancer (TNBC) is still the most aggressive cancer in women. Combination chemotherapy holds great potential for cancer therapy; however, the off‐target and side effects of free chemotherapy administration remain a major challenge. In this study, we developed a photo/thermo‐responsive nanoplatform that can be used for TNBC treatment via photothermic therapy in combination with multidrug therapy. By conjugating the chemotherapy drug PTX prodrug on the surface of mesoporous silica‐coated gold nanorod nanoparticles and then loading another chemotherapy drug, CPT, the Au@MSN‐PTX@CPT nanoparticles exhibited great photothermal response, redox response drug release and cancer cell inhibition abilities. Otherwise, we further coated the Au@MSN‐PTX@CPT nanoparticle with a temperature‐sensitive polymer poly(N‐isopropylacrylamide‐co‐methacrylic acid) (p(NIPAM‐co‐MAAc)), and the polymer‐coated Au@MSN‐PTX@TPT@polymer nanoparticles showed perfect near‐infrared (NIR) light controlled drug release. Finally, the Au@MSN‐PTX@CPT@polymer nanoparticles were injected into the 4T1 breast cancer mouse model. The Au@MSN‐PTX@CPT@polymer nanoparticles preferably accumulated at the tumor site and had reduced chemotherapy injuries and great antitumor activity when combined with 650 nm laser treatment. In summary, our developed Au@MSN‐PTX@CPT@polymer nanoparticles served as a good method for controlled chemodrug delivery and provided a good choice for TNBC combination therapy.

Mesoporous biophotonic carbon spheres with tunable curvature for intelligent drug delivery

Abstract Mesoporous carbon spheres (MCSs) are widely used in the field of pollutants adsorption, energy storage and various biomedicine applications such as targeted delivery vector, phototherapy sensitizers, bioimaging contrast agents, etc. Current synthetic strategies including soft templating and hard templating methods generally have the limits of using expensive surfactants or lack of control over the pore structures. Therefore, the complex and uncontrollable pore structures limit its further clinical application. Herein, we proposed a new synthetic strategy to control the uniformity of pore channel arrangement in MCSs which can modulate the photonic property and the corresponding light controlled drug release property in intelligent drug delivery. The as obtained MCSs with relative uniform pore channel arrangement and long pore channels are demonstrated to have the best NIR light-induced drug release performance. This work provides not only new synthetic method to modulate pore structure characteristics and biophotonic property of MCSs, but also uniform MCSs as novel delivery platforms with advanced controlled release performance.

Fabrication of a phototheranostic nanoplatform for single laser-triggered NIR-II fluorescence imaging-guided photothermal/chemo/antiangiogenic combination therapy

Phototheranostics that integrates real-time optical imaging and light-controlled therapy has recently emerged as a promising paradigm for cancer theranostics. Herein, a new small molecule dye DPP-BT-TPA with strong emission above 1000 nm and a redox-responsive prodrug camptothecin-combretastatin A4 (CPT-CA4) were designed and successfully synthesized. A multifunctional phototheranostic nanoplatform was then fabricated by encapsulating them within an amphiphilic polymer. The presence of DPP-BT-TPA enabled high-resolution imaging in the second near-infrared window (NIR-II) and efficient photothermal therapy. The prodrug was cleaved by the overexpressed glutathione (GSH) in the tumor microenvironment to release the chemotherapeutic drug CPT and the angiogenesis inhibitor CA4. Because this process can be accelerated with elevated temperature, laser-induced hyperthermia was utilized to control the drug release and enhance the therapeutic effect. Tumors in living mice were observed through NIR-II imaging after intravenous injection of the obtained nanoparticles. Improved antitumor efficacy by photothermal/chemo/antiangiogenic combination therapy was achieved with a NIR laser both in vitro and in vivo. This work provides a promising strategy for developing tumor microenvironment responsive and light-controlled theranostic platforms. Statement of significanceFluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window and near-infrared light-controlled drug release have been recognized as efficient strategies for cancer theranostics. Herein, we present a phototheranostic platform fabricated with a biocompatible NIR-II emissive dye DPP-BT-TPA and a redox-responsive prodrug camptothecin-combretastatin A4 (CPT-CA4). DPP-BT-TPA not only provides high-resolution NIR-II imaging in vivo but also enables efficient photothermal therapy. In addition, the photothermal effect largely accelerates the release of the chemotherapeutic drug CPT and the angiogenesis inhibitor CA4 in the glutathione-overexpressed tumor microenvironment. Thus, the designed phototheranostic platform can be used for NIR-II imaging-guided photothermal/chemo/antiangiogenic combination therapy for tumors with a single laser.

Chemodrug-gated mesoporous nanoplatform for new near-infrared light controlled drug release and synergistic chemophotothermal therapy of tumours.

Controlled drug release and synergistic therapies have an important impact on improving therapeutic efficacy in cancer theranostics. Herein, a new near-infrared (NIR) light-controlled multi-functional nanoplatform (GNR@mSiO2-DOX/PFP@PDA) was developed for synergistic chemo-photothermal therapy (PTT) of tumours. In this nano-system, doxorubicin hydrochloride (DOX) and perfluoro-n-pentane (PFP) were loaded into the channels of mesoporous SiO2 simultaneously as a first step. A polydopamine (PDA) layer as the gatekeeper was coated on their surface to reduce premature release of drugs at physiological temperature. Upon 808 nm NIR irradiation, the gold nanorods (GNR) in the core of the nanoplatform show high photothermal conversion efficiency, which not only can provide the heat for PTT, but also can decompose the polymer PDA to allow DOX release from the channels of mesoporous SiO2. Most importantly, the photothermal conversion of GNR can also lead the liquid–gas phase transition of PFP to generate bubbles to accelerate the release of DOX, which can realize the chemotherapy of tumours. The subsequent synergistic chemo-PTT (contributed by the DOX and GNR) shows good anti-cancer activity. This work shows that the NIR-triggered multi-functional nanoplatform is of capital significance for future potential applications in drug delivery and cancer treatment.

Red-light-triggered self-destructive mesoporous silica nanoparticles for cascade-amplifying chemo-photodynamic therapy favoring antitumor immune responses

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.

Bifunctional Smart Hydrogel Dressing with Strain Sensitivity and NIR-Responsive Performance.

Smart response hydrogel has a broad application prospect in human health real-time monitoring due to its responses to a variety of stimuli. In this study, we developed a novel smart hydrogel dressing based on conductive MXene nanosheets and a temperature-sensitive PNIPAm polymer. γ-Methacryloxypropyltrimethoxysilane (KH570) was selected to functionalize the surface of MXene further to improve the interface compatibility between MXene and PNIPAm. Our prepared K-M/PNIPAm hydrogel was found to have a strain-sensitive property, as well as a respond to NIR phase change and volume change. When applied as a strain flexible sensor, this K-M/PNIPAm hydrogel exhibited a high strain sensitivity with a gauge factor (GF) of 4.491, a broad working strain range of ≈250%, a fast response of ∼160 ms, and good cycle stability (i.e., 3000 s at 20% strain). Besides, this K-M/PNIPAm hydrogel can be used as an efficient NIR light-controlled drug release carrier to achieve on-demand drug release. This work paved the way for the application of smart response hydrogel in human health real-time monitoring and NIR-controlled drug release functions.

Singlet Oxygen-Responsive Polymeric Nanomedicine for Light-Controlled Drug Release and Image-Guided Photodynamic-Chemo Combination Therapy.

Coencapsulation of chemotherapeutic agents and photosensitizers into nanocarriers can help to achieve a combination of chemotherapy and photodynamic therapy for superior antitumor effects. However, precise on-demand drug release remains a major challenge. In addition, the loaded photosensitizers usually tend to aggregate, which can significantly weaken their fluorescent signals and photodynamic activities. To address these issues, herein, a smart nanocarrier termed as singlet oxygen-responsive nanoparticle (SOR-NP) was constructed by introducing singlet oxygen (1O2)-sensitive aminoacrylate linkers into amphiphilic mPEG-b-PCL copolymers. Boron dipyrromethene (BDP) and paclitaxel (PTX) as model therapeutic agents were coloaded into an 1O2-responsive nanocarrier for realizing light-controlled drug release and combination cancer treatment. This polymeric nanocarrier could substantially relieve the aggregation of encapsulated BDP due to the presence of a long hydrophobic chain. Therefore, the formed SOR-NPBDP/PTX nanodrug could generate bright fluorescent signals and high levels of 1O2, which could mediate cell death via PDT and rupture aminoacrylate linker simultaneously, leading to collapse of SOR-NPBDP/PTX and subsequent PTX release. The light-triggered drug release and combined anticancer effects of SOR-NPBDP/PTX were validated in HepG2 and MCF-7 cancer cells and H22 tumor-bearing mice. This study provides a promising strategy for tumor-specific drug release and selective photodynamic-chemo combination treatment.

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

Dual-sensitive dual-prodrug nanoparticles with light-controlled endo/lysosomal escape for synergistic photoactivated chemotherapy.

The clinical application of conventional chemotherapeutic agents, represented by cisplatin, is limited by severe side effects. So, it is essential to explore more safer and controlled drug delivery systems for synergistic chemotherapy. In this work, we designed dual-sensitive dual-prodrug nanoparticles (DDNPs) for photoactivated platinum-based synergistic chemotherapy. With photosensitivity, DDNPs could be photoactivated from inert Pt(IV) to toxic Pt(II) under safe UVA light in a spatiotemporally controlled manner. Concurrently, mild could be generated from DDNPs to assist the endo/lysosomal escape of DDNPs for better photoactivated chemotherapy (PACT). Furthermore, with acid-sensitivity, demethylcantharidin (DMC), a protein phosphatase 2A (PP2A) inhibitor, was released to block the DNA repair pathway and thereby could sensitize platinum-based chemotherapy in intracellular acidic microenvironments. Along with a precise ratio (Pt : DMC = 1 : 2), DDNPs had a powerful synergistic anti-cancer effect in vitro and in vivo. In the future, DDNPs have great potential as a safe and multifunctional drug delivery system for precise nanomedicine in clinical treatments.

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.

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.

Green synthesis of gold nanoparticles coated doxorubicin liposomes using procyanidins for light–controlled drug release

For the controlled drug release delivery system, gold nanomaterials have received considerable attention for their photothermal effect in medical applications. The exploration of green and facile methods for constructing efficient gold based nanomaterials to control drug release is greatly needed. Hence, we aim to prepare procyanidins (PCs) reduced gold nanoparticles (AuNPs) coated doxorubicin (DOX) liposomes (DOX–PCs–Lips@AuNPs), of which PCs were modified on phosphatidylcholine and acted as both reductant and stabilizer during the synthesis of AuNPs. As a result, AuNPs were successfully synthesized by PCs, so as to avoid the use of traditional reductants. The as prepared DOX–PCs–Lips@AuNPs were proved to have spherical shape, good photothermal property and controlled drug release behavior after 808 nm laser irradiation. As a green and facile synthesized nanomaterial, DOX–PCs–Lips@AuNPs would consolidate the medical application of AuNPs.