Peritumoral Microgel Reservoir for Long-Term Light-Controlled Triple-Synergistic Treatment of Osteosarcoma with Single Ultra-Low Dose.

Local minimally invasive injection of anticancer therapies is a compelling approach to maximize the utilization of drugs and reduce the systemic adverse drug effects. However, the clinical translation is still hampered by many challenges such as short residence time of therapeutic agents and the difficulty in achieving multi-modulation combination therapy. Herein, mesoporous silica-coated gold nanorods (AuNR@SiO2 ) core-shell nanoparticles are fabricated to facilitate drug loading while rendering them photothermally responsive. Subsequently, AuNR@SiO2 is anchored into a monodisperse photocrosslinkable gelatin (GelMA) microgel through one-step microfluidic technology. Chemotherapeutic drug doxorubicin (DOX) is loaded into AuNR@SiO2 and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is loaded in the microgel layer. The osteosarcoma targeting ligand alendronate is conjugated to AuNR@SiO2 to improve the tumor targeting. The microgel greatly improves the injectability since they can be dispersed in buffer and the injectability and degradability are adjustable by microfluidics during the fabrication. The drug release can, in turn, be modulated by multi-round light-trigger. Importantly, a single super low drug dose (1 mg kg-1 DOX with 5 mg kg-1 DMXAA) with peritumoral injection generates long-term therapeutic effect and significantly inhibited tumor growth in osteosarcoma bearing mice. Therefore, this nanocomposite@microgel system can act as a peritumoral reservoir for long-term effective osteosarcoma treatment.

Cell Membrane-Inspired Polymeric Vesicles for Combined Photothermal and Photodynamic Prostate Cancer Therapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as highly prospective therapeutic modalities in cancer therapy. Notwithstanding, a critical challenge still remains in the exploration of an effective strategy to maximize the synergistic efficacy of PTT and PDT due to low photoconversion efficiency. Herein, inspired by the phospholipid bimolecular structure of the cell membrane, bionic cell membrane polymeric vesicles with photothermal/photodynamic synergy for prostate cancer therapy at one wavelength's excitation are constructed in one step by the coordination of hexadecyl trimethyl ammonium bromide (CTAB) from the surface of hydrophobic gold nanorods (AuNRs) with indocyanine green (ICG) and polycaprolactone (PCL), achieving their self-assembly in aqueous solutions. Importantly, the aggregation of the assembly improves the stability of the vesicles, realizing the synergistic effect of PTT and PDT for prostate cancer therapy. After being assembled within polymeric vesicles, bifunctional photosensitizer ICG can generate reactive oxygen species (ROS) and photothermal effect under light treatment. Their ROS not only induce PDT efficacy but also destroy the integrity of the lysosomal membrane, promoting the translocation of ICG and another photosensitizer called gold nanorods (AuNRs) into the cytosol. Moreover, their photothermal effects produced by both photosensitizers are able to engender greater damage to the tumor cells because of the close distance with organelles. This structure manifests good cellular uptake, highly effective tumor accumulation, high photothermal conversion efficiency, and excellent properties of enhanced photobleaching resistance, which are beneficial to ICG-based fluorescence tumor imaging. Using the same near-infrared (NIR) wavelength for excitation, the AuNR/ICG vesicles can reduce the side effect rate of photodamage on the skin. In addition, by generating reactive oxygen species (ROS) and double photothermal effect, the vesicles under NIR excitation can promote the apoptosis of PC3 tumor cells. Taken together, the spontaneous self-assembled AuNR/ICG vesicles exhibit huge potential in advanced-stage prostate cancer therapy, especially for the prostate-specific membrane antigen (PSMA)-negative castration-resistant subtype.

Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents.

Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth.