Enzyme/GSH dual-responsive biodegradable nanohybrid for spatiotemporally specific photodynamic and hypoxia-augmented therapy against tumors

An enzyme/GSH dual-responsive biodegradable drug delivery system was developed by using mesoporous organosilica co-loaded with photosensitizer (IR820) and pro-drug (TPZ) for spatiotemporally PDT and PDT-induced hypoxic-activated chemotherapy, hyaluronic acid as capping agent and tumor targeting unit. [Display omitted] •The nanohybrids exhibit both HAase and GSH stimuli-responsive behavior.•The nanohybrids exhibit spatiotemporally specific targeting combined therapy against breast cancer.•The nanohybrids exert PDT-induced hypoxia for chemotherapy of hypoxic-activated prodrug.•The nanohybrids show good biosafety for potential clinical application. Photodynamic therapy (PDT) efficacy has been severely limited by the hypoxia in tumor microenvironment. A multitherapy modality was developed, integrating the advantages of each therapy and a nanocarrier: PDT and PDT-induced hypoxia-activated chemotherapy. Following PDT-induced hypoxia augmented in the periphery of the tumors, chemotherapy was locally activated. To this end, new indocyanine green (IR820) and a hypoxia-activated prodrug tirapazamine (TPZ) were loaded in glutathione (GSH) decomposable mesoporous organic silica nanoparticles (GMONs), tethered by hyaluronic acid (HA). This nanohybrid showed a tendency to accumulate and be retained in tumors, due to passive and active targeting. The IR820 produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and concomitantly tumorous abnormality exacerbated hypoxia. TPZ-mediated hypoxia-activated chemotherapy acted to kill more tumor cells. In vivo results indicated that the tumor inhibition rate of dual-loaded nanohybrids was up to 76% under NIR laser irradiation. The immunofluorescence staining of tumor slices demonstrated that the superficial part of tumors experienced exacerbated hypoxia with laser irradiation, resulting in TPZ exerting powerful chemotherapy effects. This nanohybrid is expected to be valuable as spatiotemporally specific therapy for cancer.