Light-Responsive Prodrug-Based Supramolecular Nanosystems for Site-Specific Combination Therapy of Cancer

On-demand release of chemotherapeutic drugs from their prodrugs triggered by light irradiation has been attracting great attention for effective cancer treatment. Herein, we prepared prodrug-based supramolecular nanoparticles (HA–aPS–aCPT) composed of (1) β-cyclodextrin conjugated hyaluronic acid polymer (HA–CD), (2) adamantane-modified camptothecin prodrug (aCPT) caged via reactive oxygen species (ROS) responsive thioketal linker, and (3) adamantane-modified photosensitizer (aPS), for combination photodynamic therapy and light-controlled chemotherapy. aCPT could release free camptothecin by the cleavage of ROS-sensitive thioketal linker. aPS is employed to produce ROS under light irradiation. HA–aPS–aCPT nanoparticles are formed by supramolecular means with excellent colloidal stability and monodispersity in aqueous solution. Confocal imaging and flow cytometric analysis confirm the selective uptake of HA–aPS–aCPT nanoparticles via CD44 receptor-mediated endocytosis by MDA-MB-231 cells, on account of the targeting capability of hyaluronic acid. Cell viability assays show that HA–aPS–aCPT nanoparticles possess minimal cytotoxicity in the dark, while presenting high cellular toxicity under light irradiation. In vivo experiments exhibit selective accumulation of HA–aPS–aCPT nanoparticles in MDA-MB-231 tumor of nude mice. Significant tumor regression is observed when light irradiation is applied after intravenous injection of HA–aPS–aCPT nanoparticles. Thus, HA–aPS–aCPT nanoparticles demonstrate a great potential for on-demand combination photodynamic therapy and chemotherapy of tumor.