The normoxic and hypoxic microenvironments in solid tumors cause cancer cells to show different sensitivities to various treatments. Therefore, it is essential to develop different therapeutic modalities based on the tumor microenvironment. In this study, we designed size-switchable nanoparticles with self-destruction and tumor penetration characteristics for site-specific phototherapy of cancer. This was achieved by photodynamic therapy in the perivascular normoxic microenvironment due to high local oxygen concentrations and photothermal therapy (PTT) in the hypoxic microenvironment, which are not in proximity to blood vessels due to a lack of effective approaches for heat transfer. In brief, a poly(amidoamine) dendrimer with photothermal agent indocyanine green (PAMAM-ICG) was conjugated to the amphiphilic polymer through a singlet oxygen-responsive thioketal linker and then loaded with photosensitizer chlorin e6 (Ce6) to construct a nanotherapy platform (denoted as SNPICG/Ce6). After intravenous injection, SNPICG/Ce6 was accumulated at the perivascular sites of the tumor. The singlet oxygen produced by Ce6 can ablate the tumor cells in the normoxic microenvironment and simultaneously cleave the thioketal linker, allowing the release of small PAMAM-ICGs with improved tumor penetration for PTT in the hypoxic microenvironment. This tailored site-specific phototherapy in normoxic and hypoxic microenvironments provides an effective strategy for cancer therapy.
Keywords: phototherapy; singlet oxygen-responsive; size-switchable; tumor heterogeneity; tumor penetration.