Long circulating photoactivable nanomicelles with tumor localized activation and ROS triggered self-accelerating drug release for enhanced locoregional chemo-photodynamic therapy

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effect in malignant cancers, the currently available nanocarriers offer the limited capabilities for selective toxicity, drug release and tumor penetration. Herein, we developed photoactivatable nanomicelles, which are constructed by self-assembling of poly (ethylene glycol) (PEG)-stearamine (C18) conjugate (PTS) with a ROS-sensitive thioketal linker (TL) and co-loaded with doxorubicin (DOX) and photosensitizer pheophorbide A (PM), for enhanced locoregional chemo-photodynamic therapy. Upon accumulation in tumor region, the resulting PTS nanomicelles loaded with Dox and PM (PTS-DP) demonstrated reactive oxygen species (ROS) cascade responsive release of the DOX and PM loaded inside. Initial intracellular release of DOX and PM from the PTS-DP was triggered by the intrinsic presence of endogenous ROS within cancer cells. Furthermore, upon laser irradiation on the tumor region, enhanced singlet oxygen (102) was generated by PM released initially in cancer cells, which in turns accelerated the cytoplasmic release of DOX through rapid dissociation of nanomicelles. The gradual elevation of local ROS level generated by light-activated PM subsequent ROS-triggered release of DOX synergistically inhibited tumor growth and enhances the anti-tumor immunity. Findings of our study suggested that ROS-sensitive PTS nanomicelles could be a promising and innovative nanocarrier for locoregional chemo-photodynamic therapy.