An advanced multifunctional prodrug combining photodynamic therapy with chemotherapy for highly efficient and precise tumor ablation

Abstract

It is urgently required to develop the molecular agents with high therapeutic efficacy and low side effects for precise cancer therapy. Herein, an advanced multifunctional prodrug B-BDP-CL-CPT, consisting of a glutathione (GSH)-responsive boron dipyrromethene (BDP)-based photosensitizer, a chemo drug camptothecin (CPT), a reactive oxygen species (ROS)-sensitive chain linking BDP with CPT, and a biotin fragment with specific affinity to biotin-receptor, was designed and synthesized. Owing to the introduction of 2,4-dinitrobenzenesulfonate (DNBS) as the quencher into BDP core and chemical modification of CPT at the active site, B-BDP-CL-CPT is non-cytotoxic. Having biotin as the targeting ligand, the prodrug can be efficiently internalized by biotin-acceptor positive cancer cells, and then activated to generate substantial light-induced ROS through removal of the stopper DNBS by intracellular GSH which is abundant in cancer cells. The resulting ROS can not only serve for photodynamic therapy (PDT) but also further cleave thioketal linkage causing the release of CPT, to achieve dual PDT and chemotherapy. And the combination of preferential accumulation with specific activation in tumor tissues for this prodrug is conducive to improving the dual therapeutic outcome meanwhile greatly reducing the photo-damage and the release of CPT in adjacent healthy tissues. In addition, the activated B-BDP-CL-CPT can give bright fluorescence signals which are favor for imaging-guided PDT and real-time tracking the release of therapeutic agent. The in vitro and in vivo investigations have been performed to demonstrate the targeted and combined anticancer activities of this prodrug against HepG2 and HeLa cancer cells, and the mice with H22 tumors. This study proposes a new tactics for highly efficient and precise cancer treatment.