Photodynamic PEG-coated ROS-sensitive prodrug nanoassemblies for core-shell synergistic chemo-photodynamic therapy

Abstract

The combination of chemotherapy with photodynamic therapy (PDT) holds promising applications in cancer therapy. However, co-encapsulation of chemotherapeutic agents and photosensitizers (PS) into the conventional nanocarriers suffers from inefficient co-loading and aggregation-caused quenching (ACQ) effect of PS trapped in dense carrier materials. Herein, we report a light-activatable photodynamic PEG-coated prodrug nanoplatform for core-shell synergistic chemo-photodynamic therapy. A novel photodynamic polymer is rationally designed and synthesized by conjugating pyropheophorbide a (PPa) to polyethylene glycol 2000 (PEG_2k). PPa is used as the hydrophobic and photodynamic moiety of the amphipathic PPa-PEG_2k polymer. Then, a core-shell nanoassembly is prepared, with an inner core of a reactive oxygen species (ROS)-responsive oleate prodrug of paclitaxel (PTX) and an outer layer of PPa-PEG_2k. PPa-PEG_2k serves for both PEGylation and PDT. Instead of being trapped in the inner core, PPa in the outer PPa-PEG_2k layer significantly alleviates the ACQ effect. Under laser irradiation, ROS generated by PPa-PEG_2k not only is used for PDT but also synergistically promotes PTX release in combination with the endogenous ROS overproduced in tumor cells. The photodynamic PEG-coated nanoassemblies demonstrated synergistic antitumor activity in vivo. Such a unique nanoplatform, with an inner chemotherapeutic core and an outer photodynamic PEG shell, provides a new strategy for synergistic chemo-photodynamic therapy. STATEMENT OF SIGNIFICATION: The combination of chemotherapy with photodynamic therapy (PDT) holds promising prospects in cancer therapy. However, it remains a tremendous challenge to effectively co-deliver chemotherapeutic drugs and photosensitizers into tumors. Herein, we construct a photodynamic PEGylation-coated prodrug-nanoplatform for high-efficiency synergistic cancer therapy, which is composed of a light-activatable PPa-PEG_2k shell and a ROS-responsive paclitaxel (PTX) prodrug core. The PPa-PEG_2k-generated ROS not only was used for synergistic PTX release but also synergistically facilitated tumor cell apoptosis in combination with PTX-initiated chemo-cytotoxicity. The light-activatable nanoassemblies exhibited multiple drug delivery advantages including high co-loading efficiency, self-enhanced PTX release, extended circulation time, favorable biodistribution, and potent synergistic anticancer activity. Our findings provide a new strategy for the rational design of advanced nano-DDS for high-efficiency combinational chemo-photodynamic therapy.

Keywords: Chemo-photodynamic therapy; Core-shell nanoassembly; Light-activatable; Photodynamic PEGylation; Synergistic.