Pdt-Sensitized Tumor Microenvironment-Responsive Nanosystem for Maximizing Antitumor Potency of Multi-Target Drugs Through Effective and Homogeneous Drug Release

The benefits of multi-target drugs in oncotherapy are often hindered by their multi-target nature and tissue-nonspecific distribution. To maximize the multi-target antitumor potency with reduced side effects, we proposed a ROS/pH-dual responsive nanosystem (DP) constructed from biocompatible dextran-phenylboronic acid pinacol ester conjugates. Most importantly, against the tumor heterogeneity, photodynamic therapy (PDT) was utilized to induce additional ROS to amplify and homogenize tissular oxidation level, thus achieving the effective and homogeneous drug release within tumor microenvironment (TME) or inner cells. The combination of biostimuli-responsive nanosystem with PDT facilitated multi-target delivery of drugs like gambogic acid (GA) to different locations within tumor. Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles (DP/GP) and the PDT-mediated spatiotemporal controlled drug release. Data from in vitro research among B16F10 cells and HUVECs, and in vivo investigation in B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA from the effective and homogeneous tumoral release based on this combination. This tactic based on biological-stimuli amplification and homogenization not only proposes a paradigm to improve the availability of stimuli-responsive drug delivery systems (DDS) in tumor treatment, but also provides a promising perspective to maximize the potency of multi-target drugs