Endolysosomal environment-responsive photodynamic nanocarrier toenhance cytosolic drug delivery via photosensitizer-mediated membrane disruption

The endolysosome is a major barrier for the effective intracellular delivery by conventional nanocarriers. Herein, we demonstrate that endolysosome environment-responsive photodynamic nanocarriers (EPNs) are capable of encapsulation of the hydrophobic drug paclitaxel (PTX) and photosensitizer (PS)-mediated ELB disruption for effective cancer therapy. EPNs were self-assembled from PS (chlorin e6, Ce6) or Black Hole Quencher-3 (BHQ3) conjugated covalently to polypeptide-based amphiphilic copolymers [monomethoxy polyethylene glycol-block-poly(β-benzyl-. l-aspartic acid), mPEG-pBLA]. EPNs have a spherical shape and a unimodal size distribution below 100nm. Photoquenching of the EPNs was dependent on the molar ratio of mPEG-pBLA-BHQ3/mPEG-pBLA-Ce6. However, in the presence of the endolysosomal enzyme ( e.g., esterase), the benzyl ester bond is cleaved which leads to the structural collapse of EPNs, thus triggering drug release and restoring photoactivity. Live cell imaging studies demonstrated that PS-mediated lipid peroxidation significantly increased the ability of model drug ( i.e., Nile red) to overcome the ELB. In comparison with PTX treatment alone, the combined treatment of PTX encapsulated EPNs with laser irradiation synergistically induced the death of HeLa and drug-resistant HCT-8 cells invitro, and suppressed CT-26 tumor growth invivo. These results suggest that this approach is a promising platform for cancer treatment. Furthermore, this EPN system offers significant potential for effective cytosolic delivery of chemical and biological therapeutics.