pH-Responsive Polyzwitterion Modified Photosensitizer for Precision Photodynamic Therapy

Insufficient tumor accumulation and poor selectivity of photosensitizers remain major obstacles to the efficacy of photodynamic therapy (PDT) in cancer treatment. To address these limitations, we developed a tumor targeting photosensitizer-polymer conjugate by conjugating pyropheophorbide-a (Ppa) with a pH-responsive polyzwitterion, PGlu(DET-Car). This conjugate transitions from a negative charge at physiological pH, preventing interactions with normal cells, to a positive charge in acidic tumor microenvironments, enabling pH-dependent cellular uptake and selective tumor accumulation. Compared to PEG-modified Ppa and free photosensitizers, PGlu(DET-Car)-modified Ppa showed significantly enhanced cellular uptake and phototoxicity under acidic conditions in vitro. In vivo studies demonstrated its prolonged blood circulation, superior tumor accumulation, and effective PDT performance, with minimal off-target effects on normal tissues. These results highlight the potential of pH-responsive polyzwitterion-based systems as a promising platform for tumor-targeted therapies, addressing critical limitations of conventional PDT approaches and providing new strategy for precision cancer treatment.