Polyethylene glycol modified protamine-chlorin e6 conjugate nanoparticles for enhanced cancer photodynamic therapy

Photodynamic therapy attracts great attention in cancer treatment due to its minimal invasiveness, good tolerance and specific cancer targeting. However, most of tumors are hypoxic and the tumors will become more hypoxic after photodynamic therapy, which might cause the poor prognosis by inducing tumor angiogenesis. In the present work, polyethylene glycol modified protamine-chlorin e6 conjugate (PEG-protamine-Ce6) was synthesized for enhanced cancer photodynamic therapy. PEG-protamine-Ce6 was synthesized by conjugating protamine with methoxypolyethylene glycol acetaldehyde and Ce6 sequentially. The in vitro studies show that PEG-protamine-Ce6 self-assembles into nanoparticles in aqueous solution with uniform size (similar to 200 nm), positive zeta potential and spherical morphology. The in vitro cell studies show that PEG-protamine-Ce6 nanoparticles exhibit enhanced cellular uptake amount, intracellular ROS level elevation upon laser irradiation, cell apoptosis and photocytotoxicity as compared to Ce6. The in vivo studies show that PEG-protamine-Ce6 nanoparticles exhibit enhanced antitumor effect as compared to Ce6 upon laser irradiation. PEG-protamine-Ce6 with laser irradiation not only inhibits tumor cell proliferation, but also inhibits tumor angiogenesis by suppression of VEGF expression, whereas Ce6 with laser irradiation promotes tumor angiogenesis by enhancing VEGF expression. PEG-protamine-Ce6 nanoparticles developed in this work offer a novel nanomedicine for enhancing cancer photodynamic therapy.