MR. LINGFEI HAN

Functionalized core-shell nanoparticles for smart mutual-promotion between PDT and gambogic acid

Photodynamic therapy (PDT) and chemotherapy of cancer both meet respective challenges. Tumor hypoxia, lowpenetration and high glutathione (GSH) level bear the brunt. Herein, a core-shell nanoparticle, with multifunction of hypoxia-responsiveness, specific oxygen supply and deep tumor penetration, was constructed forsmart mutual-promotion between the both to overcome the respective restrictions. The nano platform (GC@MCSNPs) was composed of hypoxia-responsive hyaluronic acid-nitroimidazole (HA-NI) as shells, MnO2 NPs as oxygenmodulators and reduction-responsive functionalized poly (L-glutamic acid) derivatives (γ-PFGA) as cores todeliver gambogic acid (GA) and Chlorine6 (Ce6). After endocytosis， the approximately 100 nm of GC@MCS NPsachieved hypoxia-responsive shell degradation and MnO2 release, followed by reduction-activated charge conversion to form positively charged cores. With the damage effect of superficial tumor cells by the partiallyreleased GA, GA&Ce6-loadedγ-PFGA penetrated deep inside through electronic interaction step by step. Uponirradiated with 638 nm of laser,  widely permeated Ce6 was activated for enhanced PDT under the highoxygenation by MnO2 NPs. The generated reactive oxygen species (ROS) in return facilitated the GA-inducedparaptosis by clearing high level of GSH. As a result,  this mutual promotion strategy contributed to 92.41% of4T1 tumor inhibition rate, exhibiting outstanding advantages. Our GC@MCS NPs provided a smart combinationof chemo-photodynamic therapy and focused on addressing the tumor hypoxia and low penetration issues.