Affiliation:
1. Department of Radiology Huaxi MR Research Center (HMRRC) Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China
2. Functional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
3. Department of Radiology West China Xiamen Hospital of Sichuan University Xiamen 361000 China
Abstract
AbstractThe effects of dendron side chains in polymeric conjugates on tumor penetration and antigen presentation are systematically examined. Three polymer‐gemcitabine (Gem) conjugates (pG0‐Gem, pG1‐Gem, pG2‐Gem) are designed and prepared. The pG2‐Gem conjugate uniquely binds to the mitochondria of tumor cells, thus regulating mitochondrial dynamics. The interaction between the pG2‐Gem conjugate and the mitochondria promotes great penetration and accumulation of the conjugate at the tumor site, resulting in pronounced antitumor effects in an animal model. Such encouraging therapeutic effects can be ascribed to immune modulation since MHC‐1 antigen presentation is significantly enhanced due to mitochondrial fusion and mitochondrial metabolism alteration after pG2‐Gem treatment. Crucially, the drug‐free dendronized polymer, pG2, is identified to regulate mitochondrial dynamics, and the regulation is independent of the conjugated Gem. Furthermore, the combination of pG2‐Gem with anti‐PD‐1 antibody results in a remarkable tumor clearance rate of 87.5% and a prolonged survival rate of over 150 days, demonstrating the potential of dendronized polymers as an innovative nanoplatform for metabolic modulation and synergistic tumor immunotherapy.
Funder
National Natural Science Foundation of China