Abstract：
The 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.
摘要：
系统地检查了聚合物缀合物中树枝状侧链对肿瘤渗透和抗原呈递的影响。三种聚合物-吉西他滨（Gem）缀合物（pG0-Gem，pG1-Gem,pG2-Gem)的设计和制备。pG2-Gem缀合物独特地与肿瘤细胞的线粒体结合，从而调节线粒体动力学。pG2-Gem缀合物与线粒体之间的相互作用促进缀合物在肿瘤部位的大量渗透和积累，在动物模型中产生明显的抗肿瘤作用。这种令人鼓舞的治疗效果可归因于免疫调节,因为在pG2-Gem处理后,MHC-1抗原呈递由于线粒体融合和线粒体代谢改变而显著增强。至关重要的是，无药树枝状聚合物，pG2被鉴定为调节线粒体动力学，并且调节独立于共轭宝石。此外，pG2-Gem与抗PD-1抗体的组合导致87.5%的显著肿瘤清除率和超过150天的延长生存率,证明树突状聚合物作为代谢调节和协同肿瘤免疫治疗的创新纳米平台的潜力。
