Jiang Xiaomin, Luo Taokun, Yang Kaiting, Lee Morten J, Liu Jing, Tillman Langston, Zhen Wenyao, Weichselbaum Ralph R, Lin Wenbin
Department of Chemistry, The University of Chicago, 929 E 57th St, Chicago, IL 60637, USA.
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, 5758 S Maryland Ave., Chicago, IL 60637, USA.
Sci Adv. 2024 Jul 19;10(29):eado0082. doi: 10.1126/sciadv.ado0082. Epub 2024 Jul 17.
The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.
癌症纳米药物的低成功率引发了关于增强渗透与滞留（EPR）效应在纳米治疗剂肿瘤沉积中作用的争论。在此，我们报道了一种双功能纳米级配位聚合物（NCP），即奥沙利铂（OX）/2',3'-环鸟苷单磷酸-腺苷单磷酸（GA），通过刺激干扰素基因（STING）激活来克服EPR限制，并增强化疗药物和STING激动剂的递送以根除肿瘤。OX/GA将GA和OX封装在NCP中，以保护GA不被酶降解，并改善GA和OX的药代动力学。OX/GA激活STING会破坏肿瘤血管，并使OX在肿瘤内的沉积比单药治疗的OX-NCP增加4.9倍。OX/GA在皮下、原位、自发和转移性肿瘤模型中表现出卓越的抗肿瘤效果，肿瘤生长抑制率>95%且治愈率高。OX/GA诱导肿瘤细胞的免疫原性细胞死亡和先天免疫细胞的STING激活，以增强抗原呈递。NCP为克服EPR限制以实现有效的癌症治疗提供了一个出色的纳米平台。
