Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China.
Adv Sci (Weinh). 2023 Oct;10(29):e2301216. doi: 10.1002/advs.202301216. Epub 2023 Aug 7.
Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment.
化疗免疫治疗在癌症治疗方面取得了重大进展。然而，癌细胞的自我防御机制，包括细胞周期检查点和程序性细胞死亡配体 1（PD-L1）的上调，极大地阻碍了治疗效果。在此，设计了具有肿瘤敏感释放特性的去甲斑蝥素（NCTD）-铂（Pt）共递纳米颗粒（NC-NP），通过协同化疗免疫治疗来克服自我防御机制。NC-NP 在正常生理条件下保持稳定，但在响应肿瘤酸度时迅速释放 1,2-二氨基环己烷铂（II）（奥沙利铂的前药 DACHPt）和 NCTD。NCTD 抑制蛋白磷酸酶 2A（PP2A）活性以缓解细胞周期阻滞，并下调肿瘤 PD-L1 表达以破坏程序性细胞死亡-1（PD-1）/PD-L1 相互作用，协同增强基于铂的化疗和免疫原性细胞死亡诱导的免疫治疗。结果，NC-NP 表现出强大的协同细胞毒性，并促进 T 细胞募集以产生强大的抗肿瘤免疫反应。这种双重协同作用对原位 4T1 肿瘤表现出强大的抗肿瘤活性，为癌症治疗提供了一种有前途的化疗免疫治疗范例。
