Du Lihua, He Haozhe, Xiao Zecong, Xiao Hong, An Yongcheng, Zhong Huihai, Lin Minzhao, Meng Xiaochun, Han Shisong, Shuai Xintao
PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
Department of pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Small. 2022 Apr;18(15):e2107732. doi: 10.1002/smll.202107732. Epub 2022 Feb 25.
Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8 T cells and reduce Treg cells to result in highly effective immunotherapy. In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.
免疫疗法在临床治疗中为肿瘤治疗带来了巨大益处，但主要由于免疫抑制性肿瘤微环境，其面临着低反应率这一严峻挑战。整合有效药物递送和医学成像的多功能纳米平台为癌症治疗提供了巨大潜力，这可能在联合免疫疗法中发挥关键作用，以克服免疫抑制性微环境从而实现高效肿瘤治疗。在此，使用谷胱甘肽（GSH）敏感的金属有机框架（MOF）制备了一种纳米药物（BMS-SNAP-MOF），用于封装免疫抑制酶吲哚胺2,3-双加氧酶（IDO）抑制剂BMS-986205以及一氧化氮（NO）供体s-亚硝基硫醇基团。高T1弛豫率使得磁共振成像能够监测纳米药物在体内的分布。纳米药物通过增强渗透滞留（EPR）效应在肿瘤组织中蓄积并随后内化进入肿瘤细胞后，其中富集的GSH引发与MOF的级联反应，使纳米药物解体以快速释放IDO抑制性药物BMS-986205并产生大量NO。因此，IDO抑制剂和NO协同调节免疫抑制性肿瘤微环境，增加CD8 T细胞并减少调节性T细胞（Treg细胞），从而实现高效免疫治疗。在一项动物研究中，使用这种诊疗纳米药物进行治疗使原发性和远处的4T1肿瘤均明显消退，突出了其在晚期肿瘤免疫治疗中的应用潜力。
