School of Pharmaceutical Science, Key Laboratory of Chemical Biology (Ministry of Education), Shandong University, Jinan 250012, China.
Key Laboratory of Colloid & Interface Chemistry (Ministry of Education), Shandong University, Jinan 250100, China.
J Control Release. 2020 Dec 10;328:617-630. doi: 10.1016/j.jconrel.2020.09.035. Epub 2020 Sep 22.
Chemotherapy sometimes can cause potential tumor-specific T-cell-mediated immune response via stimulating immunogenic cell death (ICD). However, such immune response is usually very weak in chemotherapy because of immunosuppressive tumor microenvironment (ITME), substantially nourished by immunosuppressive indoleamine-2,3-dioxygenase (IDO) and myeloid-derived suppressor cells (MDSCs). It is still a challenge to develop a minimalist drug nanoplatform which can stimulate the inherent immunotherapeutic potential in chemotherapy. Herein, a self-sufficient bi-prodrug nanomedicine strategy was reported to realize a minimalist drug nanoplatform for strengthening immunotherapeutic capability in chemotherapy through its self-owned functions. Gemcitabine (GEM) and 1-methyl-tryptophan (1MT) were designed as a bi-prodrug molecule (GEM-1MT), named for the bioactivity reason of both GEM and 1MT. GEM-1MT bi-prodrug molecules could self-assemble into waste-free nanoparticles (NPs) for cancer therapy. Our GEM-1MT NPs can give full scope to the effect of "kill four birds with one stone": (I) the released GEM could kill tumor cells for triggering ICD; (II) the selective MDSC depletion could be induced by the released GEM; (III) the released 1MT could result in IDO inhibition in tumor cells; (IV) the released 1MT could also cause IDO inhibition in MDSCs. Therefore, the GEM-1MT NPs exhibited an enhanced immunotherapy, contributing to the overall therapeutic efficacy of self-combining chemo-immunotherapy. This bi-prodrug nanomedicine strategy provides a new concept for rational design of a minimalist drug nanoplatform with a strengthened overall therapeutic efficacy of chemo-immunotherapy.
化疗有时可以通过刺激免疫原性细胞死亡（ICD）来引起潜在的肿瘤特异性 T 细胞介导的免疫反应。然而，由于免疫抑制性肿瘤微环境（ITME）的存在，这种免疫反应在化疗中通常非常微弱，ITME 主要由免疫抑制性吲哚胺 2,3-双加氧酶（IDO）和髓系来源的抑制细胞（MDSCs）滋养。开发一种能够刺激化疗中固有免疫治疗潜力的极简药物纳米平台仍然是一个挑战。在此，报道了一种自足的双前药纳米医学策略，通过其自身的功能实现了一种极简药物纳米平台，用于增强化疗中的免疫治疗能力。吉西他滨（GEM）和 1-甲基色氨酸（1MT）被设计为双前药分子（GEM-1MT），这是基于 GEM 和 1MT 的生物活性原因命名的。GEM-1MT 双前药分子可以自组装成无废物纳米颗粒（NPs）用于癌症治疗。我们的 GEM-1MT NPs 可以充分发挥“一石四鸟”的效果：（I）释放的 GEM 可以杀死肿瘤细胞以触发 ICD；（II）释放的 GEM 可以诱导选择性 MDSC 耗竭；（III）释放的 1MT 可导致肿瘤细胞中 IDO 抑制；（IV）释放的 1MT 还可导致 MDSCs 中的 IDO 抑制。因此，GEM-1MT NPs 表现出增强的免疫治疗作用，有助于提高联合化疗免疫治疗的整体疗效。这种双前药纳米医学策略为合理设计具有增强的化疗免疫治疗整体疗效的极简药物纳米平台提供了一个新的概念。
