Tian Longlong, Shao Ming, Gong Yimou, Wei Ting, Zhu Yujie, Chao Yu, Liu Zhuang
Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China.
Frontiers Science Center for Rare Isotopes, Lanzhou University, Lanzhou 730000, China.
Bioconjug Chem. 2022 Feb 16;33(2):343-352. doi: 10.1021/acs.bioconjchem.1c00576. Epub 2022 Jan 18.
Platinum complexes, despite being the most successful organometallic anticancer chemotherapy drugs, still suffer from serious side effects and therapy resistance. Inspired by the immunomodulation effect of platinum drugs, an epigenetic platinum(IV) complex was synthesized for enhanced cancer chemoimmunotherapy by conjugating oxidized oxaliplatin (OXA) with 2-bromo-1-(3,3-dinitro-1-azetidinyl)ethenone (RRx-001), the latter of which as a nitric oxide (NO) donor is also an epigenetic agent. The obtained complex (named OXA-NO) could significantly increase the level of "eat me" signal CRT expression and decrease the level of "don't eat me" signal CD47 expression on cancer cell membranes to promote their phagocytosis by macrophages. In addition, OXA-NO could release nitric oxide to trigger the transformation of pro-tumorigenic M2-type macrophages into antitumor M1-type macrophages within the tumor to reverse the immunosuppressive tumor microenvironment. Compared to commercial OXA, OXA-NO exhibited much stronger tumor growth inhibition ability and was much better tolerated, with obviously weakened side effects observed in spleen, lung, and kidneys. Therefore, this epigenetic platinum(IV) complex that exhibits excellent therapeutic efficacy and safety has great potential in the clinic.
铂配合物尽管是最成功的有机金属抗癌化疗药物，但仍存在严重的副作用和治疗耐药性。受铂类药物免疫调节作用的启发，通过将氧化奥沙利铂（OXA）与2-溴-1-(3,3-二硝基-1-氮杂环丁烷基)乙烯酮（RRx-001）共轭，合成了一种表观遗传铂（IV）配合物，用于增强癌症化学免疫疗法，后者作为一氧化氮（NO）供体也是一种表观遗传剂。所得到的配合物（命名为OXA-NO）可显著提高癌细胞膜上“吃我”信号CRT的表达水平，并降低“别吃我”信号CD47的表达水平，以促进巨噬细胞对它们的吞噬作用。此外，OXA-NO可释放一氧化氮，触发肿瘤内促肿瘤的M2型巨噬细胞向抗肿瘤的M1型巨噬细胞转化，以逆转免疫抑制性肿瘤微环境。与市售奥沙利铂相比，OXA-NO表现出更强的肿瘤生长抑制能力，耐受性更好，在脾脏、肺和肾脏中观察到的副作用明显减弱。因此，这种表现出优异治疗效果和安全性的表观遗传铂（IV）配合物在临床上具有巨大潜力。
