Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Lane 826, Zhangheng Road , Shanghai 201203 , PR China.
Department of Pharmacology and Chemical Biology , Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road , Shanghai 200025 , PR China.
Nano Lett. 2019 Jun 12;19(6):3548-3562. doi: 10.1021/acs.nanolett.9b00495. Epub 2019 Apr 30.
Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.
转移是癌症患者高死亡率的主要原因；因此，阻断转移过程对于癌症治疗至关重要。前转移灶是一种具有炎症相关异常变化的特殊微环境，允许循环肿瘤细胞（CTC）定植，并成为预防转移的潜在靶点。然而，很少有努力致力于开发纳米医学来改善前转移灶。本研究报告了一种用于调节前转移微环境和抑制肿瘤转移的前转移灶靶向胶束。胶束由二甲双胍和二十二碳六烯酸的油酸盐碳链衍生物自组装而成，这两种抗炎剂具有低毒性，并涂有岩藻聚糖以靶向前转移灶。所得功能化胶束（FucOMDs）表现出优异的血液循环特性和前转移部位靶向效率，抑制 CTC 与活化的内皮细胞的黏附，减轻肺血管通透性，并逆转前转移灶中关键标记蛋白的异常表达。结果，FucOMDs 可防止转移形成，并与靶向化疗联合使用时有效抑制原发肿瘤生长和转移形成。总之，这些发现提供了概念验证，即使用靶向抗炎剂调节前转移灶为抑制肿瘤转移提供了一个强大的平台和安全的临床转化选择。
