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Nano Lett. 2019 Jun 12;19(6):3548-3562. doi: 10.1021/acs.nanolett.9b00495. Epub 2019 Apr 30.

Metformin and Docosahexaenoic Acid Hybrid Micelles for Premetastatic Niche Modulation and Tumor Metastasis Suppression.

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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.
Department of Pharmacy, Shanghai Pudong Hospital , Fudan University , 2800 Gongwei Road , Shanghai 201399 , PR China.


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.


Premetastatic niche; docosahexaenoic acid; metastasis suppression; metformin; self-assembly micelles; targeted drug delivery

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