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

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / blood
  • Anti-Inflammatory Agents / therapeutic use
  • Docosahexaenoic Acids / administration & dosage*
  • Docosahexaenoic Acids / blood
  • Docosahexaenoic Acids / therapeutic use
  • Lung / blood supply
  • Metformin / administration & dosage*
  • Metformin / blood
  • Metformin / therapeutic use
  • Mice
  • Micelles
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / prevention & control*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neoplastic Cells, Circulating / drug effects
  • Neoplastic Cells, Circulating / pathology
  • Rats, Sprague-Dawley
  • Tumor Microenvironment / drug effects*


  • Anti-Inflammatory Agents
  • Micelles
  • Docosahexaenoic Acids
  • Metformin