期刊
JOURNAL OF CONTROLLED RELEASE
卷 329, 期 -, 页码 614-623出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.09.054
关键词
Micelle; CCR2; Peptide; Cancer; Tumor-associated macrophage
资金
- Women in Science and Engineering (WiSE) Gabilan Assistant Professorship
- Ming Hsieh Institute for Research on Engineering-Medicine for Cancer
- L. K. Whittier Foundation
- National Heart, Lung, and Blood Institute (NHLBI) [R00HL124279]
- NIH New Innovator Award [DP2-DK121328]
- University of Southern California
Signaling via MCP-1/CCR2 axis plays a crucial role in promoting cancer progression, while KLAK-MCP-1 micelles inhibit tumor growth by targeting CCR2 and altering the composition of cells in the tumor microenvironment.
Signaling between the C-C chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized. In vitro, KLAK-MCP-1 micelles were observed to bind and induce cytotoxicity to cancer cells through interaction with CCR2. In vivo, KLAK-MCP-1 micelles inhibited tumor growth (34 +/- 11%) in a subcutaneous B16F10 murine melanoma model despite minimal tumor accumulation upon intravenous injection. Tumors treated with KLAK-MCP1 demonstrated reduced intratumor CCR2 expression and altered infiltration of TAMs and CTLs as evidenced by immunohistochemical and flow cytometric analysis. These studies highlight the potential application of CCR2-targeted nanotherapeutic micelles in cancer treatment.
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