Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, United States.
Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States.
J Control Release. 2021 Jan 10;329:614-623. doi: 10.1016/j.jconrel.2020.09.054. Epub 2020 Oct 1.
Signaling between the CC 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.
CC 趋化因子受体 2（CCR2）与其配体单核细胞趋化蛋白-1（MCP-1）之间的信号传导通过直接刺激肿瘤细胞增殖和下调凋亡蛋白的表达来促进癌症进展。此外，MCP-1/CCR2 信号轴驱动循环单核细胞迁移到肿瘤微环境中，在那里它们成熟为肿瘤相关巨噬细胞（TAMs），通过诱导血管生成、组织重塑和抑制细胞毒性 T 淋巴细胞（CTL）反应来促进疾病进展。为了同时破坏 MCP-1/CCR2 信号传导并将 CCR2 表达的癌细胞作为药物输送的靶点，合成了由 CCR2 靶向肽序列（MCP-1 肽）和凋亡 KLAKLAK 肽组成的 KLAK-MCP-1 胶束。在体外，观察到 KLAK-MCP-1 胶束通过与 CCR2 的相互作用结合并诱导癌细胞产生细胞毒性。在体内，尽管静脉注射后肿瘤积累很少，但 KLAK-MCP-1 胶束仍能抑制皮下 B16F10 小鼠黑色素瘤模型中的肿瘤生长（34±11%）。用 KLAK-MCP1 治疗的肿瘤表现出肿瘤内 CCR2 表达减少和 TAMs 和 CTLs 浸润改变，这可以通过免疫组织化学和流式细胞术分析得到证明。这些研究强调了 CCR2 靶向纳米治疗胶束在癌症治疗中的潜在应用。
