CCR2-targeted Micelles for Anti-cancer Peptide Delivery and Immune Stimulation

Overview

Journal J Control Release

Specialty Pharmacology

Date 2020 Oct 4

PMID 33011241

Citations 18

Authors

Noah Trac

Leng-Ying Chen

Ailin Zhang

Chun-Peng Liao

Christopher Poon

Jonathan Wang

Yuta Ando

Johan Joo

Carolina Garri

Keyue Shen

Kian Kani

Mitchell E Gross

Eun Ji Chung

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis.

Liu X, Ren Z, Tan C, Nunez-Santana F, Kelly M, Yan Y J Clin Invest. 2024; 134(22).

PMID: 39545417 PMC: 11563681. DOI: 10.1172/JCI179527.

Oral delivery of nanomedicine for genetic kidney disease.

Huang Y, Wang J, Mancino V, Pham J, OGrady C, Li H PNAS Nexus. 2024; 3(5):pgae187.

PMID: 38807632 PMC: 11131023. DOI: 10.1093/pnasnexus/pgae187.

New insights into the role of macrophages in cancer immunotherapy.

Zhou L, Zhao T, Zhang R, Chen C, Li J Front Immunol. 2024; 15:1381225.

PMID: 38605951 PMC: 11007015. DOI: 10.3389/fimmu.2024.1381225.

Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.

Cheng L, Yu J, Hao T, Wang W, Wei M, Li G Pharmaceutics. 2023; 15(11).

PMID: 38004600 PMC: 10675796. DOI: 10.3390/pharmaceutics15112622.

Nanoparticle-based drug delivery systems to enhance cancer immunotherapy in solid tumors.

Zhang J, Wang S, Zhang D, He X, Wang X, Han H Front Immunol. 2023; 14:1230893.

PMID: 37600822 PMC: 10435760. DOI: 10.3389/fimmu.2023.1230893.

References

Guo Q, Jin Z, Yuan Y, Liu R, Xu T, Wei H . New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy. J Immunol Res. 2016; 2016:9720912. PMC: 5128713. DOI: 10.1155/2016/9720912. View

Chin D, Poon C, Trac N, Wang J, Cook J, Joo J . Collagenase-Cleavable Peptide Amphiphile Micelles as a Novel Theranostic Strategy in Atherosclerosis. Adv Ther (Weinh). 2021; 3(3). PMC: 8294202. DOI: 10.1002/adtp.201900196. View

Laniado M, Lalani E, Fraser S, Grimes J, Bhangal G, Djamgoz M . Expression and functional analysis of voltage-activated Na+ channels in human prostate cancer cell lines and their contribution to invasion in vitro. Am J Pathol. 1997; 150(4):1213-21. PMC: 1858184. View

Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang C . PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer. Lung Cancer. 2019; 136:136-144. DOI: 10.1016/j.lungcan.2019.08.023. View

Xu-Monette Z, Zhang M, Li J, Young K . PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?. Front Immunol. 2017; 8:1597. PMC: 5723106. DOI: 10.3389/fimmu.2017.01597. View

Li M, Li H, Meng Y, Wang X, Zhu X, Mei J . Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway. Fertil Steril. 2012; 97(4):919-29. DOI: 10.1016/j.fertnstert.2011.12.049. View

Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J . Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014; 5:75. PMC: 3942647. DOI: 10.3389/fphys.2014.00075. View

Franklin R, Liao W, Sarkar A, Kim M, Bivona M, Liu K . The cellular and molecular origin of tumor-associated macrophages. Science. 2014; 344(6186):921-5. PMC: 4204732. DOI: 10.1126/science.1252510. View

Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T . Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013; 13(1):89. PMC: 3849184. DOI: 10.1186/1475-2867-13-89. View

10.

Huang Y, Shi Y, Wang Q, Qi T, Fu X, Gu Z . Enzyme responsiveness enhances the specificity and effectiveness of nanoparticles for the treatment of B16F10 melanoma. J Control Release. 2019; 316:208-222. DOI: 10.1016/j.jconrel.2019.10.052. View

11.

Moreira D, Howard L, Sourbeer K, Amarasekara H, Chow L, Cockrell D . Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2016; 15(1):60-66.e2. PMC: 5536956. DOI: 10.1016/j.clgc.2016.08.018. View

12.

Poon C, Chowdhuri S, Kuo C, Fang Y, Alenghat F, Hyatt D . Protein Mimetic and Anticancer Properties of Monocyte-Targeting Peptide Amphiphile Micelles. ACS Biomater Sci Eng. 2018; 3(12):3273-3282. PMC: 5749269. DOI: 10.1021/acsbiomaterials.7b00600. View

13.

Fang W, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N . CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012; 287(43):36593-608. PMC: 3476325. DOI: 10.1074/jbc.M112.365999. View

14.

Chin D, Wang J, Mel de Fontenay M, Plotkin A, Magee G, Chung E . Hydroxyapatite-binding micelles for the detection of vascular calcification in atherosclerosis. J Mater Chem B. 2019; 7(41):6449-6457. PMC: 6812598. DOI: 10.1039/c9tb01918a. View

15.

Chung E, Cheng Y, Morshed R, Nord K, Han Y, Wegscheid M . Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma. Biomaterials. 2013; 35(4):1249-56. PMC: 3880134. DOI: 10.1016/j.biomaterials.2013.10.064. View

16.

Burke A, Ali H, OConnell E, Sullivan F, Glynn S . Sensitivity Profiles of Human Prostate Cancer Cell Lines to an 80 Kinase Inhibitor Panel. Anticancer Res. 2016; 36(2):633-41. View

17.

Lim S, Yuzhalin A, Gordon-Weeks A, Muschel R . Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016; 7(19):28697-710. PMC: 5053756. DOI: 10.18632/oncotarget.7376. View

18.

Korangath P, Barnett J, Sharma A, Henderson E, Stewart J, Yu S . Nanoparticle interactions with immune cells dominate tumor retention and induce T cell-mediated tumor suppression in models of breast cancer. Sci Adv. 2020; 6(13):eaay1601. PMC: 7096167. DOI: 10.1126/sciadv.aay1601. View

19.

Lee C, Jeong H, Bae Y, Shin K, Kang S, Kim H . Targeting of M2-like tumor-associated macrophages with a melittin-based pro-apoptotic peptide. J Immunother Cancer. 2019; 7(1):147. PMC: 6555931. DOI: 10.1186/s40425-019-0610-4. View

20.

Wang H, Zhang Q, Kong H, Zeng Y, Hao M, Yu T . Monocyte chemotactic protein-1 expression as a prognosic biomarker in patients with solid tumor: a meta analysis. Int J Clin Exp Pathol. 2014; 7(7):3876-86. PMC: 4128999. View