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Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy

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Abstract

Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox). We demonstrated earlier that macrophage-derived EVs loaded with PTX (EV-PTX) and Dox (EV-Dox) target cancer cells and exhibited high anticancer efficacy in a mouse model of pulmonary metastases. Herein, we report a manufacture and characterization of novel EV-based drug formulations using different loading procedures that were optimized by varying pH, temperature, and sonication conditions. Selected EV-based formulations showed a high drug loading, efficient accumulation in TNBC cells in vitro, and pronounced anti-proliferation effect. Drug-loaded EVs target TNBC in vivo, including the orthotopic mouse T11 tumors in immune competent BALB/C mice, and human MDA-MB-231 tumors in athymic nu/nu mice, and abolished tumor growth. Overall, EV-based formulations can provide a novel solution to a currently unmet clinical need and reduce the morbidity and mortality of TNBC patients.

Macrophage-derived extracellular vesicles (EVs) for targeted drug delivery to TNBC tumors. Chemotherapeutics with different water solubility (Dox or PTX, i.e. hydrophilic or hydrophobic drugs, respectively) were loaded into macrophage-derived EVs through parental cells (Dox), or into naïve EVs (Dox or PTX), and their antitumor efficacy was demonstrated in mouse orthotopic TNBC model.

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Acknowledgments

This study was supported by the Elsa U Pardee Foundation grant 17-4676 (to EVB), Eshelman Institute for Innovation grant UNC EII29-201 (to EVB), and the Russian Foundation for Basic Research (RFBR) grants 17-54-33027 and 18-29-09154 (to NLK). We would like to acknowledge the support of the UNC Nanomedicine Characterization Core Facility (http://ncore.web.unc.edu) in the EVs characterization.

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Authors and Affiliations

  1. Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Matthew J. Haney, Yuling Zhao, Natalia L. Klyachko, Alexander V. Kabanov & Elena V. Batrakova

  2. UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7362, USA

    Matthew J. Haney, Yuling Zhao, Yeon S. Jin, Samuel M. Li, Juli R. Bago, Natalia L. Klyachko, Alexander V. Kabanov & Elena V. Batrakova

  3. Deparment of Chemical Enzymology, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia

    Natalia L. Klyachko & Alexander V. Kabanov

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  1. Matthew J. Haney
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  2. Yuling Zhao
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  3. Yeon S. Jin
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  4. Samuel M. Li
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  8. Elena V. Batrakova
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Contributions

EVB wrote and edited the manuscript. MJH and YZ contributed to the production of EVs used in these experiments. MJH, YZ, YSJ, SML, and JRB carried out experiments and contributed to data analysis. NLK and AVK contributed to the overall direction and coordination of the study as well as contributions to experimental design and data analysis.

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Correspondence to Elena V. Batrakova.

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Haney, M.J., Zhao, Y., Jin, Y.S. et al. Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy. J Neuroimmune Pharmacol 15, 487–500 (2020). https://doi.org/10.1007/s11481-019-09884-9

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