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Article

Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer

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Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
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Percuros B.V., 2333 CL Leiden, The Netherlands
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Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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Postgraduate Program in Health Science, Health Science Department, Federal University of Rio Grande do Norte (UFRN), Natal 59078 970, RN, Brazil
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Cancer and Inflammation Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte, Natal 59078 970, RN, Brazil
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Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078 970, RN, Brazil
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Electron Microscopy, Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Postgraduate Program in Functional and Structural Biology, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal 59078 970, RN, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editors: Yi Hu and Jun Chen
Pharmaceutics 2022, 14(5), 1068; https://doi.org/10.3390/pharmaceutics14051068
Received: 16 March 2022 / Revised: 25 April 2022 / Accepted: 27 April 2022 / Published: 17 May 2022
One of the main reasons for cancer’s low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the β-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-κB was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-β. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer. View Full-Text
Keywords: extracellular vesicles (EVs); M2-TAM; M1-macrophage; doxorubicin; hyaluronic acid; carvedilol; metastasis; breast cancer extracellular vesicles (EVs); M2-TAM; M1-macrophage; doxorubicin; hyaluronic acid; carvedilol; metastasis; breast cancer
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MDPI and ACS Style

Jorquera-Cordero, C.; Lara, P.; Cruz, L.J.; Schomann, T.; van Hofslot, A.; de Carvalho, T.G.; Guedes, P.M.D.M.; Creemers, L.; Koning, R.I.; Chan, A.B.; de Araujo Junior, R.F. Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer. Pharmaceutics 2022, 14, 1068. https://doi.org/10.3390/pharmaceutics14051068

AMA Style

Jorquera-Cordero C, Lara P, Cruz LJ, Schomann T, van Hofslot A, de Carvalho TG, Guedes PMDM, Creemers L, Koning RI, Chan AB, de Araujo Junior RF. Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer. Pharmaceutics. 2022; 14(5):1068. https://doi.org/10.3390/pharmaceutics14051068

Chicago/Turabian Style

Jorquera-Cordero, Carla, Pablo Lara, Luis J. Cruz, Timo Schomann, Anna van Hofslot, Thaís Gomes de Carvalho, Paulo Marcos Da Matta Guedes, Laura Creemers, Roman I. Koning, Alan B. Chan, and Raimundo Fernandes de Araujo Junior. 2022. "Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer" Pharmaceutics 14, no. 5: 1068. https://doi.org/10.3390/pharmaceutics14051068

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