Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.

Autor:	Esser AK; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Ross MH; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Fontana F; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Su X; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Gabay A; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Fox GC; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Xu Y; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Xiang J; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA., Schmieder AH; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Yang X; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Cui G; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Scott M; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Achilefu S; Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Chauhan J; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA., Fletcher S; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA., Lanza GM; Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Weilbaecher KN; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2020 Jun 12; Vol. 10 (17), pp. 7510-7526. Date of Electronic Publication: 2020 Jun 12 (Print Publication: 2020).
DOI:	10.7150/thno.44523
Abstrakt:	Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages in vitro and in vivo where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models. Methods: In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin β3, and in vivo targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles. Results: We observed that rhodamine, delivered by αvβ3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvβ3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin β3 knock out tumors (PyMT-Bo1 β3KO) were treated with αvβ3-NP or αvβ3-MI3-PD NP. M2 macrophages were significantly reduced with αvβ3-MI3-PD nanoparticle therapy but not αvβ3-NP treatment. Conclusion: These data suggest αvβ3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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