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    Nanotherapy delivery of c-myc inhibitor targets protumor macrophages and preserves antitumor macrophages in breast cancer

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    Author
    Esser, A.K.
    Ross, M.H.
    Fontana, F.
    Su, X.
    Gabay, A.
    Fox, G.C.
    Xu, Y.
    Xiang, J.
    Schmieder, A.H.
    Yang, X.
    Cui, G.
    Scott, M.
    Achilefu, S.
    Chauhan, J.
    Fletcher, S.
    Lanza, G.M.
    Weilbaecher, K.N.
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    Date
    2020
    Journal
    Theranostics
    Publisher
    Ivyspring International Publisher
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.7150/thno.44523
    Abstract
    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. Copyright The author(s).
    Sponsors
    National Institutes of Health, NIH CA216840, CA199092; U.S. Department of Defense, DOD W81XWH-16-1-0286
    Keyword
    Breast cancer
    Drug delivery
    Macrophages
    MYC
    Nanoparticles
    β3 integrin
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087883368&doi=10.7150%2fthno.44523&partnerID=40&md5=beed2366ba92f8e7e474b0765277a110; http://hdl.handle.net/10713/13380
    ae974a485f413a2113503eed53cd6c53
    10.7150/thno.44523
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