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Goldberg, Michael

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Goldberg

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Michael

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Goldberg, Michael

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2014 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.dc2ba541-19c5-4f38-a6a8-59a5bcbbc4c4

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    Silencing HoxA1 by Intraductal Injection of siRNA Lipidoid Nanoparticles Prevents Mammary Tumor Progression in Mice
    (American Association for the Advancement of Science (AAAS), 2014) Brock, Amy Monique Lepre; Krause, Silva; Li, Hu; Kowalski, Marek; Goldberg, Michael; Collins, James; Ingber, Donald
    With advances in screening, the incidence of detection of premalignant breast lesions has increased in recent decades; however, treatment options remain limited to surveillance or surgical removal by lumpectomy or mastectomy. We hypothesized that disease progression could be blocked by RNA interference (RNAi) therapy and set out to develop a targeted therapeutic delivery strategy. Using computational gene network modeling, we identified HoxA1 as a putative driver of early mammary cancer progression in transgenic C3(1)-SV40TAg mice. Silencing this gene in cultured mouse or human mammary tumor spheroids resulted in increased acinar lumen formation, reduced tumor cell proliferation, and restoration of normal epithelial polarization. When the HoxA1 gene was silenced in vivo via intraductal delivery of nanoparticle-formulated small interfering RNA (siRNA) through the nipple of transgenic mice with early-stage disease, mammary epithelial cell proliferation rates were suppressed, loss of estrogen and progesterone receptor expression was prevented, and tumor incidence was reduced by 75%. This approach that leverages new advances in systems biology and nanotechnology offers a novel noninvasive strategy to block breast cancer progression through targeted silencing of critical genes directly within the mammary epithelium.
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    T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity
    (Nature Publishing Group UK, 2017) Schmid, Daniela; Park, Chun Gwon; Hartl, Christina A.; Subedi, Nikita; Cartwright, Adam N.; Puerto, Regina Bou; Zheng, Yiran; Maiarana, James; Freeman, Gordon J.; Wucherpfennig, Kai W.; Irvine, Darrell J.; Goldberg, Michael
    Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively into tumors. We describe antibody-targeted nanoparticles that bind to CD8+ T cells in the blood, lymphoid tissues, and tumors of mice. PD-1+ T cells are successfully targeted in the circulation and tumor. The delivery of an inhibitor of TGFβ signaling to PD-1-expressing cells extends the survival of tumor-bearing mice, whereas free drugs have no effect at such doses. This modular platform also enables PD-1-targeted delivery of a TLR7/8 agonist to the tumor microenvironment, increasing the proportion of tumor-infiltrating CD8+ T cells and sensitizing tumors to subsequent anti-PD-1. Targeted delivery of immunotherapy to defined subsets of endogenous leukocytes may be superior to administration of free drugs.