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Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization.
Leonard, Fransisca; Curtis, Louis T; Hamed, Ahmed R; Zhang, Carolyn; Chau, Eric; Sieving, Devon; Godin, Biana; Frieboes, Hermann B.
Afiliación
  • Leonard F; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
  • Curtis LT; Department of Bioengineering, University of Louisville, Louisville, KY, USA.
  • Hamed AR; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
  • Zhang C; Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt.
  • Chau E; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
  • Sieving D; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
  • Godin B; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
  • Frieboes HB; Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA. bgodin@houstonmethodist.org.
Cancer Immunol Immunother ; 69(5): 731-744, 2020 May.
Article en En | MEDLINE | ID: mdl-32036448
ABSTRACT
Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion of M1, pro-inflammatory/growth-inhibiting, to M2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization to M1 are a novel approach that harnesses the immune system to enhance therapeutic outcomes, including chemotherapy. We recently found that nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel (MSV-nab-PTX) promotes macrophage polarization towards M1 in breast cancer liver metastases (BCLM). However, it remains unclear to what extent tumor regression can be maximized based on modulation of the macrophage phenotype, especially for poorly perfused tumors such as BCLM. Here, for the first time, a CRISPR system is employed to permanently modulate macrophage polarization in a controlled in vitro setting. This enables the design of 3D co-culture experiments mimicking the BCLM hypovascularized environment with various ratios of polarized macrophages. We implement a mathematical framework to evaluate nanoparticle-mediated chemotherapy in conjunction with TAM polarization. The response is predicted to be not linearly dependent on the M1M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety of M1M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of both M1 and M2. Experimental results with the CRISPR system confirm this model-driven hypothesis. Altogether, this study indicates that response to nanoparticle-mediated chemotherapy targeting poorly perfused tumors may benefit from a fine-tuned M1M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Paclitaxel Unido a Albúmina / Neoplasias Hepáticas / Activación de Macrófagos / Macrófagos / Modelos Biológicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Immunol Immunother Asunto de la revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Paclitaxel Unido a Albúmina / Neoplasias Hepáticas / Activación de Macrófagos / Macrófagos / Modelos Biológicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Immunol Immunother Asunto de la revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos