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Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment

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journal contribution
posted on 12.06.2019, 13:58 by John D. Martin, Myrofora Panagi, Chenyu Wang, Thahomina T. Khan, Margaret R. Martin, Chrysovalantis Voutouri, Kazuko Toh, Panagiotis Papageorgis, Fotios Mpekris, Christiana Polydorou, Genichiro Ishii, Shinichiro Takahashi, Naoto Gotohda, Toshiyuki Suzuki, Matthew E. Wilhelm, Vinicio Alejandro Melo, Sabina Quader, Jumpei Norimatsu, Ryan M. Lanning, Motohiro Kojima, Matthew David Stuber, Triantafyllos Stylianopoulos, Kazunori Kataoka, Horacio Cabral
Dexamethasone is a glucocorticoid steroid with anti-inflammatory properties used to treat many diseases, including cancer, in which it helps manage various side effects of chemo-, radio-, and immunotherapies. Here, we investigate the tumor microenvironment (TME)-normalizing effects of dexamethasone in metastatic murine breast cancer (BC). Dexamethasone normalizes vessels and the extracellular matrix, thereby reducing interstitial fluid pressure, tissue stiffness, and solid stress. In turn, the penetration of 13 and 32 nm dextrans, which represent nanocarriers (NCs), is increased. A mechanistic model of fluid and macromolecule transport in tumors predicts that dexamethasone increases NC penetration by increasing interstitial hydraulic conductivity without significantly reducing the effective pore diameter of the vessel wall. Also, dexamethasone increases the tumor accumulation and efficacy of ∼30 nm polymeric micelles containing cisplatin (CDDP/m) against murine models of primary BC and spontaneous BC lung metastasis, which also feature a TME with abnormal mechanical properties. These results suggest that pretreatment with dexamethasone before NC administration could increase efficacy against primary tumors and metastases.