1. Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment
- Author
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Martin, John D., Panagi, Myrofora, Wang, Chenyu, Khan, Thahomina T., Martin, Margaret R., Voutouri, Chrysovalantis, Toh, Kazuko, Papageorgis, Panagiotis, Mpekris, Fotios, Polydorou, Christiana, Ishii, Genichiro, Takahashi, Shinichiro, Gotohda, Naoto, Suzuki, Toshiyuki, Wilhelm, Matthew E., Melo, Vinicio Alejandro, Quader, Sabina, Norimatsu, Jumpei, Lanning, Ryan M., Kojima, Motohiro, Stuber, Matthew David, Stylianopoulos, Triantafyllos, Kataoka, Kazunori, Cabral, Horacio, Stylianopoulos, Triantafyllos [0000-0002-3093-1696], Mpekris, Fotios [0000-0002-7125-4062], Papageorgis, Panagiotis [0000-0002-7595-5616], and Voutouri, Chrysovalantis [0000-0003-3172-9489]
- Subjects
medicine.medical_treatment ,General Physics and Astronomy ,Mice, Nude ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Dexamethasone ,Steroid ,Extracellular matrix ,Mice ,Breast cancer ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Tumor Microenvironment ,Animals ,General Materials Science ,Neoplasm Metastasis ,Micelles ,Cisplatin ,Tumor microenvironment ,Drug Carriers ,Mice, Inbred BALB C ,Chemistry ,General Engineering ,Mammary Neoplasms, Experimental ,021001 nanoscience & nanotechnology ,medicine.disease ,Metastatic breast cancer ,3. Good health ,0104 chemical sciences ,Cancer research ,Nanoparticles ,Female ,Nanocarriers ,0210 nano-technology ,medicine.drug - Abstract
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. 13 6 6396 6408
- Published
- 2019