Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment
Date
2019Author
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
ISSN
1936-086XSource
ACS nanoVolume
13Issue
6Pages
6396-6408Google Scholar check
Metadata
Show full item recordAbstract
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.