Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment.
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.
['Martin|John D|JD|0000-0002-9828-8203', 'Panagi|Myrofora|M|', 'Wang|Chenyu|C|', 'Khan|Thahomina T|TT|', 'Martin|Margaret R|MR|', 'Voutouri|Chrysovalantis|C|', 'Toh|Kazuko|K|', 'Papageorgis|Panagiotis|P|', 'Mpekris|Fotios|F|', 'Polydorou|Christiana|C|', 'Ishii|Genichiro|G|', 'Takahashi|Shinichiro|S|', 'Gotohda|Naoto|N|', 'Suzuki|Toshiyuki|T|', 'Wilhelm|Matthew E|ME|', 'Melo|Vinicio Alejandro|VA|', 'Quader|Sabina|S|', 'Norimatsu|Jumpei|J|', 'Lanning|Ryan M|RM|', 'Kojima|Motohiro|M|', 'Stuber|Matthew David|MD|0000-0001-8435-9552', 'Stylianopoulos|Triantafyllos|T|', 'Kataoka|Kazunori|K|0000-0002-8591-413X', 'Cabral|Horacio|H|0000-0002-4030-2631']
D000818:Animals D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D045744:Cell Line, Tumor D002945:Cisplatin D003907:Dexamethasone D004337:Drug Carriers D005260:Female D008325:Mammary Neoplasms, Experimental D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D008823:Micelles D053758:Nanoparticles D009362:Neoplasm Metastasis D059016:Tumor Microenvironment
normalization tumor microenvironment penetration polymeric micelle metastasis