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

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.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…Reduction of stroma components such as CAFs, collagen, and hyaluronan decreases the elastic modulus and alleviates intratumoral stresses, resulting in a "mechanically softer" tumor (28,29,53). We investigated the effect of varying the tumor elastic modulus within the range of experimentally measured values (28,29,53,54) on the efficacy of immunotherapy. Low values of the elastic modulus resulted in improved tumor perfusion, increased T-cell infiltration and polarization of TAMs from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype, and thus increased cancer cell killing (SI Appendix, Figs.…”

Evaluation of cytotoxic T lymphocyte-mediated anticancer response against tumor interstitium-simulating physical barriers

“…Strategies to improve the delivery of blood-borne therapeutic agents against tumor, including the anticancer immune cells, has emerged based on decompression of the tumor vessels by depletion of the collagen or hyaluronan, or increase of the flow rate of tumor vessels by normalizing the immature phenotype of the vascular network 8 , 10 . For example, improvement of tumor perfusion and consequently the efficacy of chemotherapy by stress alleviation and vascular normalization in solid tumors has been shown in vivo using losartan 12 , tranilast 13 , dexamethasone 14 , pirfenidone 15 , vismodegib 16 , metformin 17 , enzymes degrading collagen or hyaluronan 15 , 18 , 19 , and antiangiogenic agents for vascular normalization, such as bevacizumab 20 , an antibody against vascular endothelial growth factor (VEGF), and cediranib 21 , an inhibitor of VEGF receptor tyrosine kinase. In particular, scheduling lower-dose application of antibody against VEGF receptor 2 has been shown to enhance the infiltration of CTLs in breast tumor 22 .…”

“…Tranilast is a clinically approved anti-allergic drug but also effective in suppression of collagen synthesis partially via inhibition of TGF-β 1 13,23 . Dexamethasone, a glucocorticoid steroid widely used in a variety of diseases, inhibits hyaluronan expression in tumor and normalize tumor vessel phenotype by blocking angiogenesis signaling 14 . Pirfenidone downregulates collagen production in fibroblast mainly via inhibition of TGF-β 1 signaling and is clinically approved for treatment of idiopathic pulmonary fibrosis 24 .…”

Anti-Metastatic Effects on Melanoma via Intravenous Administration of Anti-NF-κB siRNA Complexed with Functional Peptide-Modified Nano-Micelles

“…While there have been good advances in clinical non-invasive modalities such as immunotherapies like Nivolumab (Opdivo, Ono Pharmaceutical Co., Ltd., Osaka, Japan) or Ipilimumab (Yervoy, Bristol-Myers Squibb, New York, NY, USA), and other antibody-based medicines, the therapeutic efficacy and patient compatibility are quite limited and with some severe side effects [6,7]. Therefore, the epochal method of controlling metastasis has been the focus of biological and clinical cancer research [7][8][9] strategies that are urgently needed. Indeed, the low efficacy of current therapies on cancer metastasis is the result of poor drug delivery of current therapeutic agents to metastatic sites [10,11].…”