| 研究実績の概要 |
Normalizing the tumor microenvironment (TME), i.e. components of solid tumors other than cancer cells, increases oxygen and drug delivery thereby making it a treatment strategy combinable with conventional chemo-, radio-, and immune therapies. Normalizing tumor vessels increases intratumor transport of oxygen and drug delivery systems (DDS) up to 30 nanometers (nm) in diameter, while normalization of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) increases delivery of DDS up to at least 120nm. The existence of an agent that does both types of normalization and whether such an agent would affect DDS in a size-dependent manner is unknown. We hypothesize there is a size-window of DDS that benefits from TME normalization and reduces hematological toxicity. Steroids like dexamethasone are given to patients post-chemotherapy to manage side effects, yet the potential of such drugs to normalize the TME is unclear. Here, we propose repurposing dexamethasone to a pre-chemotherapy schedule (Pre-TX DEX) to potentiate existing treatments through TME normalization. We elucidated the size-dependent changes of DDS delivery during Pre-TX DEX treatment. We found that Pre-TX DEX normalized the TEM and reduced the stiffness of the tumors, which promoted the enhanced accumulation of nanomedicines in tumors. Thus, Pre-TX DEX improved the efficacy of polymeric micelles loaded with platinum drugs in breast tumor and their lung metastasis.
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