Overcoming physical barriers arising in the drug delivery of nanomedicines to lung metastases

正常化肿瘤微环境（TME），即除癌细胞外实体肿瘤的组成部分，增加氧气和药物输送，从而使其成为与传统化疗、放射和免疫治疗相结合的治疗策略。肿瘤血管正常化可增加直径达30纳米（nm）的肿瘤内氧转运和药物输送系统（DDS），而癌症相关成纤维细胞（CAFs）和细胞外基质（ECM）的正常化可增加直径达至少120纳米的DDS输送。目前尚不清楚是否存在能够完成这两种规范化的代理，以及这种代理是否会以依赖于大小的方式影响DDS。我们假设存在一个DDS的大小窗口，从TME正常化中获益并降低血液学毒性。化疗后给患者使用类固醇如地塞米松来控制副作用，但这些药物使TME正常化的潜力尚不清楚。在这里，我们建议将地塞米松重新用于化疗前计划（Pre-TX DEX），通过TME正常化来增强现有治疗。我们阐明了在Pre-TX DEX治疗期间DDS递送的大小依赖性变化。我们发现，Pre-TX DEX使TEM归一化，降低了肿瘤的刚度，促进了纳米药物在肿瘤中的积累。因此，Pre-TX DEX提高了铂类药物聚合物胶束在乳腺肿瘤及其肺转移中的疗效。

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.