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

正常化肿瘤微环境（TME），即除癌细胞之外的实体瘤的组分，增加氧气和药物递送，从而使其成为可与常规化学、放射和免疫疗法组合的治疗策略。正常化肿瘤血管增加了肿瘤内氧气和药物递送系统（DDS）的运输，直径高达30纳米（nm），而癌症相关成纤维细胞（CAF）和细胞外基质（ECM）的正常化增加了DDS的递送，直径至少为120 nm。目前尚不清楚是否存在一种能同时进行两种类型正常化的药物，以及这种药物是否会以大小依赖性方式影响DDS。我们假设存在DDS的大小窗口，其受益于TME正常化并降低血液学毒性。化疗后给予患者地塞米松等类固醇以控制副作用，但此类药物使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），以通过TME正常化来加强现有治疗。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正常化并降低了肿瘤的硬度，这促进了纳米药物在肿瘤中的积累。因此，Pre-TX DEX提高了负载铂类药物的聚合物胶束在乳腺肿瘤及其肺转移中的功效。

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.