Due to the abnormal tumor vasculature and dense stroma, there is limited tumor perfusion in the immunosuppressive tumor microenvironment (TME). In order to reshape tumor blood vessels and enhance the penetration of anticancer drugs into the tumor tissue, an anionic liposome nanosystem with a “sandwich” structure was prepared. The chemotherapeutic agent topotecan (TPT) was encapsulated in the lipid hydrophilic layer, and the sensitizer indocyanine green (ICG) was loaded into the hydrophobic layer. In addition, the positively charged vascular normalization drug erlotinib (ERL) was adsorbed to the outermost layer of the microenvironment. The nanosystem showed superior tumor permeability invitro/in vivo experiments compared with the ERL-treated group. The nanosystem entered the tumor through normalization of blood vessels after the action of ERL. Ultrasound treatment improves the vascular permeability, allowing the nanoparticles to penetrate blood vessels and reach tumor cells. Finally, in addition to cytotoxic effects, TPT can also down-regulate the expression of HIF-1α and so prolong the vascular normalization time. These experimental results showed that the nanosystem effectively improves the tumor microenvironment. This work indicates the great potential of vascular normalization combined with sonodynamic therapy and chemotherapy to enhance efficiency.

中文翻译：

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使用多策略协同纳米系统重塑肿瘤血管以增强药物渗透性。

由于异常的肿瘤脉管系统和密集的基质，在免疫抑制性肿瘤微环境（TME）中的肿瘤灌注有限。为了重塑肿瘤血管并增强抗癌药物对肿瘤组织的渗透，制备了具有“三明治”结构的阴离子脂质体纳米系统。将化学治疗剂拓扑替康（TPT）封装在脂质亲水层中，并将敏化剂吲哚菁绿（ICG）加载到疏水层中。此外，带正电的血管正常化药物厄洛替尼（ERL）被吸附到微环境的最外层。纳米系统在体外/体内显示出优异的肿瘤通透性实验与ERL治疗组进行比较。在ERL作用后，纳米系统通过血管正常化进入肿瘤。超声治疗可改善血管通透性，使纳米颗粒能够穿透血管并到达肿瘤细胞。最后，除细胞毒性作用外，TPT还可以下调HIF-1α的表达，从而延长血管正常化时间。这些实验结果表明，纳米系统有效地改善了肿瘤的微​​环境。这项工作表明血管正常化与声动力疗法和化学疗法相结合以提高效率的巨大潜力。