纳米分区递送重塑肿瘤代谢稳态促进经典疗法介导的肿瘤血管正常化研究

Tumor vascular normalization treatment could overcome liver cancer treatment barriers in clinic induced by microvascular invasion through restoring tumor vascular structure and transport functions. However, combination therapy of classical anti-angiogenic therapy and metronomic chemotherapy-induced tumor vascular normalization treatment failed to induce branched and sprouted vessels to construct in normalized way. Remodeling tumor metabolic homeostasis by inhibiting the glycolysis of tumor endothelial cells (ECs) and tumor cells could overcome this limitation and facilitate to build more extensive tumor normalized vascular networks. Accordingly, tumor cell targeting therapy nanocomposite drug (LP-miR) that could combine anti-VEGF therapy, metronomic chemotherapy and glycolytic inhibition and caveolin-mediated ECs targeting glycolytic inhibitory nanocomposite drug (PP-miR) were developed respectively in this study. Furthermore, partition delivery strategy relied on metronomic administration of PP-miR and LP-miR mixed nano-formulations was employed to remodel tumor metabolic homeostasis and promote classical therapies-mediated tumor vascular normalization treatment. This study would reveal the synergistic mechanisms of tumor vascular normalization combination therapy based on anti-angiogenic therapy, metronomic chemotherapy and tumor metabolic homeostasis remodeling, providing theoretical and experimental basis for the design and development of new targeted nano-formulations.

肿瘤血管正常化治疗能够通过恢复异常肿瘤血管的结构及运输功能针对性攻克肝癌微血管侵犯造成的临床治疗困境。在基于抗血管生成治疗和节拍化疗的肿瘤血管正常化经典疗法基础上，通过抑制肿瘤血管内皮细胞和肿瘤细胞糖酵解以重塑肿瘤代谢稳态，诱导分支化血管和萌芽血管的正常化组构，能够弥补经典疗法的干预盲区，构建更为完整广泛的正常化肿瘤血管脉络。因此，本项目设计构建一种肿瘤血管内皮细胞和肿瘤细胞分区靶向递送的双单元纳米复合药物，包括小窝蛋白介导内皮细胞靶向基因药物代谢调节纳米复合药物PP-miR，以及针对肿瘤细胞进行抗VEGF治疗、节拍化疗和代谢干预协同调控的基因药物与化学药物共递送纳米复合药物LP-miR，以实现上述增强经典疗法介导的促肿瘤血管正常化疗效的目标。本项目将揭示抗血管生成治疗、节拍化疗和肿瘤代谢稳态重塑协同诱导肿瘤血管正常化的作用机制，为新型靶向纳米制剂的设计与发展提供理论与实验基础。

当前，基于抗血管生成治疗和节拍化疗的肿瘤血管正常化经典疗法可受来自肿瘤肿瘤微环境的异细胞代谢串扰介导的拮抗，导致血管正常化时间窗短、血管正常化程度低、分支化血管正常化治疗缺乏等。基于此，本项目设计构建肿瘤血管内皮细胞和肿瘤细胞分区靶向递送的双单元纳米复合药物Mix，包括小窝蛋白介导内皮细胞靶向基因药物代谢调节纳米复合药物PP-miR，以及针对肿瘤细胞进行抗VEGF治疗、节拍化疗和代谢干预协同调控的基因药物与化学药物共递送纳米复合药物LP-miR，以针对性改善经典疗法介导的促肿瘤血管正常化疗效。体内外靶向性研究结果显示PP-miR及LP-miR分别对血管内皮细胞和肿瘤细胞具有高度的选择性分布特征，可有效实现针对肿瘤血管内皮细胞和肿瘤细胞的分区分靶点递药。此外，以微血管高度侵犯的肝癌为模型，在Mix治疗后，肿瘤血管正常化时间窗显着延长了至少约 40%，周细胞覆盖率也提高了约53%至120%, 抑瘤率可达82%以上。此外，由于肿瘤细胞和内皮细胞的双重调控产生的代谢共生阻断作用，肿瘤血管的分形维数从1.266显着降低到0.995,有效改善了肿瘤血管萌芽于分支化严重的情况。同时，经Mix的代谢共生阻断治疗后，全基因组分析结果显示与促血管生成、肿瘤细胞和内皮细胞增殖和迁移以及肿瘤免疫调节相关的 24 个基因已被广泛调节，产生了肿瘤微环境泛调节效果，可有效拮抗由于肿瘤微环境代谢串扰引起的促血管生成、免疫抑制、细胞增殖与迁移等多通路的应激激活，产生持续且广泛的促血管正常化及抗肿瘤治疗治疗作用。本项目的研究结果为从代谢调控角度解决目前临床促血管正常化治疗的瓶颈问题提供了新的见解的理论支撑、为基于肿瘤血管的靶向治疗设计提供了新的思路。