State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Stability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Biomater Sci. 2019 Feb 26;7(3):1147-1160. doi: 10.1039/c8bm01350k.
Tumor vascular normalization theory opened the door for the rational use of antiangiogenic agents and chemotherapeutics. However, efforts to seize the normalization window have constrained the development of vascular normalization therapy in clinical applications owing to the lack of circulating biomarkers and the tedious dosage regimes. Applying "Occam's Razor" to therapeutic design inspired us to construct an effective and simple tumor vascular normalization prompting strategy. Herein, we developed tumor vessel normalization prompting nanomedicine lipid derivative conjugates (LGCs) made of anti-angiogenic agents with low molecular weight heparin (LMWH) and gemcitabine (Gem). This treatment exploits the complementary action of anti-vascular endothelial growth factor (VEGF) therapy and metronomic chemotherapy (MET) to strengthen the tumor vascular normalization effect. Furthermore, by loading cytotoxic drugs, such as paclitaxel (PTX), into the LGCs we constructed a "nano-community" to simultaneously restore the tumor vasculature and deliver the loaded drugs. Accordingly, improved drug delivery and therapeutic outcomes were achieved with no need to identify the precise time of the normalization window. Overall, our studies suggest that tumor vessel normalization therapy and nanomedicine design could be combined in one entity, using two waves of normalization strategies to achieve optimal chemo drug delivery into solid tumors.
肿瘤血管正常化理论为合理应用抗血管生成药物和化疗药物开辟了道路。然而，由于缺乏循环生物标志物和繁琐的剂量方案，努力抓住正常化窗口限制了血管正常化治疗在临床应用中的发展。将“奥卡姆剃刀”应用于治疗设计启发我们构建了一种有效且简单的肿瘤血管正常化促进策略。在这里，我们开发了由低分子量肝素（LMWH）和吉西他滨（Gem）与抗血管内皮生长因子（VEGF）药物组成的肿瘤血管正常化促进纳米医学脂质衍生物缀合物（LGCs）。这种治疗方法利用抗血管生成治疗和节拍化疗（MET）的互补作用来增强肿瘤血管正常化作用。此外，通过将紫杉醇（PTX）等细胞毒性药物装载到我们构建的 LGCs 中，我们构建了一个“纳米群落”，同时恢复肿瘤血管并输送负载药物。因此，无需确定正常化窗口的确切时间即可实现改善的药物递送和治疗效果。总的来说，我们的研究表明，肿瘤血管正常化治疗和纳米医学设计可以结合在一个实体中，使用两波正常化策略将最佳化疗药物递送到实体瘤中。
