Song Yang, Guo Xiangfu, Fu Jijun, He Bing, Wang Xueqing, Dai Wenbing, Zhang Hua, Zhang Qiang
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Guangzhou Medical University, School of Pharmaceutical Sciences, Guangzhou 511436, China.
Acta Pharm Sin B. 2020 Nov;10(11):2183-2197. doi: 10.1016/j.apsb.2020.07.012. Epub 2020 Jul 25.
The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors, and the related targeting nanomedicines are rarely reported. The existence of fluidic shear stress in blood circulation seems not favorable for the binding of ligand modified nanodrugs with their target receptor. Namely, the binding feature is very essential in this case. Herein, we utilized HSPC, PEG-DSPE, cholesterol and two v3 ligands (RGDm7 and DT4) with different binding rates to build dual-targeting nanovesicles, in an effort to achieve a "fast-binding/slow-unbinding" function. It was demonstrated that the dual-targeting nanovesicles actualized efficient cellular uptake and antitumor effect both for static and dynamic tumor cells. Besides, the potency of the dual-targeting vesicles for flowing tumor cells was better than that for static tumor cells. Then, a tumor metastasis mice model and a leukemia mice model were established to detect the killing ability of the drug-loaded dual-targeting vesicles to dynamic tumor cells . The therapy efficacy of the dual-targeting system was higher than other controls including single-targeting ones. Generally, it seems possible to strengthen drug-targeting to dynamic tumor cells the control of ligand-receptor interaction.
诸如白血病细胞和循环肿瘤细胞等动态或流动的肿瘤细胞面临着与实体瘤不同的微环境，且相关的靶向纳米药物鲜有报道。血液循环中流体剪切应力的存在似乎不利于配体修饰的纳米药物与其靶受体的结合。也就是说，在这种情况下结合特性非常关键。在此，我们利用氢化大豆卵磷脂（HSPC）、聚乙二醇-二硬脂酰基磷脂酰乙醇胺（PEG-DSPE）、胆固醇以及两种具有不同结合速率的v3配体（RGDm7 和 DT4）构建双靶向纳米囊泡，以期实现“快速结合/缓慢解离”功能。结果表明，双靶向纳米囊泡对静态和动态肿瘤细胞均实现了高效的细胞摄取和抗肿瘤作用。此外，双靶向囊泡对流动肿瘤细胞的效力优于对静态肿瘤细胞的效力。随后，建立了肿瘤转移小鼠模型和白血病小鼠模型，以检测载药双靶向囊泡对动态肿瘤细胞的杀伤能力。双靶向系统的治疗效果高于包括单靶向系统在内的其他对照组。总体而言，通过控制配体-受体相互作用来增强对动态肿瘤细胞的药物靶向作用似乎是可行的。
