Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China; Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
Eur J Med Chem. 2019 Dec 1;183:111720. doi: 10.1016/j.ejmech.2019.111720. Epub 2019 Sep 18.
At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT and integrin αβ were designed and prepared in this work. Firstly, a Y-shaped Fru-RGD-chol ligand, where a fructose and peptide Arg-Gly-Asp (RGD) were covalently attached to cholesterol, was designed and synthesized. Then, the Fru-RGD-Lip was constructed by inserting Fru-RGD-chol into liposomes, while Fru+RGD-Lip was obtained by inserting both Fru-chol and RGD-chol (with the molar ratio of 1:1) into liposomes. The particle size, zeta potential, encapsulation efficiency and serum stability of the paclitaxel-loaded liposomes were characterized. The results indicated that the paclitaxel-loaded Fru-RGD-Lip had the strongest growth inhibition against GLUT and αβ overexpressed MDA-MB-231 and 4T1 cells. The cellular uptake of Fru-RGD-Lip on MDA-MB-231 cells and 4T1 cells was 3.19- and 3.23-fold more than that of the uncoated liposomes (Lip). The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively. The mechanism study demonstrated that the cellular uptake of both dual-targeting liposomes was likely to be recognized and mediated by GLUT and αβ firstly, then endocytosed through comprehensive pathways in an energy-dependent manner. Moreover, Fru-RGD-Lip displayed the maximum accumulation, which was 2.62-fold higher than that of Lip for instance, at the tumor sites compared to other liposomes using in vivo imaging. Collectively, the liposomes co-modified by fructose and RGD have enormous potential in the development of targeted TNBC treatment, especially the covalently modified Fru-RGD-Lip, making it a promising multifunctional liposome.
目前，化疗和放疗仍然是治疗三阴性乳腺癌（TNBC）的主流方法，这种癌症预后不良，死亡率高。本工作设计并制备了两种新型的双重靶向 TNBC 脂质体（Fru-RGD-Lip 和 Fru+RGD-Lip），它们可以主动识别果糖转运蛋白 GLUT 和整合素 αβ。首先，设计并合成了一种 Y 形 Fru-RGD-胆固醇配体，其中果糖和肽 Arg-Gly-Asp（RGD）与胆固醇共价连接。然后，将 Fru-RGD-胆固醇插入脂质体中构建 Fru-RGD-Lip，而 Fru+RGD-Lip 则是通过将 Fru-胆固醇和 RGD-胆固醇（摩尔比为 1:1）插入脂质体中获得的。对载紫杉醇脂质体的粒径、Zeta 电位、包封率和血清稳定性进行了表征。结果表明，载紫杉醇的 Fru-RGD-Lip 对 GLUT 和 αβ 过表达的 MDA-MB-231 和 4T1 细胞的生长抑制作用最强。Fru-RGD-Lip 在 MDA-MB-231 细胞和 4T1 细胞上的细胞摄取量分别是未涂层脂质体（Lip）的 3.19 倍和 3.23 倍。Fru+RGD-Lip 的摄取量略低，在两种细胞系中分别比 Lip 增加 2.81 倍和 2.90 倍。机制研究表明，两种双重靶向脂质体的细胞摄取可能首先被 GLUT 和 αβ 识别和介导，然后通过综合途径以能量依赖的方式内吞。此外，与其他脂质体相比，Fru-RGD-Lip 在肿瘤部位的最大积累量，例如，比 Lip 高 2.62 倍，通过体内成像观察到。总之，同时修饰果糖和 RGD 的脂质体在开发靶向 TNBC 治疗方面具有巨大的潜力，特别是共价修饰的 Fru-RGD-Lip，使其成为一种有前途的多功能脂质体。
