Li Zhiyang, Lu Jiaqi, Tang Baolan, Shi Yuesen, Hai Li, Guo Li, Wu Yong
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Department of Pharmacy, Jingzhou Central Hospital, Jingzhou 434000, China.
Bioorg Med Chem. 2022 Apr 15;60:116704. doi: 10.1016/j.bmc.2022.116704. Epub 2022 Mar 10.
Glioma, as one of the most common primary intracranial tumors, is in an urgent need for specific targeting agents. Multi-branched RGD ligand is a promising alternative for liposome functionalization which combines the benefits of high affinity with αβ receptors and proper branching structure in response to the receptor clustering. Herein, we designed and synthesized single branched, double branched and triple branched RGD ligand (1RGD-Chol, 2RGD-Chol and 3RGD-Chol) respectively, which were then modified on the liposomes to prepare six different kinds of liposomes (including 1RGD-Lip, 2RGD-Lip, 3RGD-Lip, 2 × 1RGD-Lip, 3 × 1RGD-Lip and unmodified Lip). Subsequently, a series of assays were conducted. The results exhibited that the liposome decorated with 3RGD-Chol ligand possessed superior cellular internalization ability in C6 cells and bEnd.3 cells, suggesting the strongest ability of 3RGD-Lip to target the blood-brain barrier (BBB) and glioma cells. Besides, both the cytotoxicity and pro-apoptotic assays revealed that PTX-3RGD-Lip had the strongest ability to inhibit the survival of C6 cells. Moreover, the enrichment of liposomes at tumor site was 3RGD-Lip > 3 × 1RGD-Lip ≈ 2RGD-Lip ≈ 2 × 1RGD-Lip > 1RGD-Lip > Lip according to the in vivo imaging of C6-bearing mice, which was consistent with the result of in vitro targeting experiments. To sum up, the targeting efficiency of liposomes can be strongly promoted by improving the amount of targeting molecules, whereas the branching structure and spatial distance of RGD residues also accounted for the affinity between liposomes and αβ receptors. Collectively, PTX-3RGD-Lip would be a prospective strategy in glioma treatment.
胶质瘤作为最常见的原发性颅内肿瘤之一，迫切需要特异性靶向药物。多分支RGD配体是脂质体功能化的一种有前景的选择，它结合了与αβ受体高亲和力以及响应受体聚集的适当分支结构的优点。在此，我们分别设计并合成了单分支、双分支和三分支RGD配体（1RGD-Chol、2RGD-Chol和3RGD-Chol），然后将其修饰在脂质体上，制备了六种不同类型的脂质体（包括1RGD-Lip、2RGD-Lip、3RGD-Lip、2×1RGD-Lip、3×1RGD-Lip和未修饰的Lip）。随后，进行了一系列实验。结果表明，用3RGD-Chol配体修饰的脂质体在C6细胞和bEnd.3细胞中具有优异的细胞内化能力，表明3RGD-Lip靶向血脑屏障（BBB）和胶质瘤细胞的能力最强。此外，细胞毒性和促凋亡实验均显示，PTX-3RGD-Lip抑制C6细胞存活能力最强。而且，根据荷C6小鼠的体内成像，脂质体在肿瘤部位的富集情况为3RGD-Lip > 3×1RGD-Lip ≈ 2RGD-Lip ≈ 2×1RGD-Lip > 1RGD-Lip > Lip，这与体外靶向实验结果一致。综上所述，通过增加靶向分子的数量可显著提高脂质体的靶向效率，而RGD残基的分支结构和空间距离也影响脂质体与αβ受体之间的亲和力。总体而言，PTX-3RGD-Lip在胶质瘤治疗中可能是一种有前景的策略。
