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 Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Eur J Med Chem. 2020 May 1;193:112204. doi: 10.1016/j.ejmech.2020.112204. Epub 2020 Mar 5.
A series of liposome ligands (Bio-Chol, Bio-Bio-Chol, tri-Bio-Chol and tetra-Bio-Chol) modified by different branched biotins that can recognize the SMVT receptors over-expressed in breast cancer cells were synthesized. And four liposomes (Bio-Lip, Bio-Bio-Lip, tri-Bio-Lip and tetra-Bio-Lip) modified by above mentioned ligands as well as the unmodified liposome (Lip) were prepared to study the targeting ability for breast cancer. The cytotoxicity study and apoptosis assay of paclitaxel-loaded liposomes showed that tri-Bio-Lip had the strongest anti-proliferative effect on breast cancer cells. The cellular uptake studies on mice breast cancer cells (4T1) and human breast cancer cells (MCF-7) indicated tri-Bio-Lip possessed the strongest internalization ability, which was 5.21 times of Lip, 2.60 times of Bio-Lip, 1.67 times of Bio-Bio-Lip and 1.17 times of tetra-Bio-Lip, respectively. Moreover, the 4T1 tumor-bearing BALB/c mice were used to evaluate the in vivo targeting ability. The data showed the enrichment of liposomes at tumor sites were tri-Bio-Lip > tetra-Bio-Lip > Bio-Bio-Lip > Bio-Lip > Lip, which were consistent with the results of in vitro targeting studies. In conclusion, increasing the density of targeting molecules on the surface of liposomes can effectively enhance the breast cancer targeting ability, and the branching structure and spatial distance of biotin residues may also have an important influence on the affinity to SMVT receptors. Therefore, tri-Bio-Lip could be a promising drug delivery system for targeting breast cancer.
一系列通过不同支化生物素修饰的脂质体配体（Bio-Chol、Bio-Bio-Chol、三-Bio-Chol 和四-Bio-Chol）被合成，这些配体可以识别过度表达于乳腺癌细胞中的 SMVT 受体。四种由上述配体修饰的脂质体（Bio-Lip、Bio-Bio-Lip、三-Bio-Lip 和四-Bio-Lip）以及未经修饰的脂质体（Lip）被制备出来，以研究它们对乳腺癌的靶向能力。载紫杉醇脂质体的细胞毒性研究和凋亡实验表明，三-Bio-Lip 对乳腺癌细胞具有最强的抗增殖作用。在小鼠乳腺癌细胞（4T1）和人乳腺癌细胞（MCF-7）上的细胞摄取研究表明，三-Bio-Lip 具有最强的内化能力，分别是 Lip 的 5.21 倍、Bio-Lip 的 2.60 倍、Bio-Bio-Lip 的 1.67 倍和四-Bio-Lip 的 1.17 倍。此外，用携带 4T1 肿瘤的 BALB/c 小鼠来评价体内靶向能力。数据表明脂质体在肿瘤部位的富集程度为三-Bio-Lip > 四-Bio-Lip > Bio-Bio-Lip > Bio-Lip > Lip，这与体外靶向研究的结果一致。总之，增加脂质体表面靶向分子的密度可以有效地增强乳腺癌的靶向能力，而生物素残基的分支结构和空间距离也可能对 SMVT 受体的亲和力有重要影响。因此，三-Bio-Lip 可能是一种有前途的靶向乳腺癌的药物递送系统。
