Chen Conghui, Hu Haiyang, Qiao Mingxi, Zhao Xiuli, Wang Yinjie, Chen Kang, Chen Dawei
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China.
J Drug Target. 2015 May;23(4):311-22. doi: 10.3109/1061186X.2014.994182. Epub 2014 Dec 24.
In the present study, we devised a strategy that paclitaxel (PTX) with lipid and octadecylamine were prepared to lipid nanoparticle (PTX-LNP) with positive charge, folic acid-modified bovine serum albumin (FB)-coated surface of PTX-LNP through electrostatic attraction and generated the lipoprotein-mimicking nanocomplex (FB-PTX-LNP) for dual-targeting therapy. Bovine serum albumin (BSA) was used as the protein model due to its specific targeting to tumor by increased transendothelial gp60-mediated transport and increased intratumoral accumulation as a result of the secreted protein, acidic and rich in cysteine (SPARC)-albumin interaction. The further conjugating folic acid to BSA achieved the dual active targeting. In vitro cytotoxicity tests suggested FB-PTX-LNP and BSA-PTX-LNP exhibited significantly higher cytotoxic activity against MCF-7 and HepG2 cells compared to PTX-LNP. The cellular uptake experiments indicated that FB-coumarin-6-LNP modified with dual-targeting had a faster and greater cellular uptake when compared to BSA-coumarin-6-LNP and coumarin-6-LNP by MCF-7 cells. Thus, both BSA and FA did play roles in in vitro cytotoxicity and cellular uptake. Furthermore, the targeting ability and therapeutic efficacy of FB-PTX-LNP were assessed in vivo. FB-PTX-LNP produced very marked targeting ability and anti-tumor activity in MDA-MB-231 tumor-bearing mice. These results indicate the protein-lipid nanocomplex FB-PTX-LNP is a potential nanocarrier for Paclitaxel dual-targeting to tumor.
在本研究中，我们设计了一种策略，将脂质和十八烷基胺与紫杉醇（PTX）制备成带正电荷的脂质纳米颗粒（PTX-LNP），通过静电吸引在PTX-LNP表面用叶酸修饰的牛血清白蛋白（FB）进行包被，从而生成用于双靶点治疗的脂蛋白模拟纳米复合物（FB-PTX-LNP）。由于牛血清白蛋白（BSA）通过跨内皮gp60介导的转运增加而对肿瘤具有特异性靶向作用，并且由于分泌蛋白、富含酸性和半胱氨酸的蛋白（SPARC）与白蛋白的相互作用导致肿瘤内蓄积增加，因此将其用作蛋白质模型。进一步将叶酸与BSA偶联实现了双活性靶向。体外细胞毒性试验表明，与PTX-LNP相比，FB-PTX-LNP和BSA-PTX-LNP对MCF-7和HepG2细胞表现出显著更高的细胞毒性活性。细胞摄取实验表明，与BSA-香豆素-6-LNP和香豆素-6-LNP相比，经双靶点修饰的FB-香豆素-6-LNP被MCF-7细胞摄取的速度更快且摄取量更大。因此，BSA和FA在体外细胞毒性和细胞摄取中均发挥了作用。此外，还在体内评估了FB-PTX-LNP的靶向能力和治疗效果。FB-PTX-LNP在携带MDA-MB-231肿瘤的小鼠中产生了非常显著的靶向能力和抗肿瘤活性。这些结果表明，蛋白质-脂质纳米复合物FB-PTX-LNP是一种用于紫杉醇双靶点靶向肿瘤的潜在纳米载体。
