Gao Wei, Yang Xiucong, Lin Zhiqiang, Gao Shanyun, He Bing, Mei Bong, Wang Dan, Yuan Lan, Zhang Hua, Dai Wenbing, Wang Xueqing, Wang Jiancheng, Zhang Xuan, Zhang Qiang
J Biomed Nanotechnol. 2016 Jun;12(6):1183-98. doi: 10.1166/jbn.2016.2246.
In addition to showing the specific interaction between a generalized ligand and its receptor and the electrostatic effect between positive cell-penetrating peptides and negative cell membranes, our last study demonstrated the hydrophobic interactivity between a hydrophobic binding peptide (HBP) and biomembranes to be favorable in drug delivery. To yield more evidence for this new strategy and to find more effective HBPs, here we designed and established a novel nanomedicine associated with cyclosporin A (CsA) because this peptide is electrically neutral, highly hydrophobic, very stable in vivo and safe at the given dose. First, isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) studies showed a strong hydrophobic interaction between the CsA molecules and the lipid membrane. The lactate dehydrogenase release assay proved that CsA exhibited low toxicity to cell membranes. These facts encouraged us to explore the potential application of CsA as an HBP to actualize intracellular delivery of nanomedicines for tumor therapy. When conjugated to lipid nanocarriers, CsA significantly enhanced their binding with cells and,. consequently, increased the internalization of recoded nanomedicines into cells. The in vivo experiments further showed that the CsA-associated nanocarriers could achieve better delivery to tumor tissues and improve the tumor therapy of doxorubicin (DOX) compared to the nonmodified control; these findings were identical to the observations-in cell studies. In conclusion, CsA, a readily obtainable molecule with favorable characteristics, is indeed a good candidate for an HBP, and this study provides solid, novel evidence for the use of HBP-based nanocarriers as effective antitumor drug delivery systems.
除了显示广义配体与其受体之间的特异性相互作用以及阳性细胞穿透肽与阴性细胞膜之间的静电效应外，我们的上一项研究还表明，疏水结合肽（HBP）与生物膜之间的疏水相互作用有利于药物递送。为了为这一新策略提供更多证据并找到更有效的HBP，我们在此设计并建立了一种与环孢素A（CsA）相关的新型纳米药物，因为这种肽呈电中性、高度疏水、在体内非常稳定且在给定剂量下安全。首先，等温滴定量热法（ITC）和表面等离子体共振（SPR）研究表明CsA分子与脂质膜之间存在强烈的疏水相互作用。乳酸脱氢酶释放试验证明CsA对细胞膜毒性低。这些事实促使我们探索CsA作为HBP在实现纳米药物细胞内递送用于肿瘤治疗方面的潜在应用。当与脂质纳米载体偶联时，CsA显著增强了它们与细胞的结合，并因此增加了编码纳米药物进入细胞的内化。体内实验进一步表明，与未修饰的对照相比，与CsA相关的纳米载体可以更好地递送至肿瘤组织并改善阿霉素（DOX）的肿瘤治疗效果；这些发现与细胞研究中的观察结果一致。总之，CsA是一种易于获得且具有良好特性的分子，确实是HBP的良好候选者，并且本研究为基于HBP的纳米载体作为有效的抗肿瘤药物递送系统的应用提供了确凿的新证据。
