Medina Scott H, Schneider Joel P
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
J Control Release. 2015 Jul 10;209:317-26. doi: 10.1016/j.jconrel.2015.05.267. Epub 2015 May 13.
Many lead molecules identified in drug discovery campaigns are eliminated from consideration due to poor solubility and low cell permeability. These orphaned molecules could have clinical value if solubilized and delivered properly. SVS-1 is a de novo designed peptide that preferentially folds at the surface of tumor cells, adopting a β-hairpin conformation that rapidly translocates into the cytoplasm, and ultimately nucleus, of cells. SVS-1 is stable in serum and small molecules attached to the peptide are effectively delivered to cancer cells via mechanisms involving physical translocation and, to a lesser extent, clathrin-dependent endocytosis. For example, ligating the model hydrophobic drug Paclitaxel (PTX) to SVS-1 improved its aqueous solubility by ~1000-fold and successfully delivered and released PTX to cancer cells in vitro and tumors in vivo without toxic adjuvants. These results suggest that SVS-1 can serve as a simple, effective delivery platform for molecules with poor solubility and permeability.
在药物研发过程中，许多被鉴定出的先导分子因溶解度差和细胞通透性低而被排除在考虑范围之外。如果能正确增溶并递送这些被搁置的分子，它们可能具有临床价值。SVS-1是一种从头设计的肽，它优先在肿瘤细胞表面折叠，形成β-发夹构象，这种构象能迅速转运到细胞的细胞质，最终进入细胞核。SVS-1在血清中稳定，与该肽相连的小分子通过物理转运机制，并在较小程度上通过网格蛋白介导的内吞作用有效地递送至癌细胞。例如，将模型疏水药物紫杉醇（PTX）与SVS-1连接，使其水溶性提高了约1000倍，并在无毒性佐剂的情况下成功地在体外将PTX递送至癌细胞，并在体内递送至肿瘤组织并释放。这些结果表明，SVS-1可以作为一种简单、有效的递送平台，用于递送溶解度和通透性差的分子。
