Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
PLoS One. 2013 Jun 11;8(6):e66084. doi: 10.1371/journal.pone.0066084. Print 2013.
Cell-penetrating peptides (CPPs) have proven very effective as intracellular delivery vehicles for various therapeutics. However, there are some concerns about non-specific penetration and cytotoxicity of CPPs for effective cancer treatments. Herein, based on the cell-penetrating motif of an anticancer peptide, buforin IIb, we designed several CPP derivatives with cancer cell specificity. Among the derivatives, a 17-amino acid peptide (BR2) was found to have cancer-specificity without toxicity to normal cells. After specifically targeting cancer cells through interaction with gangliosides, BR2 entered cells via lipid-mediated macropinocytosis. Moreover, BR2 showed higher membrane translocation efficiency than the well-known CPP Tat (49-57). The capability of BR2 as a cancer-specific drug carrier was demonstrated by fusion of BR2 to a single-chain variable fragment (scFv) directed toward a mutated K-ras (G12V). BR2-fused scFv induced a higher degree of apoptosis than Tat-fused scFv in K-ras mutated HCT116 cells. These results suggest that the novel cell-penetrating peptide BR2 has great potential as a useful drug delivery carrier with cancer cell specificity.
细胞穿透肽（CPPs）已被证明是将各种治疗药物递送至细胞内的非常有效的载体。然而，对于有效的癌症治疗，CPPs 的非特异性穿透和细胞毒性仍然存在一些担忧。在此，我们基于抗癌肽 Buforin IIb 的细胞穿透基序，设计了几种具有癌细胞特异性的 CPP 衍生物。在这些衍生物中，发现一种 17 个氨基酸的肽（BR2）具有癌症特异性，而对正常细胞没有毒性。通过与神经节苷脂的相互作用特异性靶向癌细胞后，BR2 通过脂质介导的巨胞饮作用进入细胞。此外，BR2 显示出比著名的 CPP Tat（49-57）更高的膜转位效率。通过将 BR2 融合到针对突变型 K-ras（G12V）的单链可变片段（scFv）上，证明了 BR2 作为癌症特异性药物载体的能力。BR2 融合的 scFv 在突变型 K-ras 的 HCT116 细胞中诱导的细胞凋亡程度高于 Tat 融合的 scFv。这些结果表明，新型细胞穿透肽 BR2 具有作为具有癌细胞特异性的有用药物递送载体的巨大潜力。
