Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells
Cell penetrating peptides (CPPs) were considered as potential drug delivery vectors due to their remarkable membrane translocation capacity. However, lack of specificity and extreme systemic toxicity hamper their successful application for drug delivery. Here, we designed a new pH‐activatable CPP, LHHLLHHLHHLLHH‐NH2 (LH), by substitution of all lysines and two leucines of LKKLLKLLKKLLKL‐NH2 (LK) with histidines. As expected, histidine‐rich LH could be activated and penetrate into cells at pH 6.0, whereas its membrane transduction activity could be shielded at pH 7.4. In contrast, LK showed no obviously different cellular uptake at both pH conditions. Importantly, LH was significantly less cytotoxicity compared with LK at both pH values, suggesting a better safety for further application. In addition, after conjugation of camptothecin (CPT) with LH, this conjugate displayed remarkably pH‐dependent antitumor activity than free CPT and LK‐CPT. This study provides a new tumor pH‐responsive CPP with low toxicity for selective anticancer drug delivery.
细胞穿透肽（CPPs）由于其显著的膜易位能力而被认为是潜在的药物输送载体。然而，缺乏特异性和极端的全身毒性妨碍了它们药物输送的成功率。现在，我们设计了一种新的pH可激活细胞穿透肽，LHHLLHHLHHLLHH‐NH2 (LH)，来取代所有赖氨酸和LKKLLKLLKKLLKL‐NH2 (LK) +组氨酸两种亮氨酸。正如预期的那样，富含组氨酸的LH可以在pH 6.0下被激活并渗透到细胞中，而其膜转导活性可以在pH 7.4下被屏蔽。相反，LK在两种pH条件下均未显示出明显不同的细胞摄取。重要的是，与LK相比，LH在两种pH值下的细胞毒性显着降低，表明进一步应用具有更好的安全性。此外，在喜树碱（CPT）与LH缀合后，该缀合物显示出比游离CPT和LK-CPT显著的pH依赖抗肿瘤活性。该研究提供了一种新的低毒性肿瘤pH响应CPP，来输送选定的抗癌药物。
首次发表: 2019-5-6: https://doi.org/10.1111/cbdd.13537