Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells
用于藥物輸送到腫瘤細(xì)胞pH可激活細(xì)胞穿透肽的設(shè)計

Abstract
摘要

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.

細(xì)胞穿透肽（CPPs）由于其顯著的膜易位能力而被認(rèn)為是潛在的藥物輸送載體。然而，缺乏特異性和極端的全身毒性妨礙了它們藥物輸送的成功率?，F(xiàn)在，我們設(shè)計了一種新的pH可激活細(xì)胞穿透肽，LHHLLHHLHHLLHH‐NH2 (LH)，來取代所有賴氨酸和LKKLLKLLKKLLKL‐NH2 (LK) +組氨酸兩種亮氨酸。正如預(yù)期的那樣，富含組氨酸的LH可以在pH 6.0下被激活并滲透到細(xì)胞中，而其膜轉(zhuǎn)導(dǎo)活性可以在pH 7.4下被屏蔽。相反，LK在兩種pH條件下均未顯示出明顯不同的細(xì)胞攝取。重要的是，與LK相比，LH在兩種pH值下的細(xì)胞毒性顯著降低，表明進一步應(yīng)用具有更好的安全性。此外，在喜樹堿（CPT）與LH綴合后，該綴合物顯示出比游離CPT和LK-CPT顯著的pH依賴抗腫瘤活性。該研究提供了一種新的低毒性腫瘤pH響應(yīng)CPP，來輸送選定的抗癌藥物。

首次發(fā)表: 2019-5-6: https://doi.org/10.1111/cbdd.13537

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