a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
Drug Deliv. 2016 Jun;23(5):1734-46. doi: 10.3109/10717544.2015.1028601. Epub 2015 Apr 8.
Doxorubicin (DOX) is a potent anticancer drug for the treatment of tumors, but the poor specificity and multi-drug resistance (MDR) on tumor cells have restricted its application. Here, a pH and reduction-responsive peptide-drug conjugate (PDC), pHLIP-SS-DOX, was synthesized to overcome these drawbacks. pH low insertion peptide (pHLIP) is a cell penetrating peptide (CPP) with pH-dependent transmembrane ability. And because of the unique cell membrane insertion pattern, it might reverse the MDR. The cellular uptake study showed that on both drug-sensitive MCF-7 and drug-resistant MCF-7/Adr cells, pHLIP-SS-DOX obviously facilitated the uptake of DOX at pH 6.0 and the uptake level on MCF-7/Adr cells was similar with that on MCF-7 cells, indicating that pHLIP-SS-DOX had the ability to target acidic tumor cells and reverse MDR. In vitro cytotoxicity study mediated by GSH-OEt demonstrated that the cytotoxic effect of pHLIP-SS-DOX was reduction responsive, with obvious cytotoxicity at pH 6.0; while it had poor cytotoxicity at pH 7.4, no matter with or without GSH-OEt pretreatment. This illustrated that pHLIP could deliver DOX into tumor cells with acidic microenvironment specifically and could not deliver drugs into normal cells with neutral microenvironment. In summary, pHLIP-SS-DOX is a promising strategy to target drugs to tumors and provides a possibility to overcome MDR.
多柔比星（DOX）是一种有效的抗癌药物，可用于治疗肿瘤，但由于其对肿瘤细胞的特异性差和多药耐药性（MDR），限制了其应用。在这里，合成了一种 pH 和还原响应的肽-药物偶联物（PDC），即 pHLIP-SS-DOX，以克服这些缺点。pH 插入肽（pHLIP）是一种具有 pH 依赖性跨膜能力的细胞穿透肽（CPP）。由于其独特的细胞膜插入模式，它可能逆转 MDR。细胞摄取研究表明，在敏感的 MCF-7 和耐药的 MCF-7/Adr 细胞上，pHLIP-SS-DOX 在 pH 6.0 时明显促进了 DOX 的摄取，并且在 MCF-7/Adr 细胞上的摄取水平与 MCF-7 细胞相似，表明 pHLIP-SS-DOX 具有靶向酸性肿瘤细胞和逆转 MDR 的能力。GSH-OEt 介导的体外细胞毒性研究表明，pHLIP-SS-DOX 的细胞毒性具有还原响应性，在 pH 6.0 时具有明显的细胞毒性；而在 pH 7.4 时，无论是否有 GSH-OEt 预处理，其细胞毒性都很差。这表明 pHLIP 可以特异性地将 DOX 递送到酸性微环境中的肿瘤细胞中，而不能将药物递送到中性微环境中的正常细胞中。总之，pHLIP-SS-DOX 是一种有前途的靶向肿瘤药物的策略，为克服 MDR 提供了可能性。
