title: A smart tumor targeting peptide-drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells.
abstract: 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.
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Qin
authors: Q
authors: Song
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Xingxing
authors: X
authors: Chuan
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Binlong
authors: B
authors: Chen
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Bing
authors: B
authors: He
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Hua
authors: H
authors: Zhang
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Wenbing
authors: W
authors: Dai
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Xueqing
authors: X
authors: Wang
authors: a State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences, Peking University , Beijing , China.
authors: Qiang
authors: Q
authors: Zhang
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004220:Disulfides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry*; D009279:Naphthacenes / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004220:Disulfides; D004337:Drug Carriers; D009279:Naphthacenes; D010455:Peptides; C000615637:pHLIP-SS-DOX; D004317:Doxorubicin
keywords: Doxorubicin; multi-drug resistance; pH and reduction dual responsive; pH low insertion peptide; peptide–drug conjugate