title: Reversion of multidrug resistance by a pH-responsive cyclodextrin-derived nanomedicine in drug resistant cancer cells.
abstract: Multidrug resistance (MDR) is one of the major problems responsible for inefficiency of cancer chemotherapy. Currently, there is still unmet demand for innovative strategies as well as effective and safe sensitizers to overcome MDR. In this study, we developed a nanosensitizer based on a pH-responsive nanoparticle (NP) derived from acetalated α-cyclodextrin (Ac-aCD). This pH-responsive NP could be effectively endocytosed by MDR cancer cells, and intracellularly transported by endolysosomal compartments. Ac-aCD NP was able to dramatically potentiate the activity of anticancer drugs including paclitaxel, docetaxel, cis-diamminedichloroplatinum, camptothecin, and doxorubicin. This sensitizing capability of Ac-aCD NP on MDR cells was resulted from the combined effects of decreased Pgp expression, attenuated Pgp ATPase activity, and the reduced intracellular ATP level. Ac-aCD NP exerted these diverse biological functions by intracellularly released α-cyclodextrin molecules, which were produced due to hydrolysis of Ac-aCD in acidic subcellular organelle. On the other hand, treatment with Ac-aCD NP showed no significant effects on the integrity of the plasma membrane, cytoskeleton, cell cycle, mitochondrial membrane potential, and apoptosis. These findings suggest that this pH-responsive NP has great potential for effective therapy of resistant cancers by combining with chemotherapeutic agents. It may also serve as a pharmacologically active nanocarrier for intracellular delivery of a plethora of antitumor drugs.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Radiation, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Clinical Biochemistry, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: lpsh008@aliyun.com.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: jxzhang@tmmu.edu.cn.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D020112:Rhodamine 123 / Q000378:metabolism; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047391:alpha-Cyclodextrins; D020112:Rhodamine 123; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D017239:Paclitaxel; C032613:alpha-cyclodextrin
keywords: Cyclodextrin; Drug delivery; Multidrug resistance; Nanomedicine; Pgp inhibitor; pH-responsive