title: A pH-Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P-Glycoprotein-Mediated Multidrug Resistance.
abstract: Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT-11) and a NO-releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell-killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.
authors.affiliation: Department of Chemical Engineering and Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan (ROC).
authors.forename: Ming-Fan
authors.initials: MF
authors.lastname: Chung
authors.affiliation: Department of Chemical Engineering and Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan (ROC).
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan (ROC).
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan (ROC). 4926602@yahoo.com.tw.
authors.forename: Wei-Tso
authors.initials: WT
authors.lastname: Chia
authors.affiliation: Department of Chemical Engineering and Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan (ROC). hwsung@mx.nthu.edu.tw.
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009569:Nitric Oxide; D000077146:Irinotecan; D002166:Camptothecin
keywords: antitumor agents; cancer; drug delivery; fluorescence microscopy; multidrug resistance