A pH-Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P-Glycoprotein-Mediated Multidrug Resistance
Journal
Angewandte Chemie - International Edition
Journal Volume
54
Journal Issue
34
Pages
9890-9893
Date Issued
2015
Author(s)
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. Two is better than one: A carrier system is developed that can generate NO bubbles in the acidic environment of tumor tissues to trigger localized drug release (specifically irinotecan, denoted CPT-11) and to reverse Pgp-mediated multidrug resistance (Pgp=P-glycoprotein). The combined system enhances intracellular drug accumulation in cancer cells so that the concentration exceeds the therapeutic threshold, eventually leading to antitumor activity. ? 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Subjects
antitumor agents; cancer; drug delivery; fluorescence microscopy; multidrug resistance
SDGs
Other Subjects
Chemotherapy; Diseases; Drug delivery; Fluorescence microscopy; Glycoproteins; Tissue; Tumors; Acidic environment; Anti-cancer agents; Anti-tumor activities; Anti-tumor agents; Cancer; Hollow microsphere; Intracellular accumulation; Multidrug resistance; Drug products; antineoplastic agent; camptothecin; irinotecan; multidrug resistance protein; nitric oxide; analogs and derivatives; animal; antagonists and inhibitors; chemistry; drug effects; drug release; drug resistance; female; human; Mammary Neoplasms, Experimental; MCF 7 cell line; metabolism; mouse; multidrug resistance; nude mouse; pathology; pH; synthesis; Animals; Antineoplastic Agents; Camptothecin; Drug Liberation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Hydrogen-Ion Concentration; Mammary Neoplasms, Experimental; MCF-7 Cells; Mice; Mice, Nude; Nitric Oxide; P-Glycoprotein
Type
journal article