A pH-Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P-Glycoprotein-Mediated Multidrug Resistance

• Published in: Angewandte Chemie International Edition Vol. 54; no. 34; pp. 9890 - 9893
• Main Authors: Chung, Ming-Fan, Liu, Hung-Yi, Lin, Kun-Ju, Chia, Wei-Tso, Sung, Hsing-Wen
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 17.08.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bubbles; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacology; Cancer; Carriers; Chemotherapy; drug delivery; Drug delivery systems; Drug Liberation; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drugs; Efflux; Female; fluorescence microscopy; Glycoproteins; Humans; Hydrogen-Ion Concentration; Irinotecan; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; Mice; Mice, Nude; Multidrug resistance; Multidrug resistant organisms; Nitric Oxide - chemical synthesis; Nitric Oxide - chemistry; pH effects; Protons; Thresholds; Tumors; multidrug resistance; cancer; drug delivery; fluorescence microscopy; antitumor agents
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201504444

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.