Water-soluble withaferin A polymer prodrugs via a drug-functionalized RAFT CTA approach. (January 2019)

• Record Type: Journal Article
• Authors: Van Herck, Simon; Hassannia, Behrouz; Louage, Benoit; Pita Compostizo, Raquel; De Coen, Ruben; Vanden Berghe, Wim; Vanden Berghe, Tom; De Geest, Bruno G.
• Is Part Of: European polymer journal. Volume 110(2019)
• Page Start: 313
• Page End: 318
• Publication Date: 2019-01
• Subjects: Withaferin A -- Polymer conjugate; Polymers -- Periodicals; Polymerization -- Periodicals; Polymères -- Périodiques; Polymérisation -- Périodiques; Polymerization; Polymers; Periodicals; Electronic journals; 547.705
• DOI: 10.1016/j.eurpolymj.2018.11.043
• Languages: English
• ISSNs: 0014-3057

Abstract

Graphical abstract: Highlights: Solubility of the anti-cancer drug withaferin A is dramatically improved by polymer-conjugation. Grafting-from chain transfer agent is a powerful route to well-defined polymer-drug conjugates. Withaferin A-polymer conjugates are polymeric pro-drugs. Abstract: To cope with the poor aqueous solubility of withaferin A, a broad-spectrum anti-cancer agent effective against therapy-resistant cancers, a polymer-drug conjugate was synthesized via a grafting-from-drug approach. Modification of withaferin A at the C27-OH with a chain transfer agent (CTA) for reversible addition-fragmentation chain transfer (RAFT) polymerization through a degradable ester bond was achieved with excellent control on the regioselectivity via a PFP-ester transesterification route. Subsequent RAFT polymerization with the hydrophilic N, N-dimethylacrylamide yielded a fully water-soluble conjugate. A decreased cytotoxicity in vitro indicated that withaferin A exists as a prodrug in the conjugate form and requires hydrolysis of the ester to regain its activity.