Synthesis of poly(oxyethylene phosphate)-g-poly(ethylene oxide) via the “grafting onto” approach by “click” chemistry

Abstract

INTRODUCTION Brush copolymers, composed of polymeric arms regularly and densely spaced along a polymeric backbone, have been actively investigated for pharmaceutical applications like polymer carriers of drugs, because of their ability to self-assemble into well-defined nano-objects. Among the numerous macromolecular systems potentially available as drug delivery, polymers with alkylene H-phosphonate repeating units in the backbone are of particular interest due to their biodegradability and biocompatibility. Moreover, the pendant functional ability enables modification of the polymer backbone, which alters physical and chemical properties. Previous works describe successful strategies for appending functionalities onto polyphosphoester backbone by postpolymerization modification, via oxidation or addition reactions. In particular, Atherton–Todd reaction has been widely used to immobilize bioactive substances onto poly(alkylene H-phosphonate)s as this reaction proceeds in mild conditions with practically a quantitative yield. Introduction of biocompatible polymeric poly(ethylene oxide) (PEO) pendant groups has also been reported. Penczek and Pretula have first functionalized poly(alkylene H-phosphonate)s into the corresponding poly(alkylene phosphate)s. The hydroxyl functionality has then been used to initiate the polymerization of ethylene oxide according to a ‘‘grafting from’’ strategy, leading to poly(alkylene phosphate)-g-poly(ethylene oxide)s with a calculated graft length higher than two. They have also used the grafting onto strategy to anchorage PEO 200 onto poly(alkylene H-phosphonate)s beforehand oxidized. Recently, Wang et al. have reported the grafting of azide-functionalized PEO 2,000 onto ‘‘clickable’’ poly(alkylene phosphate) copolymer by Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition, obtained by ring-opening polymerization of an alkyne-functionalized five-membered cyclic phosphoester monomer, with a grafting efficiency of 42%. The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition is so far the most studied and reliable example of ‘‘click’’ chemistry philosophy initially introduced by Sharpless and coworkers. ‘‘Click’’ chemistry benefits from the facile introduction of azide and alkyne groups into organic and polymer molecules, the stability of these groups to many reaction conditions, and the tolerance of the reaction to the presence of other functional groups. Thus, the application of ‘‘click’’ chemistry to aliphatic polyesters appeared promising and particularly valuable, given the sensitivity of the polyester backbone to the conditions required for many conventional organic transformations and couplings.