Stimuli-responsive amphiphilic (co)polymers via RAFT polymerization

Abstract

Over the last decade reversible addition–fragmentation chain transfer (RAFT) polymerization has become a powerful technique for the preparation of well-defined copolymer architectures. Specifically, water-soluble, stimuli-responsive block, graft, and star copolymers have become especially significant in targeted delivery of diagnostic and therapeutic agents. In many cases RAFT polymerization is carried out directly in water at ambient temperature without the need for protecting group chemistry. Incorporation of functional monomers and selection of appropriate chain transfer agents (CTAs) allows facile, post-polymerization transformations of structopendant or structoterminal groups. This review focuses specifically on advances in the synthesis of (co)polymers from water-soluble monomers yielding stimuli-responsive systems. Additionally, we focus on recent reports of assembly into micelles and polymersomes induced by external stimuli including temperature, pH, and ionic strength. Reversible cross-linking methods to “lock” such assembled morphologies are addressed as well as potential applications in nanomedicine.

Introduction

Since the advent of polymer science as a discipline, chemists have sought to design and synthesize “smart” macromolecules that respond to external signals such as temperature, pH, electrolytes, light, mechanical stress, etc. Such stimuli-responsive polymers have found a plethora of applications in widely diverse fields including, but not limited to: biomedicine, optics, electronics, diagnostics, and in the formulations of pharmaceuticals and cosmetics. In many cases, synthetic polymers have been constructed to mimic the behavior of an enormously diverse array of biological polymers including proteins, nucleic acids, polysaccharides, and their naturally occurring conjugates.

Prior to the development of controlled radical polymerization (CRP) techniques [1], [2], [3], [4], [5], [6], [7], [8], functional monomer selection, broad polydispersity, and lack of structural and molecular weight control limited synthesis of systems with requisite primary, secondary, and tertiary features for conformational response and assembly featured in stimuli-responsive biomolecules. In this review we focus on developments in the area of stimuli-responsive polymers based on the CRP technique reversible addition–fragmentation chain transfer (RAFT) polymerization. This technique, first reported by the CSIRO group [9], [10] and a French group as MAcromolecular Design via the Interchange of Xanthates (MADIX) [11], [12], has only been in existence for a little over 10 years. In terms of application to all stimuli-responsive systems, and in particular those of biological relevance, RAFT is currently the most versatile of the CRP techniques. It should, however, be noted that the rapid advances in RAFT and aqueous RAFT polymerization technology have been spawned in many cases by predecessor CRP techniques, including stable free radical polymerization (SFRP) [1], [2] and atom transfer radical polymerization (ATRP) [3], [4] as well as classical anionic, ring opening, and group transfer polymerization methods. The powerful synthetic tools developed for RAFT polymerization and subsequent transformations now allow polymerization of highly functional monomers under benign conditions (often in water at ambient temperature without the need of protecting groups) to afford complex, but highly controlled architectures with tailored ranges of response to external stimuli.

The versatility of RAFT polymerization has resulted in rapidly increasing utilization as demonstrated by publications over the last 10 years (Fig. 1). There have been a number of reviews on the RAFT process [5], [6], [13], [14], [15], [16], [17], [18], aqueous RAFT [7], [8], the mechanism of RAFT polymerization [19], RAFT in heterogeneous media [20], [21], and computational studies [22], [23]. Additionally, a book entitled Handbook of RAFT Polymerization containing reviews on all aspects of RAFT technology has recently been published [24].

Our review to follow is organized into sections that first introduce the chain transfer agent (CTA) structures necessary for controlled polymerization and then briefly describe the RAFT mechanism, control of molecular weight, and key issues to successful polymerization in aqueous media. A discussion of those monomers that lead to thermally responsive polymers, pH-responsive copolymers, and polymers responsive to other stimuli follows. In general our discussion of these monomers will not be comprehensive, but rather will present important milestones. For a more detailed discussion of the water-soluble monomers polymerized by RAFT under homogeneous organic and aqueous conditions (including those that are not stimuli-responsive) the reader is directed to our previous review [7]. In the final sections we focus on stimuli-responsive assembly of the block copolymers synthesized via RAFT polymerization and examine the various methods of stabilizing the self-assembled aggregates to prevent dissociation upon removal of external stimuli.