Synthesis of terminal-functionalized thermoresponsive diblock copolymers using biodegradable macro-RAFT agents

Amphiphilic diblock copolymers form a variety of multi-molecular assemblies (for example, polymeric micelles and polymer vesicles) in aqueous phases and are being explored for biomedical applications, including biomaterials and drug delivery.¹ Currently, the introduction of various functional moieties (for example, biorelated molecules for increasing active interactions with target cells or fluorescent units for visualization) to hydrophilic block termini is being used to provide additional unique functions to polymeric assemblies.^{2, 3, 4} In addition, stimuli-responsive polymers applied to single or both blocks of diblock copolymers provide the controlled structural and property changes of polymer assemblies in response to physical and chemical signals (for example, heat, light and pH).^{5, 6, 7}

In recent years, well-defined polymers have been efficiently synthesized, using the recently developed living radical polymerizations, such as the reversible addition-fragmentation chain transfer radical (RAFT) polymerization⁸ and atom-transfer radical polymerization.⁹ Living radical polymerizations produce polymers with controlled molecular weights that are applicable for a wide range of monomers under facile conditions. Among several living radical polymerizations, the RAFT polymerization possesses an attractive advantage for functionalizing polymer termini in biomedical applications.¹⁰ Dithiobenzoate groups at the ω-position of RAFT-mediated polymers are sensitive to nucleophiles and are converted to thiol groups, which can be utilized for introducing biorelated molecules and other functional moieties via thiol chemistry. In addition, functional RAFT agents allow polymers to be functionalized at the α-positions. By utilizing these unique features of RAFT polymerization, our laboratory has synthesized diblock copolymers comprised of thermoresponsive poly(N-isopropylacrylamide) (PIPAAm)-based blocks and biodegradable blocks by combining the RAFT and ring opening polymerization (ROP) techniques.^{2, 11, 12} During our synthetic process for block copolymers, the α-hydroxyl, ω-dithiobenzoate poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(IPAAm-co-DMAAm)) block was prepared using hydroxylated RAFT agents. DMAAm was copolymerized with IPAAm for regulating the lower critical solution temperature of the thermoresponsive block around a physiological temperature for use in biomedical applications. Subsequently, the fabrication of biodegradable blocks, which was initiated from the α-hydroxyl groups of the thermoresponsive blocks, was achieved by the ROP of D,L-lactide. Intelligent polymeric micelles comprised of block copolymers were investigated for use in biomedical applications involving thermally modulated drug release and intracellular micellar uptake. However, this synthetic approach includes some problems associated with preparing dithiobenzoate-terminated block copolymers with various molecular weights. The deactivation of the terminal dithiobenzoate groups is caused by thermal decomposition during the ROP process using tin (II) 2-ethylhexanoate with heating at 120 °C.^{12, 13} In addition, polyester blocks with short chain lengths are often obtained because of the low solubility of α-hydroxylated PIPAAm derivatives, which are used as the macro-initiators in reactive solvents (for example, toluene and xylene). To solve these issues, the present study focused on the acid-based cationic ROP (CROP)¹⁴ in conjunction with RAFT polymerization. The advantages of CROP include a fast polymerization rate at a low temperature (for example, 0 °C), free heavy metal catalysts and a controlled polymer molecular weight. Herein, the CROP-mediated synthesis of poly(ɛ-caprolactone) (PCL) as a macro-RAFT agent was first performed using a hydroxyl-dithiobenzoate compound. Subsequently, the thermoresponsive PIPAAm-based block was propagated using PCL with a terminal dithiobenzoate moiety, and the polymerization kinetics were compared with that of a low molecular weight RAFT agent. Furthermore, the terminal dithiobenzoate groups were converted to thiol groups, which were biotinylated via thiol-maleimide chemistry for preparing bioactive-terminated block copolymers comprised of thermoresponsive, biodegradable blocks.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account

Continue with Google

Continue with ORCiD