2-Methacryloyloxyethyl phosphorylcholine (MPC) is commonly used to prepare biocompatible copolymers that have delivered clinically proven benefits in various biomedical applications. Recently, we reported that MPC could be homopolymerized to high conversions with good control via atom transfer radical polymerization (ATRP) in protic media. In the present study we describe the synthesis of a wide range of well-defined MPC-based block copolymers using either near-monodisperse macroinitiators or sequential monomer addition. With the former approach, the macroinitiators were based on either poly-(alkylene oxides) or poly(dimethylsiloxane). With the latter approach, suitable comonomers included a wide range of methacrylic and other monomers, including 2-(dimethylamino)ethyl methacrylate (DMA) and its quaternized derivatives, 2-(diethylamino)ethyl methacrylate (DEA), 2-(diisopropylamino)ethyl methacrylate (DPA), methyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, and glycerol monomethacrylate. Polymerization of MPC using the three macroinitiators yielded novel PEO-MPC, PPO-MPC, and PDMS-MPC diblock copolymers. The PPO-MPC diblock copolymer proved to be thermoresponsive: molecular dissolution occurred in cold water, with colloidal aggregates being formed reversibly at elevated temperatures due to the inverse temperature solubility behavior of the PPO block. For the sequential monomer addition syntheses, the MPC monomer was generally polymerized first under optimized conditions, followed by the second monomer. High conversions were obtained for both stages of polymerization, and where applicable, aqueous GPC analyses indicated reasonably low polydispersities and good blocking efficiencies. Above pH 8, the MPC-DMA diblock copolymers also exhibited thermoresponsive behavior, forming DMA-core aggregates at elevated temperature. Spontaneous dissociation occurred on cooling to ambient temperature as the hydrophobic DMA block became hydrophilic again. The MPC-DMA, MPC-DEA, and MPC-DPA diblock copolymers proved to be pH-responsive polymeric surfactants at ambient temperature: molecular dissolution occurred in dilute acidic solution with well-defined, near-monodisperse micelles being formed at around neutral pH. In each case, the MPC block formed the biocompatible micelle coronas and the tertiary amine methacrylate block formed the hydrophobic micelle cores. In the case of the MPC-DPA diblock copolymer, the pyrene partition constant for the DPA-core micelles at pH 9 was similar to that reported previously for polystyrene-core micelles. These new MPC-based diblock copolymers are being evaluated as new nonviral vectors for DNA condensation and "stealthy" nanocapsules for the delivery of hydrophobic drugs and also for the synthesis of biocompatible shell cross-linked micelles.
ABA triblock copolymers [A = 2-(diisopropylamino)ethyl methacrylate), DPA or 2-(diethylamino)ethyl methacrylate), DEA; B = 2-methacryloyloxyethyl phosphorylcholine, MPC] prepared using atom transfer radical polymerization dissolve in acidic solution but form biocompatible free-standing gels at around neutral pH in moderately concentrated aqueous solution (above approximately 10 w/v % copolymer). Proton NMR studies indicate that physical gelation occurs because the deprotonated outer DPA (or DEA) blocks become hydrophobic, which leads to attractive interactions between the chains: addition of acid leads to immediate dissolution of the micellar gel. Release studies using dipyridamole as a model hydrophobic drug indicate that sustained release profiles can be obtained from these gels under physiologically relevant conditions. More concentrated DPA-MPC-DPA gels give slower release profiles, as expected. At lower pH, fast, triggered release can also be achieved, because gel dissolution occurs under these conditions. Furthermore, the nature of the outer block also plays a role; the more hydrophobic DPA-MPC-DPA triblock gels are formed at lower copolymer concentrations and retain the drug longer than the DEA-MPC-DEA triblock gels.
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