No abstract

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.

Biocompatible polymers based on 2-methacryloyloxyethyl phosphorylcholine (MPC) have delivered clinically proven benefits in various biomedical applications. In a recent communication [Lobb, E. J.; et al. J. Am. Chem. Soc. 2001, 123, 7913-7914], we reported that MPC can be polymerized to high conversions in both water and methanol at ambient temperature via atom transfer radical polymerization (ATRP). Low polydispersities were obtained, but the living character of this polymerization was not thoroughly explored. In the present paper we report a more detailed optimization study of the ATRP of MPC. Excellent yields, first-order monomer kinetics, linear M n vs conversion plots, and relatively narrow polydispersities (Mw/Mn ) 1.15-1.35) were obtained in both aqueous and alcoholic media at 20 °C. However, slower polymerizations and narrower polydispersities were always obtained in alcoholic solution, and chain extension experiments indicated significantly greater living character (i.e., greater self-blocking efficiency) under these conditions. The rate of ATRP was significantly slower in 2-propanol (IPA) than methanol due to the reduced polarity of the former solvent. However, acceptable rates of polymerization and reasonable control were obtained at elevated temperature in IPA. Alternatively, the addition of a relatively small amount of water to the IPA led to a significantly faster polymerization at ambient temperature. The effect of varying the ligand type and target DP n was also investigated. The best results were obtained using 2,2′-bipyridine for target DPn's of 20-200, with two alternative ligands giving either inferior control or slower rates of polymerization. Higher target DPn's resulted in significantly higher polydispersities even when using the 2,2′-bipyridine ligand. The spent ATRP catalyst was conveniently removed by treating aqueous solutions of MPC homopolymer with silica. This produced residual catalyst levels of less than 2 ppm, as measured by inductively coupled plasma atomic emission spectrometry, which may be sufficiently low for some biomedical applications. This synthetic advance is expected to allow the preparation of a wide range of novel biocompatible diblock and triblock copolymers for various biomedical applications.

The synthesis of biocompatible, thermo-responsive ABA triblock copolymers in which the outer A blocks comprise poly(N-isopropylacrylamide) and the central B block is poly(2-methacryloyloxyethyl phosphorylcholine) is achieved using atom transfer radical polymerization with a commercially available bifunctional initiator. These novel triblock copolymers are water-soluble in dilute aqueous solution at 20 degrees C and pH 7.4 but form free-standing physical gels at 37 degrees C due to hydrophobic interactions between the poly(N-isopropylacrylamide) blocks. This gelation is reversible, and the gels are believed to contain nanosized micellar domains; this suggests possible applications in drug delivery and tissue engineering.