The Pmaa - Co - Pnipaam Brush Copolymer Synthesis And Temperature/ph Sensitive Self-assembly Behavior Research

In recent years, amphiphilic block copolymers and their assembled micelles as drug controlled release carriers have attracted great interest since they can minimize drug degradation and loss, decrease harmful side-effects and drug toxicity, and improve drug bioavailability. In particular, the block copolymers consisting of poly(N-ispropylacrylamide)(PNIPAAm) and poly(methacrylic acid)(PMAA) can produce special phase transition behavior with environmental temperature and pH values. Consequently, this polymer micelle drug carrier not only has a passive target function, but also can realize the active and passive targeting with human physiological environmental changes at the same time, receiving extensively attention. Unique architecture and the intramolecular phase separation in selective solvent of brush-shaped copolymers have important impact on the static and dynamic stability, morphology, size and size distribution of the micelles, and further affect the performances of micelles including drug loading and release rate, even in vivo circulation and distribution. Therefore, it may be very useful to design and synthesize polymer micelles with brush-like architectures as drug delivery vectors. In view of these descriptions, this work is concerned with the following development to tackle two crucial challenges.1. Brush-like copolymers with poly(t-butyl methacrylate)(PBMA) and poly(N-ispropylacryl amide)(PNIPAAm) as side arms, PBMA-co-PNIPAAm, were designed and synthesized via a simple free radical polymerization route. The chemical structure and molecular weight of these polymer brushes were characterized and determined by nuclear magnetic resonance (1H NMR), Fourier transform infrared spectrometry (FT-IR) and gel permeation chromatography (GPC). The polymer brushes can spontaneously assembled into regularly spherical core-shell nanostructured micelles with well-dispersed individual nanoparticles in aqueous solutions, and physiochemical properties of the micelles formed were detected by a surface tension technique, nanoparticle analyzer, transmission electron microscope (TEM), dynamic light scattering (DLS) and UV-vis transmittance measurements. Low critical micelle concentration (CMC) and high zeta potentials revealed the micellar stability and the micellar particle size was in the range from36to93nm by TEM and less than200nm by DLS. The resulting polymer brushes were temperature-sensitive with low critical solution temperature (LCST) about28.80-29.40℃. These characteristic parameters were affected by their compositional ratios and the length of hydrophilic or hydrophobic chains. The evaluation for caffeine drug release and release kinetics demonstrated that the drug release and bioavailability may be mediated or improved by the temperature-induced structural changes of the micelles. At25℃, the release modes of caffeine in the micelles are primarily controlled by Fickian diffusion. At37℃, the drug release behavior deviates from the Fickian diffusion control mechanism. In this case, both Fickian diffusion and polymer chain conformation change influence the drug release.2. A thermo-and pH-stimuli-responsive brush-shaped copolymer, PMAA-co-PNIPAAm, which is composed of poly(methacrylic acid)(PMAA) and poly(N-ispropylacrylamide)(PNIPAAm) as side arms, was synthesized via atom transfer radical polymerization (ATRP) using methyl2-bromopropionate as an initiator. The chemical structure and molecular weight were characterized and determined by nuclear magnetic resonance (1H NMR), Fourier transform infrared spectrometry (FT-IR) and size exclusion chromatography (SEC). The copolymers can self-assemble to form spherically-shaped core-shell micelles in different media, with the critical micelle concentration (CMC) in aqueous solution from6.6to32.8mg L"1, and the hydrodynamic diameters varying with pH and temperature, from120to195nm. The resultant brush-shaped copolymer micelles exhibited pH-triggered thermoresponsive behavior, with low critical solution temperature (LCST) about30-48℃. The polymer micelles were observed to be stable under simulated physiological conditions. The cytotoxicity studies by MTT assay and in vitro prednisone drug release demonstrated that the PMAA-co-PNIPAAm copolymer micelles were not directly toxic to L929mouse embryonic fibroblasts and the in vitro release behavior under various physiological environments depended upon pH and temperature change. Therefore the as-prepared brush-shaped copolymer micelles may serve as a promising "intelligent" drug delivery carrier.