Ph Sensitive Pmaa - B - Peg - B - Pmaa Three Block Copolymer Synthesis, Self-assembly And Drug Release

Currently, synthesis and micellization of the amphiphilic block copolymers are internationally a very stirring cutting-edge research in the realm of biomedical polymer science, involving in the interdisciplinary cross field of life science, material science, pharmacology and chemistry, and widely used as carriers for controlled drug release, targeted drug, and gene therapy. It is very essential for polymer micelles to have special core-shell architecture, low critical micelle concentration (CMC), small particle size (<200nm) and high stability as well as in-vivo long cyclicity to their applications as drug carriers. On the other hand,80%of the tumor tissues have pH values less than7.2while the pH value of the normal organization is generally7.4. Therefore, the pH-dependent tumor target can be achieved by preparing pH-responsive polymer micelles. The micelles as drug carrier can achieve the purpose of drug control release through the local pH change. Consequently, the polymer micelle drug carrier not only have passive target, but also can realize the active and passive target with human physiological environmental changes. In consideration of these descriptions, this paper is concerned with the following development to tackle several crucial challenges.1. pH-Responsive poly(methacrylic acid)-b-poly(ethylene glycol)-b-poly(methacrylic acid)(PMAA-b-PEG-b-PMAA) triblock copolymers were achieved via hydrolysis or acidolysis of amphiphilic PtBMA-b-PEG-b-PtBMA triblock copolymers, while the latter was synthesized by atom transfer radical polymerization (ATRP) using Br-PEG-Br as a macroinitiator and tertiary-butyl methacrylate (tBMA) with various molar ratios as a monomer. The chemical structure of these copolymers was characterized by FT-IR,1H-NMR and GPC measurements.2. Supramolecular self-assembly micellization behavior of the PMAA-b-PEG-b-PMAA triblock copolymers in aqueous solution and PBS solutions with various pH values was examined by means of a fluorescence spectroscopy technique using pyrene as a probe molecule. Some important physiochemical properties such as micelle morphologies, size, size distribution as well as CMC were investigated by combining UV-vis, dynamic light scattering (DLS) and transmission electron microscope (TEM) with the fluorescence spectroscopy. The unique pH-responsive sensitivity of these copolymer micelles was revealed by a change in fluorescent intensities and DLS particle diameters. The results indicated that the as-synthesized PMAA-b-PEG-b-PMAA triblock copolymers can self-assemble into spherical nanomicelles in aqueous solution with a hydrodynamic diameter less than120nm and narrow size distribution, depending on the micellar concentrations. The CMC values change with the systematical composition ratios and the length of hydrophobic chains. The CMC values of PMAA30-PEG45-PMAA30and PMAA25-PEG90-PMAA25samples less than34mg L-1demonstrated that the triblock copolymer micelles are stable even in the diluted PBS solution. These polymer micelles produced remarkable phase transition at pH=5.2; and formed stable core-shell nanoparticles within the range of pH4.8<pH<7.4; when the pH value is greater than7.4, the core-shell micelle structure was destroyed due to the ionization of the carboxylic groups.3. The MTT assay was conducted to value the biocompatibility or cytotoxicity of the pH-responsive triblock copolymers, and prednisone was selected as model drug to appreciate pH-triggered drug release and release dynamics of the as-prepared triblock copolymer micelles. The experimental results showed that these triblock copolymers are generally low cytotoxicity at a micellar concentration. The prednisone release and release kinetics studies disclosed that these pH-sensitive polymeric micelles are good carriers for the drug delivery. The micelles can encapsulate almost68%hydrophobic drug into their cores, and the drug release rate is fast at a pH=7.4PBS solution. The drug release in aqueous solution deviates from the Fickian diffusion control mechanism, while in PBS solution of pH7.4(37℃), the drug release is primarily controlled by the Fickian diffusion. Therefore, the drug release behavior may be mediated by the structural changes of the micelles as well as the environment-induced diffusion. Considering pH ranges in some therapeutic targets such as tumors, and inflammation or ischemia sites from5.7to7.8, as well as faster release rates in pH7.4PBS solution, the as-synthesized triblock copolymer micelles are much suitable for pH-response drug carriers.