Synthesis, Micellization And Drug Release Behavior Of Temperature And PH Sensitive Brush Block Block Copolymer

Drug carriers are emerging biomedical materials with the development of biomaterials science, and widely used in clinical medicine and pharmacology. Carriers primarily act as a drug targeting transport that takes drugs into human body, and avoid drug leakage in non-lesion sites. As biomaterials used in human body, the carriers should have such characteristics as human-friendly characteristics, good biocompatibility, and non-toxic side effects. Although various carreiers have adopted in the field of drug targeting release, some of them, for example, the low molecular surfactants, still exhibit unsatisfactory solubilization effect and major toxicity. As a new kind of carriers, polymer micelles can overcome the above shortcomings, and have a wide range drug loading, structural stability, excellent permeability, and long residence time in the body, etc. But there are some physiochemical properties that fail to meet the biomedical requirements, such as critical micelle concentrations (CMC), particle size, drug encapsulation efficiency (EE), stability and biodegradability. For these reasons, pH-sensitive copolymer of three block with hydroxyl-terminated polybutadiene (HTPB) as hydrophobic blocks and thermo-triggered brush/comb block copolymers were synthesized in this work in order to obtain a new type of drug carriers with lower CMC, small hydrodynamic size, good micelle stability and biodegradability as well as drug controlled release performance. This study mainly focuses on the following two areas.1. Synthesis and drug release applications of pH-sensitive PMAA-b-HTPB-b-PMAA triblock copolymers. The block copolymer was synthesized through atom transfer radical polymerization (ATRP). The polymer is made up of hydrophobic HTPB and methylacrylic acid blocks. The structure of the products was characterized by infrared spectrum (FT-IR),1H NMR spectrum, and gel permeation chromatography (GPC). The morphology, size and CMC of polymer self-assembled micelles were characterized by transmission electron microscopy (TEM), fluorescence spectroscopy and dynamic light scattering (DLS) or the surface tension. The experimental results revealed that the size of spherical micelle nano-particles was less than100nm at different physiological environments. The CMC values were very low from3.90to5.75to7.76mg L-1with increasing the proportions of the monomers, which is extremely important for drug delivery. Zeta potential determinations confirmed that the micelles were negtively charged, which determines good stability of the micelles. The fluorescence intensity ratios and particle size changes by DLS disclosed that the pH transition produced at pH=5. In different environments, the triblock copolymer micellar nanoparticles with core-shell structure showed good stability. Biocompatibility studies indicated that the toxicity of the drug-loaded nanoparticles was higher than the blank ones but much lower than the free anti-cancer drug camptothecin (CPT) at corresponding concentrations. Release tests of the CPT-loaded nanoparticles under body environment conditions suggested that the release behavior of the pH sensitive polymer nanoparticles was closely concerned not only with the environment but also the composition. The results proved that the triblock copolymers with hydrophobic HTPB blocks could become delivery carriers for encapsulation and release of instability or poor water soluble drugs.2. Synthesis and application of thermosensitive brush-shaped mPEG-b-PA-g-PNIPAM block copolymers. The macroinitiator (mPEG-Br) was prepared using mPEG and acyl bromide system, and then the target products were synthesized via ATRP using the macromonomer (PNIPAM-AA), which was obtained by free radical chain transfer polymerization of NIPAM. The structure of the polymers was verified with1H NMR and FT-IR, and the molecular weight was determined by GPC. Spherical nanoparticles were observed by TEM, and the micelle size was varying between100-200nm with charge proportions measured by DLS. Surface tension measurements confirmed that the polymers had a small CMC value in aqueous solution, and UV-vis technology verified that the LCST values of temperature-sensitive polymers were between40-45℃. MTT assay hinted that the blank micelles were almost non-toxic, and the toxicity of the CPT-loaded micelles was much lower than free drugs. The HPLC determinations suggested that the hydrolysis the lactone ring of CPT was obviously decreased, signifying that the copolymer micelles could protect the lactone ring of CPT and eliminated the defect of poor stability of drugs. Drug release experiments displayed that the release profiles had a very good rule, and larger release amounts produced at tumor sites. So the brush copolymer micelles can potentially be used as drug carriers with desired performances.