Preparation Of Functional Amphiphilic Block Copolymers Micelles And The Application In Drug Controlled Release Systems

Polymeric micelles self-assembled by block copolymers has been widely studied due to their potential applications in the field of drug delivery in the past decades.The technology can protect a drug from the surroundings, provide a controlled and sustaine d release,the micelles have high drug efficiency,targeted delivery, suitable size and sufficient stability to prevent from uptake by reticuloendothelial system and excretion from body, thus reducing the side effect of drugs on healthy cells and tissues. Polymeric micelles were formed mainly by the self-assembly of amphiphilic block copolymers, in which the hydrophilic blocks form the outer shell,the hydrophobic blocks form the inner core,which can incorporate a variety of hydrophobic drugs. However,there is a disadvantage, polymeric micelles self-assembled by amphiphilic block copolymers cannot load ionic drugs.Another method of forming micelles from polymers is by electrostatic complexation between two oppositely charged polyelectrolytes, which are termed"polyion complex (PIC) micelles".As with amphiphilic block copolymers micelles, the PIC micelles can encapsulate not only hydrophobic drugs through hydrophobic interaction but also hydrophilic drugs and charged macromolecules through electrostatic interactions, besides, the PIC micelles display the ability to respond to pH and ionic strength. But, PIC micelles are not fairly stable under acid or alkaline conditions.If a kind of polymeric micelles with a complex inner core by the polyion complex of cationic and anionic segments,a hydrophobic outer core and a hydrophilic shell,it would eliminate the shortcomings of PIC micelles and Polymeric micelles of amphiphilic block copolymers, besides,possess all advantages of them. The work was complised as follow:1. A novel of amphiphilic diblock copolymer (P(IBA-co-DMAEMA)-b-PHPA), which composed of poly(isobutyl acrylate-co-N,N-dimethylaminoethyl methacrylate) random copolymer block and poly(hydroxypropyl acrylate), was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, and its structure and composition were conformed by gel permeation chromatography (GPC), 1H nuclear magnetic resonance (1H NMR) spectroscopy and FTIR spectroscopy. This copolymer could self-assemble into stable polymeric micelles. The critical micelle concentration values of the self-assembled micelles were about 2.1 mg/L in distilled water relying on fluorescent probe technique. The results measured by Dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that the self-assembled P(IBA-co-DMAEMA)-b-PHPA micelles exhibited spherical core-shell structure with mean hydrodynamic diameter around 110-136 nm and uniform and narrow distribution in aqueous media. The model drug folic acid (FA) was loaded into the micelles as drug carrier material and the in vitro drug release behavior was investigated at physiological conditions. We found that the FA-loaded content and the entrapment efficiency reach up to 38% and 76%, respectively. In phosphate buffer solution(PBS)at ionic strength I=0.15M, temperatures T=37℃, and different pH=2.0,7.4, and 9.2, in vitro release rates of folic acid (FA) from polymeric micelles were all relatively faster within 40 h, and increased with pH value increased. Followed by slow release, the largest accumulation release percentage was 36%, 61% and 80%, respectively. Thus, the polymeric micelles are expected to be a novel type of carrier material with pH-responsive and high drug loading capacity for drug delivery.2. Multilayered micelles with a poly(acrylic acid)(PAA)/poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) complex inner core , a poly (methyl methacrylate)(PMMA) outer core and a poly(hydroxypropyl acrylate)(PHPA) shell was synthesized by complexation between triblock copolymers PHPA-b-PMMA-b-PDMAEMA and PHPA-b-PMMA-b-PAA in acetone due to the hydrogen bonding between the DMAEMA units and AA units, then the solution was dialyzed against acidic water.The critical micelle concentration (CMC), hydrodynamic size, and surface morphology of the polymeric micelles were characterized by ?uorescence spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM), respectively. The resulting CMC was about 2.42 mg/L, dynamic light scattering (DLS) analysis and transmission electron micrographs (TEM) showed that the micelles to be spherically shaped with mean diameter around 110 nm. In addition, the polymeric micelles display ability to response to external stimuli. All of theses features are quite feasible for utilizing it as a novel intelligent drug delivery system. In order to assess its application in biomedical area, The model drug FA was loaded into the micelles and the in vitro drug release behavior was investigated. We found it was possible to control the releasing rate of FA by manipulating the pH value concentration of the release solution.