Preparation And Properties Of Polymeric Micelles Based On Starch

Recently, amphiphilic polymeric micelles have received more and more attention as a novel drug delivery carrier. Because amphiphilic polymers could self-assemble to from micelles with core-shell structures in water, the hydrophobic inner core could encapsulate anti-tumors drugs, and hydrophilic outer shell could offer protection to inner core. In addition, polymeric micelles have some outstanding advantages as drug delivery carrier, such as, high drug loading capacity, improved solubility, prolonged in vivo circulation time and preferential accumulation at the tumor site via the enhanced permeability and retention (EPR) effect However, an ideal drug delivery carrier should have excellent biocompatible and biodegradable, abundant nature polysaccharide becomes ideal materials to prepare polymeric micelles. Based on the above considerations, in this thesis we selected soluble starch as main material, and prepared polymeric micelles based on starch. And we studied the self-assemble behavior, drug release behavior and cytotoxicity of polymeric micelles based on starch under the different conditions. The three main parts of this thesis is as described below:1. The novel amphiphilic polymeric micelles based on starch-deoxycholic acid (St-DCA) have been prepared, and their self-assemble behaviors are studied. The size and CMC of St-DCA micelles decreased with increasing degree of substitution (DS) about DCA. When DS was 8.9, the size and CMC of St-DCA micelles were 182 nm and 0.0185 mg/mL, respectively. In addition, the size and CMC of St-DCA micelles increased in PBS solution of different pH values varying from 7.4 to 5.5, because of the hydrolysis of ester linkages and weak hydrogen-bond interaction under the acidic conditions. Thus, the above results of self-assemble behaviors have indicated that St-DCA micelles has pH-response.2. The novel self-assembled amphiphilic mPEGylated starch-deoxycholic acid (mPEG-St-DCA) polymeric micelles have been prepared. In order to improve solubility of starch, hydrophilic mPEG was used to modify starch, and then hydrophobic DCA was used to further modified mPEGylated starch. The results showed that with degree of substitution of DCA increasing, the sizes of mPEG-St-DCA micelles decreased to below 200 nm. Correspondingly, the CMC decreased from 0.048 to 0.022 mg/mL. And the results indicated that when pH values decreased from 7.4 to 6.5, the sizes and CMC increased from 130.7 nm and 0.022 mg/mL to 177.82 nm and 0.058 mg/mL. The TEM results showed that the spherical mPEG-St-DCA micelles underwent a dramatic process of structural change from clearly comp[ete core-shell structure to complete structural collapse and aggregation. DOX was selected as a model drug to study in vitro DOX release behavior, it was found that DOX-loaded mPEG-St-DCA micelles in pH 5.5 exhibited faster drug release than in pH 7.4. And 59% of drug was released in 71 h under pH 5.5. In contrast, only 32% of drug was released in pH 7.4. MTT assays showed that mPEG-St-DCA micelles were biocompatib[e with HeLa cells. And the results of CLSM analyses showed that mPEG-St-DCA micelles could be internalized efficiently by HeLa cells.3. Reduction-responsive polymeric micelles based on starch (mPEG-St-DPA) have been prepared through crosslinking reaction between mPEGylated starch and 3, 3’-dithiodipropionic acid (DPA) as a cross-linker with disulfide linkages. With the degree of crosslinking increasing, the size and CMC of mPEG-St-DPA micelles started to decrease. When degree of crosslinking was 15, the size was 92 nm, which is the most ideal size about EPR effect The mPEG-St-DPA micelles showed redox-response under 10 mM GSH. And they had good stability, because the sizes of mPEG-St-DPA micelles showed only slight change under 1000-fold dilution with PBS solution and 10-fold dilution with organic solvent. The results of protein adsorption test indicated mPEG-St-DPA micelles were hemocompatible. In vitro release studies revealed that the DOX release rate from DOX-loaded mPEG-St-DPA micelles was accelerated in the presence of 10 mM GSH, which was 70% in 72 h. The results of MTT showed that mPEG-St-DPA micelles had good biocompatible, and DOX-loaded mPEG-St-DPA micelles had good cellular proliferation inhibition ability.