New Drug/Gene Delivery Systems based on PEOz and PLLA Block Copolymers

• Main Authors: Chau-Hui Wang, 王朝暉
• Other Authors: Ging-Ho Hsiue
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/72722459518196351710

博士 === 國立清華大學 === 化學工程學系 === 93 === Polymeric micelles based on poly(L-lactide)-poly(2-ethyl-2- oxazoline)-poly(L-lactide) (PLLA-PEOz-PLLA) ABA triblock copolymers were designed as intracellular drug carriers. The PLLA-PEOz-PLLA micelles adopt a “flower-like” arrangement with A-blocks at the core and a B-block on the shell under neutral condition. The deformation of the core-shell structure is then promoted by the aggregation of PEOzs due to the formation of inter- and intra-hydrogen bonding between protonated nitrogen and carbonyl groups. The doxorubicin (DOX)-loaded micelles were stable at pH 7.4 aqueous solution over 19 days. In contrast, about 60 wt.% of DOX was released from micelles at pH 5.0 within the first 3 h. The growth inhibition effect of micelles approached that of free DOX at a concentration of 1000 μg/mL after 24 h of coincubation with HeLa cells. The result of CLSM observation indicated that the release of drug was successfully triggered in the acidic organelles due to the deformation of the micelle structure. The combined mechanisms of pH-triggered release and biodegradability emerge as having great potential to overcome the disadvantages of conventional dosage forms. On the other hand, the ability of amphiphilic block copolymers that comprise polyethylenimine (PEI) and poly(L-lactide) (PLLA) to modulate the delivery of plasmid DNA was evaluated. Folate-polyethylenimine-block-poly(L-lactide) (FEA) was synthesized by linking folic acid and PLLA to PEI diamine. Water-soluble polycation PEI provides gene-loading capability. Additionally, PEI, which consists of second amine and tertiary amide functional groups, is considered to exhibit high transfection efficiency and endosomal disrupting capacity. Hydrophobic PLLA that is incorporated into the gene delivery vector is believed to enhance the cell interactions and tissue permeability of the delivery system. Polymeric carrier containing folic acid is expected to be able to identify tumor surface receptors and transfect cells by receptor-mediated endocytosis. The results of agarose retardation assay indicated that the FEA began to form polyplexes at a P/D ratio of over 10X, whereas branched polyethylenimine (B-PEI) formed polyplexes with DNA at a ratio of above 1X. The spherical particle morphology was supplemented with a particle size of approximately 100 nm at 10X P/D ratio. However, FEA exhibited lower cytotoxicity but also lower transfection efficiency than those of B-PEI and L-PEI, and the expression of luciferase increased as the free folic acid concentration declined.