Functionalized polyethylene glycol-polyamidoamine star polymers for pharmaceutical applications.

摘要

Polyamidoamine (PAMAM) StarburstRTM dendrimers possess precise and very low polydispersed size, high functionality and regular structural features. PEG was conjugated onto the dendrimer surface to generate favorable surface properties for PAMAM dendrimers. PAMAM dendrimers have been extensively investigated for pharmaceutical applications; however, PEG-PAMAM star polymers have not been thoroughly investigated previously. Therefore, PEG-PAMAM star polymers as drug delivery carriers in this dissertation were studied broadly in different aspects with the desire to create a safer and more effective delivery system for achieving better pharmaceutical treatments.; In this work, Penicillin V was successfully coupled with PAMAM dendrimer through PEG spacer. The methods presented in this dissertation could be extended to prepare star polymers with different PEG arm lengths and to couple different functional groups (drugs) of interest. PEG-PAMAM star polymers are able to increase water solubility of hydrophobic compounds because their hydrophobic inner core and hydrophilic PEG arms make them unimolecular dendritic micelles. The results also suggest pyrene solubilization could be associated with both the dendrimer core and PEG layer. Therefore, the arm length of PEG should be taken into account in designing such micelles for optimizing solubility enhancement of hydrophobic compounds. Dosage forms for the controlled release of venlafaxine were successfully designed based on anionic PAMAM dendrimers and semi-interpenetrating networks. Venlafaxine was released over extended time periods from venlafaxine-PAMAM conjugates. PEG-containing semi-interpenetrating polymer networks could effectively release venlafaxine in a controlled way by optimizing the PEG concentration and molecular weight. PEG long arms on the dendrimer surface could provide steric hindrance to the conjugated drug molecules on the dendrimer surface. We have demonstrated an alpha-chymotrypsin specific substrate became resistant to alpha-chymotrypsin hydrolysis when the substrate was directly conjugated to the dendrimer surface of PEG-PAMAM star polymer. PEGylation successfully reduced the cytotoxicity of G3.0 and G4.0 PAMAM dendrimers. A few PEG arms on dendrimers are still able to allow dendrimers good biocompatibility and leave unoccupied surface groups for coupling more ligands and drug molecules. The work revealed that PEG-PAMAM star polymers are promising as a drug carrier with a relatively wide spectrum of pharmaceutical applications.