Study On Functional Nanomicelles Based On Diblock Copolymers And Dual-templates Molecularly Imprinted Polymers For Drug Delivery System

Background and Aims: Recently, poly(ethylene glycol)(PEG)-polypeptide block copolymers have been attracting significant interest for polymer therapeutics, such as drug and gene delivery systems. To further enhance the target efficiency to specific cells, we used the receptor-mediated delivery method, namely targeting ligands which are linked to various polymeric carriers to deliver genes. Methods: In the first part, we firstly modified the target ligands by different chemical methods to synthesize cholesterol-PEG-folate/cholesterol-PEG-galactose, which could combine with PEG-PLL polymer by physical mixing method. During the mixing, PEGs of polymer and ligands could combine with each other automatically by the hydrophilic effect, and cholesterol could interact with the polypeptide of PEG-PLL, so the ligands exposed on the surface of micelles. Results: The MALDI-TOF result showed that we successfully synthesized cholesterol-PEG-folate/cholesterol-PEG-galactose; And there are not big difference between just polyper and the polymer combined with ligands in particle sizes; From the cellular uptake test and transfection test, we can see that the uptake and transfection efficiency improved; The confocal flurescence microscope showed that 5% folate and 10% galactose could improve the flurescence expression; Finally, a certain amount of ligands doesn’t have obvious cytotoxicity. So cholesterol-PEG-folate/galactose ligands could be used in other cationic polymers/DNA or lipid/DNA complexs by flexible and various methods. Except for the gene vector, PEG-polypeptide also could be used as vector for drug delivery. As we all know, the interaction between drugs and vectors plays an important role in controlling drug delivery. Methods: For the second part, we synthesized PEG-PBLG, PEG-PLG polymer by ring-opening method to investigate the different drug release behavior, because PLG block could load more drugs by electrostatic and hydrophobic effect, but PBLG block just by hydrophobic effect. Results: The DLS result showed that the PEG-PBLG and PEG-PLG with DOX could form stable micelles with the size around 100 nm, but PEG-PLG/DOX micelle has a little bigger size; According to the drug loading content and efficiency, PEG-PLG(DLE 61.3%) is higher than PEG-PBLG(DLE 53.5%); In the vitro release, PEG-PLG(released over 60%) showed better release under lower p H, especially at p H 4.0, which means the it has the p H-sensitive property; The cytotoxicity tset showed that there is no toxicity for just polymer, once combined with DOX,the micells have some toxicity, which are dose-dependent, and the cytotoxicity of PEG-PBLG/DOX is a litter lower than another. In conclusion, compared to PEG-PBLG, PEG-PLG is more promising and competitive used in anticander drugs release. Multi-template imprinting is one of the new fields for molecular imprinting and molecular crowding technology is an effective way to promote the molecular imprinting effect. Methods: In the third part of this work, with methacrylic acid(MAA) as functional monomer, ethylene glycol dimethacrylate(EDMA) as cross linker, and polystyrene as molecular crowding agent, imprinted polymer was synthesized in the presence of dual-templates. The resulting MIPs were used as controlled release materials. We chose S-OFX as the first template, and investigated the effect of different kinds of the second-template to S-OFX. The second-template included triazines, nonsteroidal, quinolone and nimodipine analogues. Results: When nonsteroidal analogues were chosen as the second-template, the IF value for S-OFX was higher than others. When we chose S-OFX and S-NAP as the dual-templates, IF for S-OFX was 20.1 and IF for S-NAP was 10.9. In contrast, for the single-template MIPs, IF for S-OFX was 22.4, and IF for S-NAP was 11.9. No apparent difference in the single-template MIPs and dual-template MIPs meant that the molecular crowding reagent can improve the competition between dual-templates. Through equilbrium adsorption experiment, the adsorption properties of MIPs among different ratios of S-OFX/S-NAP was studied. When S-OFX/S-NAP ratio was 1/1, Qmax of S-OFX was 37.33 mmol/g, Qmax of S-NAP was 18.70 mmol/g, showing that crowding reagent can give rise to stronger adsorption properties. As a conclusion, the dual-templates imprinted polymer prepared with molecular crowded reagent is promising as drug delivery system.