Surface Modification And Properties Of Polylactic Acid Nanoparticles With Crosslinked Cell Membrane Mimetic Structure

The suface of PLA nanoparticles (NPs) is hydrophobic. The hydrophobic nanoparticles can be rapidly eliminated from the bloodstream by the mononuclear phagocytic system immediately upon intravenous injection. The biocompatibility and hydrophilicity of a material will be significentily improved when modified by polymers bearing phosphorylcholine (PC) groups. In order to build a cell outer membrane mimetic structure on the suface of PLA NPs, block copolymers with PLA and Methacryloyloxyethyl phosphorylcholine MPC were reported by living polymerization methods. But the application of these block copolymers in drug carrier systemes is limited due to their harmful catalyst used, complicated operation and high cost. Surface modification with cell outer membrane mimetic structure on the surface of PLA NPs was also reported by physical adsorption of an amphiphilic random copolymer. However, the modification with cell outer membrane mimetic structure on the surface of PLA NPs via crosslinking treatment to get stable coating is rarely reported.In this dissertation, the crosslinked modification with cell outer membrane mimetic structure on the surface of PLA NPs was performed by solvent evaporation and nanoprecipitation methods. In this strategy the crosslinker is the trimethoxysilylpropyl group, which is crosslinked in pH8-9aqueous dispersion. The nanoparticles showed excellent drug controlled release capability and anti-cytophagy performance. Major works are summarized as follows:(1) Two phosphorylcholine based polymer PMB and PMBT were synthesized by the radical polymerization of MPC, n-butyl methacrylate (BMA), and the crosslinkable monomer trimethoxysilylpropyl methacrylate (TSMA).1H-NMR measurement results showed that the polymers were synthesized successfully. The aggregation behavior of the two polymers in aqueous solution was explored by dynamic light scattering(DLS). The results suggested that the impact of the MPC polymer micelles to the PLA-nanoparticle systems could be eliminated by several times of centrifugation and washing.(2) Cell outer membrane mimetic structure modified PLA nanoparticles were prepared by solvent evaporation method. The influnce of stirring speed and the PC polymer concentration to the preparation system was explored. From the nanoparticles size determination characterized by DLS, we concluded that nanoparticles were prepared successfully, and its size was about220nm. PVA modified PLA NPs were also prepared by nanoprecipitation method, the size of the nanoparticles was about220nm.(3) The PMB, PMBT, PVA modified drug loaded-PL A NPs were prepared via solvent evaporation and nanoprecipitation methods.Adriamycin was choosen as a hydrophobic model medicine. The crosslinked cell outer membrane mimetic structure modified PLA NPs were prepared by the crosslinking of trimethoxysilylpropyl in pH8-9. The drug loading capacity (8%-14%) and entrapment efficiency (20%-40%) of adriamycin loaded nanoparticles were obtained. The drug controlled release capacity of the NPs were estimated by in vitro dialyse methods. The PMB, PMBT and PVA modified drug loaded NPs have longer release time than the free drug. Under pH=4.0condition, the cumulative release rate of adriamycin loaded NPs was20%-50%in62hours, but the free drug was70%in7hours. And the crosslinked cell outer membrane mimetic structure modified NPs showed the longest drug controlled release time. The crosslinked sample released24.2%in16days. But the PMB-coated NPs which was uncrosslinked released41.2%in the same period. It could be proved that the crosslinked networks on the surface of PLA NPs is successfully constructed.(4) Finally, the PMB, PMBT or PVA modified PLA NPs containning fluorescent probe coumarin were prepared by nanoprecipitation method. The anti-cytophagy capacity of these NPs were evaluated by cytophagy experiment. The PMBT crossllinking modified PLA NPs showed the best anti-cytophagy capacity. This crosslinked cell outer membrane mimetic structure modified NPs could be used as a potential long cycle drug carrier.