Construction Of Natural And Synthetic Phosphorylcholine-containing Nanocarriers For Drug Delivery

Phosphorylcholine is one of the compositions of the organism and plays important roles in cell membrane and exocrine bodies.Phosphorylcholine-based polymers have been extensively investigated in medical devices and tissue engineering due to their excellent biocompatibility and biosecurity.Many reports have revealed the unique in vivo circulation performance of phosphorylcholine-containing nanoparticles,demonstrating the important prospect of nanocarrier based on phosphorylcholine.As a natural phosphorylcholine-rich nanocarrier,exosomes were researched firstly in this dissertation.By taking advantage of superparamagnetic nanoparticles cluster technology,an exosome-based superparamagnetic nanoparticles cluster was developed by anchoring multiple superparamagnetic nanoparticles onto each reticulocyte-derived exosome through transferrin-transferrin receptor interaction.These clusters increase the magnetization in a controllable manner while retaining its superparamagnetic characteristics,realizing the efficient separation of blood exosomes and the re-dispersion of exosomes after removing the external magnetic field.Moreover,these clusters can realize the magnetic targeting delivery of drug to tumor under external magnetic field facilitating the inhibition of tumor.This is the first time to separate exosomes from blood for drug delivery.The concept of exosome-based superparamagnetic nanoparticles cluster simultaneously solves the three major problems of unsuitable donors,low scalability,and insufficient targeting ability in the design of exosome-based drug delivery systems,facilitating the clinical translation of exosomes.Secondly,a kind of microenvironment-responsive nanocapsules was synthesized by in situ radical polymerization employing 2-Methacryloyloxyethyl phosphorylcholine as monomer and matrix metalloproteinase-2 responsive peptide as crosslinker.The phosphorylcholine-rich polymer shell shields the internal protein from attack of protease and opsonin,leading to the enhancement of circulation time and lesion retention of proteins and the reduction of side effects and immune responses of proteins.Once accumulated in matrix metalloproteinase-2 overexpressed lesions,nanocapsules can be degraded to release cargo protein for therapy.By using Nimotuzumab and Bone Morphogenetic Protein-2 as models,the tumor inhibition and bone healing promotion in vivo were studied respectively.Nimotuzumab nanocapsules could retain in glioma for 30 days after intravenous injection,dramatically improving the therapeutic effects of Nimotuzumab.Bone Morphogenetic Protein-2 nanocapsules could also accumulate and retain in bone injury site after intravenous injection,releasing Bone Morphogenetic Protein-2 under the action of matrix metalloproteinase-2.The bone injury repair of Bone Morphogenetic Protein-2 nanocapsules is obviously faster than native Bone Morphogenetic Protein-2,and no ectopic osteogenesis was found.These studies explore new ways for the clinic protein therapy.