The Study Of Cell Membrane Mimicking Micelles For Cancer Imaging And Therapy

Polymeric micelles,which could reduce side effect and improve therapeutic effect of diagnostic or therapeutic agents by enhancing their solubility and tumor accumulation,have emerged as one of the most common nanoscale platforms for oncotherapy.This dissertation focused on the design and synthesis of cell membrane mimicking polymeric micelles,of which the shells were all constructed by zwitterionic phosphorylcholine(PC)and the cores were well-designed to offer various functions for cancer imaging and therapy.The main content are described as below:1.Acid-sensitive PC-shelled micelles were prepared for controlled drug delivery.The PC-based block copolymer(PMPC-b-PDDMMA)was synthesized via RAFT polymerization and could self-assemble into monodispersed micelles which possessed excellent stability in both protein and culture medium solutions.The 1H NMR result confirmed that the ketal-based hydrophobic PDDMMA block could be degraded into hydrophilic diol moieties under acidic condition.Meanwhile,accelerated release of anticancer drug(DOX)was observed at acidic pH 5.0.Cell experimental results indicated efficient internalization and DOX release of micelles,leading to considerable inhibition of the proliferation of HepG2 cancer cells.Moreover,targeted tumor accumulation was confirmed via in vivo imaging of NIR dye IR-780 loaded micelles.2.Acid-sensitive zwitterionic prodrug micelles were further prepared based on non-covalent host-guest interactions.The random copolymer poly(MPC-co-Ada)was synthesized via RAFT polymerization and the host-guest interaction between pendant adamantane groups and DOX decorated ?-cyclodextrins(DOX-hyd-CD)was confirmed by 2D NOES Y NMR.Theresultant supramolecular copolymer could self-assemble into prodrug micelles.In vitro drug release results exhibited efficient DOX release due to the cleavage of hydrazine bonds under acidic endo/lysosomal condition.Moreover,the prodrug micelles could successfully delivery DOX into cell nuclei and subsequently induce cytotoxicity to HepG2 cancer cells.3.Zwitterionic theranostic micelles were further designed for combined AIE imaging and pH-responsive drug delivery.The PC-based copolymer poly(MPC-co-FPEMA)with pedant benzaldehyde groups was synthesized via RAFT polymerization and further converted to PMPC-hyd-TPE after conjugation of AIE active TPE molecules.PMPC-hyd-TPE could self-assemble into micelles with TPE molecules incorporated in the micellar core to excite the AIE effect and for encapsulation of DOX.The swelling of DOX loaded PC-hyd-TPE-DOX micelles at pH 5.0 was observed by DLS,which could be due to the cleavage of TPE.Accelerated drug release behavior at pH 5.0 was also confirmed.Moreover,PC-hyd-TPE-DOX micelles could be efficiently internalized and induce remarkable cytotoxicity to HepG2 cells.Meanwhile,high-quality AIE imaging of PC-hyd-TPE micelles was realized in HepG2 cells.In addition,excellent micellar stability in DMEM culture medium and high protein resistance against plasma model proteins were confirmed by DLS and Brandford assay,respectively.Further ex vivo fluorescence imaging results demonstrated enhanced accumulation and DOX delivery of PC-hyd-TPE-DOX micelles in tumor tissue.4.Theranostic phospholipid mimicking micelles were further obtained through only one step polymerization and single dye encapsulation.The amphiphilic monomer MDPC was synthesized by simply increasing the alkyl chain length of the famous monomer MPC.Subsequently,amphiphilic homopolymer PMDPC was generated via RAFT polymerization and utilized to encapsulate the hydrophobic NIR dye IR-780,leading to improved light stability and phtothermal property.Cell experimental results indicated that IR-780 loaded micelles could induce remarkable cytotoxicity to pancreatic BxPC-3 cells upon NIR light irradiation.Further in vivo research confirmed targeted tumor accumulation as well as high resolution and long-term NIR imaging of IR-780 loaded micelles.