Design And Synthesis Of Amphiphilic Macromonomers And Study On Their Polymer Properties

Because amphiphilic polymers have both hydrophili c and hydrophobic segments,they can self-assemble in the aqueous phase to form nanometer-sized polymer micelles.Because of its unique core-shell structure,micelles are widely used as drug carriers for loading hydrophobic anticancer drug molecules and improving their bioavailability.Linear amphiphilic copolymers are generally composed of independent hydrophilic and hydrophobic segments.Therefore,in the process of preparing the copolymer,it is required to introduce the hydrophilic and hydrophobic segments by a controlled polymerization method.But this undoubtedly increases the difficulty of regulating the hydrophilic and hydrophobic ratios of the copolymer.In order to achieve convenient control of the hydrophilic and hydrophobic ratios of copolymers,amphiphilic macromonomers with clear structures can be prepared first.Then based on the direct polymerization of the macromonomer,we can conveniently obtain amphiphilic polymers with the same hydrophilic and hydrophobic ratios.And because of the polymer's unique amphiphilic brush-like structure,the resulting amphiphilic brush copolymer will have different properties and self-assembly behavior from traditional linear polymers.Therefore,this dissertation is based on the above ideas to carry out research work.After successful preparation of amphiphilic brush polymer by controlled living radical polymerization,we can get some rules that can be used to guide the construction of micelle drug carriers based on this idea by further comparing the self-assembly behavior of amphiphilic macromonomers and amphiphilic brush polymers and the performance of self-assembled micelles as drug carriers.The specific research content of each chapter is as follows:The first chapter of the dissertation mainly introduces the research background and project basis of the dissertation.The next research is divided into two parts.In Chapter 2,we used hydroxyethyl methacrylate(HEMA)as the initiator,and prepared the hydrophobic macromonomer HEMA-PLA containing an average of 5 LA units by ring-opening polymerization of lactide(LA),and at the same time,a hydrophilic oligoethylene glycol monomethyl ether(mPEG)segment modified with weakly acidic pH-sensitive acetal bonds was prepared.The target amphiphilic macromonomer,HEMA-PLA-a-PEG,was prepared by coupling the two through the acyl chloride reaction between the two segments.Furthermore,the method of reversible addition-fragmentation chain transfer polymerization(RAFT)was used to directly polymerize the above macromonomers with 4-cyanovalerate dithiobenzoic acid(CPADB)as a chain transfer reagent to obtain amphiphilic copolymer,P-(HEMA-PLA-a-PEG).The molecular weight(M_n)is 13.6 kDa,and the molecular weight distribution index(PDI)is 1.31.We compared the stability of the micelles formed by the self-assembly of amphiphilic macromonomers and amphiphilic brush polymers under pH conditions of 7.4,6.8,and 5.0 by dynamic light scattering(DLS).The morphology of the self-assembled micelles was observed with a transmission electron microscope(TEM).Finally,using doxorubicin(DOX)as a model drug,the drug-loaded micelles were further prepared,and the in vitro drug release behavior of brush-shaped amphiphilic polymer micelles was studied.In drug release experiments,agglomeration of drug-loaded micelles was observed.The reason for the instability of drug-loaded micelles may be that changes in the environment have a greater influence on the acetal bond,and the instability caused by easy breakage.The above results indicate that in the design of polymer structures,when we want to design pH-sensitive polymers,we should choose to introduce more stable pH-sensitive bonds.In Chapter 3,in order to test the hypothesis of the instability of drug-loaded micelles caused by the acetal bond breaking in Chapter 2,we bridged the hydrophilic mPEG and hydrophobic HEMA-PLA segments in Chapter 2 with reduction-sensitive disulfide bonds.We keep the ratio and so on,and prepared the macromonomer with reduction sensitivity,HEMA-PLA-SS-PEG,and further synthesized amphiphilic brush polymer by RAFT polymerization.The successful preparation of macromonomers and polymers was characterized by H~1NMR,Size Exclusion Chomatography-Multi-Angle Laser Light Scattering(SEC-MALLS)and other methods.Its M_n is 22.9 kDa and PDI is 1.71.At the same time,in order to compare and explain the effect of the introduction of disulfide bonds on the drug loading performance and drug release behavior of self-assembled micelles,we also prepared non-reduction sensitive amphiphilic macromers without disulfide bonds and corresponding amphiphilic brush copolymer,its M_n is 3.4kDa and PDI is 1.06.This system is relatively stable.The next step is still in progress.