| Biodegradable polyesters have been used in the field of drug release in recent years due to their excellent degradability.Currently,biodegradable polyester material for the release of drugs,which mostly containing ester bonds,carbonate bonds and other groups,their degradation rate is very slow,resulting in the drug release is slow,which will reduce the efficacy of a certain extent,increase the cells of the drug resistance,is not conducive to the treatment of cancer.In order to further accelerate the release of drugs,the pH-sensitive poly(HPMA-polycaprolactone)(PHPMA-PCL)block polymer was prepared by introducing an acid labile hydrazone bond into the polycaprolactone backbone.In the caprolactone backbone,a disulfide bond was introduced to prepare a PCB-PNAS-PCL with a cross-linking reduction sensitive.Preparation of triblock reductive sensitive PCB-PCL-s-s-PCL-PCB by introducing disulfide bond in Polycaprolactone.The contents in this thesis are as follows:(1)Synthesis,characterization and property of PHPMA-Hyd-PCLThe acid-sensitive amphiphilic block polymer was prepared by using a hydrazone bond capable of hydrolyzing hydrazine under acidic conditions to form hydrophilic-amphiphilic block polymer as a carrier of anti-cancer drug doxorubicin.Simulated tumor conditions for rapid release.First,the RAFT reagent was used as the starting material,and the terminal was modified to form the RAFT reagent containing the aldehyde group at the end.Then,hydroxyethyl hydrazine was used as the initiator,caprolactone as the monomer and stannous octoate as the catalyst.And then the addition of polycaprolactone with the above-mentioned terminal modified RAFT reagent was carried out.Finally,macromolecule RAFT reagent was used as initiator and HPMA as monomer was used for RAFT polymerization,which preparated of an acid-sensitive polymer carrier.The blank micelles and adriamycin-loaded micelles of pH-responsive PHPMA-Hyd-PCL diblock copolymers were prepared by dialysis.The particle size,morphology,entrapment efficiency and drug loading of the micelles were determined.The propane release behavior of adriamycin loaded micelles was studied.The results showed that the release behavior of the micelles was significantly accelerated after reducing the pH(pH 5.0)behavior under simulated normal physiological conditions(pH 7.4),indicating that the release behavior of the micelles was pH-responsive.(2)Synthesis,characterization and property of PCB-NAS-PCLHerein,versatile shell-cross-linked nanoparticles(SCNPs)were prepared by one-stepassemblyofzwitterioniccopolymers,polycarboxybetaine methacrylate-copolymer-N-(acryloyloxy)succinimide)-block-poly(2-(caprolactone)P(CB-co-NAS)-b-PCL,which was well-defined via reversible additive fragment transfer(RAFT)polymerization,followedbycross-linkingbetweenthe N-hydroxysuccinimide(NHS)-activated acrylic acid(NAS)functionalities presented within the shell by the addition of cystamine,a diamine crosslinker containing a central,cleavable disulfide linkage.The structure of the copolymer was characterized by ~1H NMR.Thus,the P(CB-co-NAS)-b-PCL SCNPs cooperatively combine the ultra redox sensitive PCL core for efficient drug loading and redox-responsive drug release,the disulfide-cross-linked NAS shell that prevents premature drug release,the zwitterionic PCB corona to stabilize the SCNPs and prolong its systemic circulation.Doxorubicin(DOX)wasloadedasamodelmedicine(termedas P(CB-co-NAS)-b-PCL/DOX SCNPs).DOX release from the nanoparticles in PBS buffer was accelerated in the presence of glutathione at pH 7.4,reaching 80.59%cumulative drug release after 8 h,whereas only 17.25%extents of release were observed in the absence of glutathione at pH 7.4,respectively.The self-assembly behavior of the polymer in aqueous solution was detected by transmission electron microscopy(TEM)and dynamic laser light scatterometer(DLS).(3)Synthesis,characterization and property of PCB-PCL-SS-PCL-PCBTo minimize cardiotoxicity and to increase the bioavailability of doxorubicin,polymersomes based on redox sensitive amphiphilic triblock copolymer poly(carboxybetaine methacrylate)-poly(caprolactone)-s-s-poly(caprolactone)-poly-(carboxybetaine methacrylate)(pPCB-PCL-ss-PCL-p PCB)with disulfide linkage were designed and developed.The polymers were synthesized by ring opening polymerization(ROP)ofε-caprolactonefollowedbyreversible addition-fragmentation chain transfer(RAFT)of PCB.The triblock copolymers demonstrated various types of nanoparticle morphologies by varying hydrophobic/hydrophilic content of polymer blocks,with PCB content of 40%in the triblock copolymer leading to the formation of polymersomes in the size range 150 nm.High doxorubicin loading content of 21%was achieved in the polymersomes.Disulfide linkages were incorporated in the polymeric backbone to facilitate degradation of the nanoparticles by the intracellular tripeptide glutathione(GSH),leading to intracellular drug release.Release studies showed 85.78%drug release in pH 7.4 in the presence of 10 mM DTT,whereas only 12.68%was released in pH 7.4. |
