Physiochemical Properties And Drug Release Behaviors Of Carboxyl Functional Polyester Magnetic Nanocomposites

Tumor was one of the major diseases threatening human health in the 21st century.Although conventional chemotherapy has achieved some success in the treatment of cancer,it still has many defects,such as low bioavailability,high dose requirements,significant side effects,easy to produce drug resistance.In order to improve the therapeutic effect of traditional chemotherapy,advanced nano sustained-release preparations have been widely concerned and studied.However,the system still has many limitations in clinical application,because of its insufficient drug loading,insignificant targeted,burst behavior,short half-life and single function.Therefore,it is necessary to design a new drug delivery system and study its release mechanism.In this thesis,mPEG-b-PCCL block copolymers were synthesized,which used its side chain carboxyl group to improve the sensitivity of the carrier to the tumor microenvironment,and constructed a series of nano drug delivery systems with different drug loading and multi stimulant response by blending with superparamagnetic Fe₃O₄ NPs and other copolymers.Through ¹H-NMR,GPC,IR,DSC,TGA,DLS,TEM,VSM,the molecular structure and molecular weight of the carrier material were analyzed,and the self-assembly behavior,physicochemical properties and drug release characteristics of the drug carrier system were studied.First,through anionic activation ofε-caprolactone（CL）and treatment with benzyl chloroformate,α-benzyl caprolactone（BCL）was synthesized.The synthesis of mPEG-b-PCCL was obtained by deprotected of mPEG-b-PBCL which was prepared by ring-openging polymerization of BCL using mPEG as the initiator.¹H-NMR and GPC results indicated that mPEG-b-PCCL structure could be well controlled with polydispersity index staying narrow.Second,the superparamagnetic nanocomposites mPEG-b-PCCL@Fe₃O₄ was prepared and used to encapsulate magnetite and paclitaxel to form drug-loaded magnetic nanocomposite with negative charges on the surface due to extending of carboxylic groups and PEG segment to aqueous phase.The nanocomposite with zeta potential-1.83mV was proved to have high PTX loading rate（25.6wt%）,high saturation magnetization and low cytotoxic in vitro.The nanocomposites presented faster PTX release in vitro at pH 6.5 than pH 7.4.After being injected with mPEG-b-PCCL@Fe₃O₄ and PTX/mPEG-b-PCCL@Fe₃O₄ formulation intravenously via vial vein,the mice showed no significant histological changes on lung,liver,kidney and spleen compared with saline control,whereas the histological tissue slides of tumor treated with PTX loaded mPEG-b-PCCL@Fe₃O₄ displayed significant atrophy and necrosis area.These results suggested that PTX loaded mPEG-b-PCCL@Fe₃O₄formulation can targeted release PTX to tumor site under external magnetic field.This anionic magnetite nanocomposite can be used as an anti-tumor drug vector potentially.Third,core-shell-mPEG-b-PCCL@Fe₃O₄ was successfully prepared by changing the composite mode of mPEG-b-PCCL@Fe₃O₄.Core-shell-mPEG-b-PCCL@Fe₃O₄ had smaller particle size,more carboxyl groups on the surface and enough saturation magnetic strength induced by external magnetic field.The stability of core-shell-mPEG-b-PCCL@Fe₃O₄ in distilled water at 37℃and buffer solution with different pH values was studied systematically.The results showed that the complex could be degraded in aqueous solution,and its degradation was divided into initial surface degradation and full swelling bulk degradation.The results of PTX release in vitro showed that core-shell-mPEG-b-PCCL@Fe₃O₄ could effectively inhibit drug burst in neutral environment while maintaining high drug loading efficiency and pH sensitivity.Fourth,in order to enhance the pH response of the drug loading system,the nanocomposites mPEG-b-PCL/mPEG-b-PCCL@Fe₃O₄ were successfully prepared by blending the block copolymers of mPEG-b-PCL,mPEG-b-PCCL and Fe₃O₄ NPs.In this nanocomposite system,the surface was smoother,the magnetic particles and PTX were more easily dispersed,and the carboxyl side groups on PCCL were more easily oriented towards the water phase to make zeta potential increase to-36.8mV,the drug loading was 16.91±1.98wt%.The release data in vitro showed significantly enhanced pH response.Finally,in order to construct an on-demand drug release system with double drug carriers,monomethoxy polyethylene glycol polythreonine（mPEG-b-PThr）block thermosensitive copolymer was introduced.The nanocomposites with thermosensitive nano hydrophilic microgel and hydrophobic microdomains were successfully prepared by double emulsion method.The spherical nanocomposites were regular in shape,smooth in surface.After the composite Fe₃O₄ NPs and different regions of the composites were loaded with hydrophilic molecules labeled with BSA_TITC and hydrophobic molecular Pyrene,respectively.The magnetocaloric effect of Fe₃O₄ NPs could initiate phase transformation of mPEG-b-PThr nanogel for achieving the on-demand drug delivery of the composite system.The drug loading rate of Pyrene was11.6±2.1wt%,and that of BSA_TITC was 5.2±0.6wt%.The drug release in vitro showed that dual drugs showed obvious on-demand release characteristics under the action of alternating magnetic field,and the pH sensitivity of Pyrene was higher than that of BSATITC.In summary,based on mPEG-b-PCCL block copolymers,Fe₃O₄ nanoparticles were blended,and further self-assembled with other functional copolymers to build a series of intelligent drug delivery systems with adjustable release characteristics.By controlling the self-assembly mode,the structure of composite particles can be controlled,and then the drug release characteristics can be controlled and improved.The magnetocaloric effect of magnetic particles is cleverly combined with thermosensitive hydrogel materials to form an on-demand drug release mode.The research results of this paper will provide valuable data and reference for precise and personalized treatment of tumor.