Synthesis And Controlled Drug Release Of Nanocarriers Based On Supramolecular Polymers And Graft Copolymers

To date,functional nano-drug carriers have become an important and indispensable mean for the diagnosis and therapy of cancer.Therefore the preparation and application of functional nano-drug carriers have been hot researches for chemistry and biomedicine researcher.The key part in preparing nano-drug carriers is materials' functionality.Compared with traditional covalent polymer,supramolecular polymers show a variety of amazing properties,such as stimuli-responsiveness,easyprocessability,and self-healing,in virture of their nature of non-covalent interactions.Simultaneously,due to the fact that graft polymers contain more side chains,it has a unique advantage in functional modification and self-assembly.Although,the self-assembly of supramolecular polymers and graft polymers has been widely reported,they are seldom used in the preparation of functional nano drug carriers.Meanwhile,it is necessary to improve the drug carriers' preparation and functionality through changing the construction to seek a simple with a simple modification process or with reversible polymer.Thus,in this dissertation,a series of supramolecular and graft polymers were prepared,We invested the relationship between the supramolecular and graft polymers' structures on the nano-drug carriers' morphology,functionality and the drug delivery,controlled release and targeting capabilities of those supramolecular polymer and graft polymer self-assembles were also studied.The major contents of this thesis are as follows:(1)Supramolecular self-assembly and drug release research of ?-cyclodextrin dimers.Two ?-cyclodextrin dimers LA-(CD)2 and AZO-(CD)2 were prepared by click reaction,with lithocholic acid(LA),azobenzene(AZO)and beta cyclodextrin(?-CD)as raw materials.The self-assembly behaviors of LA-(CD)2 and AZO-(CD)2 were tested by UV/Vis absorption spectroscopy,1H NMR,2D NOESY spectra,dynamic light scattering(DLS)and transmission electron microscopy(TEM),respectively.The results indicated that LA-(CD)2 and AZO-(CD)2 self-assembled into micelles in DMSO/H2 O mixed solvent.In an aqueous solution,LA-(CD)2 and AZO-(CD)2 self-assembled into spherical micelles without ultrasonication.The primary micelles dissociated and then secondarily self-assembled into branched structures under ultrasonication.The branched aggregates of LA-(CD)2 and AZO-(CD)2 could revert to primary micelles at high temperature and UV light,respectively.The ultrasound-driven secondary self-assembly was confirmed by ultrasonic solution and Cu2+-responsive experiments.The primary micelles are driven by hydrophilic-hydrophobic interactions,whereas host-guest interactions promote the formation of the secondary assemblies.LA and DOX are all hydrophobic anticancer drugs,DOX encapsulated LA-(CD)2micelles could form a LA and DOX co-delivery nano-drug carrier LA-(CD)2/DOX.In vitro drug release experiments indicated that the release of DOX is controlled by both ultrasound and pH,while the release of LA is controlled by pH only.Biological experiments confirmed that LA-(CD)2/DOX shows a DOX and LA synergistic anticancer effect.(2)Preparation and controlled drug release of “breathing” hollow nanospheres based onhost-guest interaction of ?-cyclodextrin.Fistly,?-CD ended polymer ?-CD-PDEA was prepared through atom transfer radical polymerization(ATRP),and AZO ended block polymer AZO-PIEMA-b-PNIPAM containing carbon-carbon double bond in side-chain was prepared by a two-step ATRP reaction and an acid anhydride ring-opening reaction.The linear supramolecular copolymer PDEA-b-PIEMA-b-PNIPAM was first constructed through the host-guest inclusion complexation between AZO and ?-CD in pH 6.0 aqueous solution.PDEA-b-PIEMA-b-PNIPAM-based solid nanospheres with PDEA core and PIEMA-b-PNIPAM shell were prepared by adjust the pH from 6.0 to 9.0 and 253 nm UV light-triggered cross-linking of the C=C double bond in the shell layer.Finally,PIEMA-b-PNIPAM hollow nanospheres were constructed through removing the PDEA core using dialyzed method at pH 6.0 and 365 nm UV light irradiation.The preparation process and structure of PIEMA-b-PNIPAM hollow nanospheres were confirmed by UV/Vis absorption spectroscopy,1H NMR,2D NOESY spectra,dynamic/static light scattering(DLS/SLS),and transmission electron microscopy(TEM),respectively.The hollow nanospheres demonstrated a thermo-induced ‘‘breathing'' behavior owing to the presence of the thermo-responsive PNIPAM segments.The hollow nanospheres exhibited controlled drug release behavior triggered by their distinct “breathing” characteristics and good biocompatibility.The DOX · HCl-loaded hollow nanospheres showed a statistically higher cytotoxicity against A2780 cells at 37 oC than that at 25 oC.(3)Reversible morphology transitions of cyclodextrin supramolecular polymer self-assemblies for switch-controlled drug release.We prepared a series block polymer(?-CD)2-g-(PDEA-b-PEG-b-PDEA)-g-(?-CD)2)(P1,P2 and P3)with different degrees of polymerization of DEA.Three different branched supramolecular polymers(SBCP)were prepared by host-gest interaction between ?-CD in P1,P2 and P3 and AZO in mPEG-AZO,.The structure and self-assembly were confirmed by UV/Vis absorption spectroscopy,1H NMR,2D NOESY spectra,dynamic/static light scattering(DLS/SLS),and transmission electron microscopy(TEM),respectively.We found that SBCP constructed by P1 and mPEG-AZO can first self-assemble into vesicles without UV light irradiation and reassemble into solid nanoparticles with the dissociation of vesicles induced by 365 nm UV light irradiation.The nanoparticles can be further dissociated with the association of similar vesicles under visible light irradiation.The reversible self-assembly morphology transition process,accompanied by the destruction and reconstruction of SBCP,can be utilized to conduct switch-controlled drug release.Drug release can be enhanced at the dissociation stage of vesicles and nanoparticles and inhibited when vesicles and nanoparticles were associated.(4)Preparation and application of thermo and pH dual-controlled charge reversal amphiphilic graft copolymer micelles.A series of thermo and pH dual-responsive PSMA89-g-P(DMA16-co-SD)graft copolymer micelles with a fixed content of PDMA and different amounts of SD were conveniently prepared.The content of SD influenced the size,CMC,LCST,and zeta potential of these micelles.The enhanced degree of ionization of SD and COOH groups induced the zeta potential of PSMA89-g-P(DMA16-co-SD56)micelles toreverse from positive charges to negative ones at pH 7.4 and 37 oC,whereas the protonated PDMA segments drove the zeta potential to reverse into positive again at pH 6.8 and 37 oC.DOX-loaded PSMA89-g-P(DMA16-co-SD56)micelles showed pH-and thermo-controlled drug release and charge reversal behaviors.The cellular uptake efficiency,fluorescence microscopy observations and MTT assays indicated that the thermo and pH dual-controlled charge reversal property enhanced the efficiency of DOX-loaded PSMA89-g-P(DMA16-co-SD56)micelles to overcome the MDR of A2780/DoxR cells at pH 6.8and 37 oC.The DOX loaded PSMA89-g-P(DMA16-co-SD56)micelles showed a longer circulation time and higher tumor uptake than free DOX.