| Cyclodextrins(CDs)are one of the most representative cyclic polymers due to the widely applications,facile functionalization,unique amphiphilicity and the ability to form inclusion complexes.The combination of cyclodextrin chemistry and polymer science has created a novel interdiscipline via elegant integration of host-guest chemistry and controlled living polymerization.The self-assemblies formed by cyclodextrin-based supramolecular polymers as drug delivery systems are the most widely investigated drug controlled delivery systems in recent years.Among the various drug carriers,the drug carries formed by cylodextrin-based supramolecular polymers has attracted great attention for their unique properties due to their good biodegradability and biocompatibility.Moreover,CDs unique hydrophobic cavity with specific dimensions confers them to associate/disassociate with specific guest molecules to fabricate supramolecular inclusion complexes under certain stimuli.In this thesis,?-cyclodextrin was selected as raw oligosaccharide,and was further modified to associate with ferrocene derivative to obtain a ROS-responsive amphiphilic supramolecular self-aggregates,which was utilized as drug carriers.The self-assemblies were further investigated in terms of self-assemble behavior,ROS/GSH-triggered behavior,drug release behavior in vitro.The specific contents of this dissertation were summarized as follows:(1).Three types of CD-functionalized polymers were summarized according to the location of the CDs in the polymer chain.I.CDs embedded in the polymer backbone.II.CDs centered/bridged to construct polymer.III.CDs suspended on the polymer side chain.Polymers with a CD-embedded backbone can be formed ether by host-guest interaction to construct polyrotaxanes or by covalent linkage in the backbone.CD-pendant polymers can be prepared by two strategies.One is the direct polymerization of CD-based monomers,while the other is to conjugate CD derivatives to pre-existing polymers.CD-functionalized polymers for cancer therapy were discussed in this dissertation.(2).By using a reducible ?-cyclodextrin-ferrocene double-head unit,novel dual-redox responsive supramolecular copolymers was prepared.The hydrophobic supramolecular unit was composed of a disulfide-bridged ?-cyclodextrin-ferrocene(Fc-SS-?-CD)double-head unit,which could be self-assembled sequentially via the host-guest recognition,while the traditional hydrophilic segment was a homopolymer composed of poly(oligoethylene glycol methacrylate)with Fc terminus(Fc-P(OEGMA)).By mixing hydrophobic Fc-SS-?-CD and hydrophilic Fc-P(OEGMA)in solution,supramolecular amphiphilic block copolymers with ?-CD/Fc junctions were prepared.The resultant supramolecular amphiphilic block copolymers could be adjusted easily by changing the molar mixed ratio from 1:1 to 3:1,leading to the formation of different self-assemblies.The hydrodynamic size of micelles and vesicles are 147 nm and 381 nm,respectively.The supramolecular micelles and vesicles deformed and promoted drug release in response to the intracellular oxidizing or reducing environments,in which a high concentration of ROS and GSH would dissociate the noncovalent ?-CD/Fc connection or disrupt the covalent disulfide bond.To further investigate the ROS and GSH-triggered pharmacokinetics for potential cancer therapy,DOX was encapsulated into the supramolecular self-aggregates.Incubation with 10 mM TCEP resulted in over 60% and 52% DOX release from micelles and vesicles,respectively.Treating with 1 mM NaClO resulted in over 54% and 43% DOX release from micelles and vesicles,respectively,after 72 h.Thus,this work provides a new platform achieving dual-redox responsive anticancer drug delivery.(3).A series of novel ROS-responsive supramolecular star copolymers were prepared via host-guest recognition between ?-CD and Fc.These supramolecular micelles were constructed by host-guest complexation between a multi-armed hydrophobic poly(?-caprolactone)with Fc terminus(Fc-PCL)and a hydrophilic poly(oligoethylene glycol methacrylate)(3Br-?-CD-(POEGMA))initiated by ?-CD in an aqueous solution.To investigate the stability of the polymeric micelles formed by the supramolecular star polymers,three hydrophilic blocks with different degrees of polymerization(DPs)of 24,31,and 48 were prepared,and employed to assemble with a four-armed Fc modified poly(?-caprolactone)in an aqueous phase.The DLS data revealed that the 12-armed amphiphiles with the hydrophilic block of DP 48 showed the best stability in PBS(pH 7.4,150 mM)due to the highest critical aggregation concentration(CAC).In addition,the 12-armed amphiphiles also had a higher CAC compared to that of 9 and 18-armed amphiphiles with the same hydrophilic moiety.To further investigate the ROS-responsive drug release profiles for potential cancer therapy,DOX was encapsulated into the supramolecular micelles.Incubation with 0.2 mM NaClO resulted in over 70%,63% and 69% DOX release from 9-armed,12-armed,18-armed amphiphiles,respectively,after 72 h.Among these amphiphiles,the 12-armed supramolecular self-aggregates possess the highest drug loading content(DLC)and entrapment efficiency(EE).Hence,this work presents novel ROS-sensitive supramolecular star-shaped copolymers as potential anticancer drug delivery systems. |
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