Synthesis And Application Of Photo-and Reduction-Responsive Amphiphilic Block Copolymers

Stimuli-responsive polymers can respond to different external environmental stimuli by changing their physical or(and)chemical properties,and various types of stimuli have been applied including physical,chemical,or biological stimuli,such as temperature,light,pH,GSH,H2O2,or trypsin and so on.Among the stimuli-responsive polymers,amphiphilic stimuli-responsive copolymer can self-assemble into stimuli-responsive aggregates with various morphologies such as micelles,vesicles,and so on.And these stimuli-responsive aggregates are able to undergo diverse processes upon specific external stimulation,for instance,the morphological transformation or structure disruption,etc.In this regard,there have been a range of applications developed in controlled drug release,gene transfer,and biological signal molecules detection,etc.Stimuli-responsive vesicles play a crucial part in these applications.On the other hand,learning from the concept of prodrug,drug molecules can be introduced into the framework of stimuli-responsive amphiphilic copolymer and further self-assembled as drug nanocarriers.Compared with the traditional physical loading mode,the above method can bring about a higher loading rate,reduced toxicity and side effects,as well as optimized biodistribution and pharmacokinetics in vivo,etc.In this context,this thesis mainly studies the synthesis,self-assembly of amphiphilic stimuli-responsive diblock prodrug copolymer,and it application in controlled drug release.1.Inspired by the " traceless cross-linking " strategy,photo-and reductive-responsive methacrylate monomer derivative,CSSMA,containing the coumarin moiety and disulfide bond in the side group is designed and synthesized,which can undergo photolysis rapidly under visible light(e.g.,430 nm)irradiation.Then a series of dual responsive amphiphilic block copolymers,PEO-b-PCSSMA,are synthesized via RAFT(Reversible Addition-Fragmentation Chain Transfer)polymerization in the presence of a poly(ethylene oxide)(PEO)-based macroRAFT agent,based on which dual-responsive vesicles are prepared via a cosolvent self-assembly approach.Upon irradiation with a 430 nm LED light,the coumarin moieties embedded within the vesicular bilayer membranes are removed,uncaging the active primary amine groups that can spontaneously undergo inter/intrachain amidation reactions with the ester moieties in the polymer matrix or partially be protonated.The above processes not only improve the stability of the vesicle by crosslinking the bilayer membrane,but also lead to the hydrophobic-to-hydrophilic transformation and the improved permeability of the bilayer membrane.Therefore,the hydrophilic doxorubicin hydrochloride(DOX)small molecules loaded in the vesicular lumen can be released,while the relatively large hydrophilic molecules,tetramethylrhodamine labeled dextran(TR-dextran,Mw?1w),are still retained in the vesicular lumen.However,due to the existence of the disulfide linkage in the hydrophobic blocks of the polymers,the cross-linked vesicle can be disintegrated upon incubation with glutathione(GSH),resulting in the release of TR-dextran.Therefore,the dual-stimuli responsive vesicles enable the sequential release of co-loaded encapsulants with different molecular weight.2.A new type of photo-responsive prodrug monomer capable of alternative copolymerization is designed and synthesized via modifying 7-amino-4-hydroxymethyl coumarin.Two alkynyl groups are introduced through the reaction between propargyl bromide and the amino group,and the anti-cancer drug camptothecin(CPT)moiety is connected with the hydroxyl group using carbonate bond.Subsequently,the light-triggered drug release property of the prodrug monomer is verified.Upon irradiation with 365 nm LED light,the coumarin-CPT prodrug monomer can undergo photolysis to release CPT molecules completely within 18 min.