Synthesis,Self-assembly And Application Of Stimuli-responsive Multi-block Copolymers

Stimuli-responsive copolymers, whose behaviors depend strongly on the external stimuli, such as temperature, pH, ionic strength, light and electric field, have attracted increasing research attentions for their wide range of applications in genetics, drug delivery, chemical and biological sensors, etc.. This dissertation mainly focuses on the controlled synthesis, fabrication, and structural tuning of stimuli-responsive copolymers. A series of amphiphilic and double hydrophilic linear block copolymers with stimulus response were synthesized. In aqueous solution, chain architectural effects on their self-assembling properties under varying solution conditions were investigated. Finally, we studied the drug delivery behaviors of the embedding of this anti-cancer drug doxorubicin (DOX) micelles in a simulated human body environment. This dissertation can be further categorized into four main parts as described below:1. A well-defined thermoresponsive poly(ethylene glycol)-block-poly(N-isopropy-lacrylamide)-block-poly(ε-caprolactone)(PEG43-b-PNIPAM82-b-PCL87) triblock copolymer was synthesized by combination of atom transfer radical polymerization (ATRP), ring opening polymerization (ROP) and click chemistry, and all the structures of the polymers were determined. The thermoresponsive triblock copolymer can disperse in water at room temperature to form core-shell micelles with the hydrophobic PCL block as core, the thermoresponsive PNIPAM and hydrophilic PEG blocks as shell. At temperature above lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PCL core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing.2. Well-defined linear amphiphilic tetrablock quaterpolymers with dual stimulus-response, poly(ethylene glycol)-b-poly(styrene)-b-poly(N-isopropylacrylamide)-b-poly(2-(dimethylamino)ethyl methacrylate)(PEG-b-PS-b-PNIPAM-b-PDMAEMA), were successfully synthesized through the combination of ATRP and RAFT by a click chemistry site transformation approach. Bromine-terminated diblock copolymer PEG-b-PS-Br was first prepared by ATRP of styrene initiated with macro-initiator PEG-Br, which was prepared from the esterification of PEG and2-bromoisobutyryl bromide. PEG-b-PS-Br can then be converted into the azido-terminated diblock copolymer, PEG-b-PS-N3, by nucleophilic substitutions. Site transformation of PEG-b-PS-N3into a macro-chain transfer agent (CTA) for RAFT polymerization was accomplished using a copper-catalyzed click chemistry approach. Afterwards, the novel linear tetrablock quaterpolymers PEG-b-PS-b-PNIPAM-b-PDMAEMA were synthesized by successive RAFT polymerizations of NIPAM and DMAEMA. The polymerization data indicated that both RAFT processes were well controlled. The structures of the linear amphiphilic tetrablock quaterpolymers and corresponding precursors were characterized by1H NMR, FTIR and GPC. In aqueous solution, the obtained amphiphilic tetrablock quaterpolymers, which contained a pH-responsive PDMAEMA block and a thermo-responsive PNIPAM block, self-assembled into micelles consisting of PS cores and hybrid PEG/PNIPAM/PDMAEMA shells, which were characterized by DLS and TEM.3. Multi-responsive hydrophilic ABCBA-type pentablock copolymer, consisting of poly(ethylene glycol), poly(N-isopropylacrylamide), and poly(2-(diethylamino)ethyl methacrylate), PDEA-b-PNIPAM-b-PEG-b-PNIPAM-b-PDEA, was synthesized by consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymerization showed all the expected features of living radical polymerization and allowed the synthesis of copolymers with controlled lengths of the PNIPAM and PDEA blocks. Due to multi-component, and multi-functional nature of the pentablock copolymer, the solution properties can be manipulated by changing the parameters such as temperature, pH etc. For example, the copolymer can be dissolved in acidic aqueous solution at room temperature, since the pH was below the pKa of the PDEA block, and the temperature was below the lower critical solution temperature (LCST) of the PNIPAM block. While in alkaline solution at room temperature, the copolymer self-assembled into core-shell-corona micelles with the hydrophobic PDEA block as core, the thermo-responsive PNIPAM block as shell and the hydrophilic PEG block as corona. At elevated temperatures in acidic media, the copolymer self-assembled into PNIPAM-core micelles with mixed hydrophilic PEG and pH-responsive PDEA coronas.4. The hydroxyl-terminated RAFT reagent was employed to mediate the ring-opening polymerization (ROP) of ε-caprolactone (CL). Then RAFT polymerization of glycidyl methacrylate (GMA) and poly(ethylene glycol) methyl ether methacrylate (PEGMA) was carried out using PCL as macro-RAFT agent to produce the triblock copolymers, PCL-b-PGMA-b-P(PEGMA). Finally, the azido-terminated polymers were coupled by click chemistry with a fluorescent alkyne,7-propinyloxy coumarin, to prepare fluorescent copolymers. The obtained coumarin unit containing polymers were characterized with UV-vis and fluorescence spectra techniques. The triblock copolymer with fluorescent coumarin can disperse in water at room temperature to form core-shell micelles with the hydrophobic PCL and fluorescent-terminated PGMA blocks as core, the hydrophilic P(PEGMA) block as shell. This work investigated the controlled drug release behavers obtained from DOX-loaded micells in aqueous solution. The results showed these micelles achieved high drug loading efficiencies of77%at an initial DOX loading content of10wt%, and the resulting micelles exhibited significantly inhibited DOX release. MTT assays in fibroblasts (3T3) and human bladder cancer cells (UMUC3) showed that the micelles were non-toxic. These core-shell micelles with excellent biocompatibility, superior drug loading, high extracellular stability, and controlled drug release are promising for anticancer drug delivery.