Synthesis And Properties Of Multi-Stimuli-Responsive Miktoarm Stars And Cyclic Polymers

Synthesis, properties and applications of topological polymers are important topics in current polymer science. The topology plays a crucial role in physicochemical properties of nonlinear polymers such as star, cyclic and hyperbranched polymers. Meanwhile, the introduction of cleavable linkages and stimuli-sensitive segments can further enhance the functions and multipurpose applications of topological polymers. Thus far, the examples of multi-stimuli-responsive star and cyclic polymers are relatively scarce. In this context, it is very important to develop facile methods to prepare various types of complex topological polymers and explore the structureproperty-application correlations. This study aims at controlled synthesis of multi-stimuli-responsive star copolymers and cyclic polymers and their versatile properties such as bioapplications, stimuli responsivenesses and thermoresponsive solution behaviors. Main contents and results are listed below.The research in Part 1 aims at synthesis of multi-responsive 3-arm star quaterpolymer and potential application in drug delivery for cancer therapy. First, three-step reactions were combined to synthesize the target 3-arm star copolymers PEG-a-PCL-SS-P（NIPAM-co-DMA）（S1-S3） and PEG-a-PCL-SS-PDMA（S4）. Starting from 2-（（2-（（2-hydroxymethyl-2-（pent-4-ynoyloxy）methyl）propionyloxy）ethyl）disulfanyl）ethyl 4-cyano-4-（phenylcarbonothioylthio）pentanoate（HCP）, successive ringopening polymerization（ROP） and reversible addition-fragmentation chain transfer（RAFT） process and copper（I）-catalyzed azide-alkyne cycloaddition（CuAAC） reaction gave 3-arm miktoarm stars S1-S4. The thermoresponsive behaviors could be efficiently tuned by changing the composition and chain length, and their cloud points were 34.4 oC（S1）, 44.7 oC（S2）, 47.6 oC（S3） and 60.0 oC（S4）. Second, multi-stimuli-responsive nanoparticles（MS-NPs） were prepared via coassembly of S2 with NIR photothermal agent Cypate and chemotherapeutic compound PTX. The nanoparticles could exhibit NIR light/pH/reduction-responsive drug release. Dynamic laser scattering（DLS） revealed that MS-NPs had an average hydrodynamic diameter（Dh） of 126 nm with particle size distribution（PD） of 0.051. 99.8% Cypate and 98.2% PTX were entrapped within MS-NPs at the total drug loading level of 40%（w/w）, indicating a highly effective loading capacity. Meanwhile, MS-NPs had good stability under different conditions. Third, the drug releases from MS-NPs were evaluated in response to acidic, reductive, thermo as well as NIR light-triggered thermal stimuli. The results demonstrate that MS-NPs possessed stimuli-triggered drug release properties, especially thermo-responsive resulting from the rapid dissociation generated by phase transition of P（NIPAM-co-DMA） segment of the star quaterpolymer. To precisely mimic NIR light-responsive drug release instead of the incubation at 45 oC, we evaluated the release of PTX from MS-NPs under 15-min irradiation（1.5 W cm-2） at 0 h, 4 h, 8 h or 12 h, respectively. Remarkably, the short-term NIR light irradiation was able to induce the enhanced continuous release of PTX from MS-NPs without turn-off. Fourth, we explored the anticancer efficacy of cellular level including cellular uptakes, endocytosis pathway, cytotoxicity, and lysosomal disruption. The nanoparticles possessed good capacity to improve the cellular uptakes of encapsulated agents due to suitable size and narrow size distribution. S2 star was found to have a negligible cytotoxicity even at the concentration of 200 μg mL^-1, revealing the good biocompatibility of MS-NPs. Importantly, MS-NPs exhibited the most severe cytotoxicity of 1.8 μg mL^-1 IC50 under NIR light irradiation, which is much lower than others. Last, in vivo biodistribution and NIRF imaging, tumor hyperthermia, and synergistic anticancer efficacy were investigated. We evaluated the biodistribution of MS-NPs on the mice bearing 4T1 tumors at the dose of 7.5 mg kg-1 Cypate/PTX. Both Cypate and PTX from MS-NPs were mainly accumulated in tumors at 24 h post-injection, and the NIRF signal of MS-NPs was much higher than other groups. In particular, MS-NPs generated the potent in vivo hyperthermia that can trigger the direct PTT efficacy, and NIR light-triggered smart drug release through fast phase transition, and subsequent drug translocation, which finally synergized the thermo-chemotherapeutic efficacy with tumor ablation. Therefore, MS-NPs had an ideal anticancer efficacy with tumor ablation.The study in Part 2 aims at synthesis of multi-stimuli-responsive cyclic poly（N,N-dimethylaminoethyl methacrylate）（PDMAEMA） and thermal properties. Starting from 3-（2-formyl-3-methylphenoxy）propyl 4-（benzodithioyl）-4-cyanopentaneate（FBCP）, RAFT polymerization and UV-induced Diels-Alder click reaction were combined to generate three examples of cyclic polymers. The ring-closure reaction was successfully conducted, evident from ¹H NMR, GPC, and MALDI-TOF MS analyses. The thermoresponsive behaviors of PDMAEMAs in water were affected by some factors such as polymerization degree, polymer concentration, additive of NaCl, and pH/CO₂. The cloud points of ring PDMAEMAs were usually higher than their linear precursors, and the ?Tc values obtained under a fixed condition could reach up to 20.7 oC due to the combined influences of topology effect and other factors. This study can not only afford insight into structure-property relationships of smart ring homopolymers but pave way for exploring the unique properties and applications of multifunctional cyclic polymers and their derivatives.In summary, controlled polymerization and click chemistry were combined to prepare multi-stimuli-responsive 3-arm star quaterpolymers and cyclic polymers, and our study further enriches the family of nonlinear polymers. On the basis, their potential bioapplications and thermal properties were further investigated. Our study can not only favor to understand the structure-property relationship but also underlie synthesis and application of multifunctional smart materials.