| “Click” chemistry is a kind of chemical reactions with high yield and high selectivity undermild conditions, and can be used in aqueous solution. It has proved to be an efficient strategy forsynthesis and functionalization of various complex polymers, especially has been applied tosynthesis star-shaped polymers, dendrimers, functional polymers, multi-block copolymers.Owing to their excellent biodegradability, both poly(-carpolactone) and polylactides have beenwidely applied for drug delivery systems and tissue engineering. However, their highcrystallinity and strong hydrophobicicity of polymer backbone limited their clinical applications.There are two methods to modify the polyester, one is to change the topology of the polymers;the other is to introduce hydrophilic poly(ethylene glycol) or saccharide to polymer backbone toregulate hydrophilicity-hydrophobicity blance. Environment-responsive polymers have been ahotspot in medicine field and received much attention in the field of drug delivery and genetherapy, which provide the feasible pathway for effective and site specific drug delivery to thediseased site.Taking the three factors into account, we developed two types of “click” chemistry forconstructing biocompatible block polymers, and synthesizing bioreducible, photo-responsive,both sugar-targeted and photo-sensitive polymers. In this paper, the self-assembly process,stimuli-responsive behaviors, as well as their applications as anticancer drug delivery systems ofthe three kinds of environment-responsive polymer nanoparticles were investigated in detail. Themain contents are listed as follows:(1) Synthesis and characterization of triblock and pentablock copolymers composed ofpoly(-carpolactone), poly(L-lactide) and poly(ethylene glycol)Biocompatible and biodegradable PEO-PCL-PLA triblock and PLA-PCL-PEO-PCL-PLApentablock copolymers were synthesized by CuAAC, and they were characterized by means of FT-IR,~1H NMR, GPC, DSC and WXRD. The crystalline PEO, PCL, and PLA blocks influencedmutually, and these copolymers formed microphase-separates crystalline materials in solid stateand at room temperature. The triblock and pentablock copolymers self-assembled into sphericalmicelles, and they were dynamically stable over27days in aqueous solution at pH7.4and37°C.The DOX-loaded nanoparticles of pentablock copolymers showed a higher drug loading and alonger drug-release period (25days).(2) Synthesis of bioreducible multiarmed star copolymers via click chemistry and theirstimuli-response micelles and supramolecular hydrogelsBioreducible disulfide-bond is often positioned in the junction linking the hydrophobic andhydrophilic blocks. After micelles entered into cells, disulfide-bond broke because of the largedifference glutathione concentration within intracellular cytosol, and the hydrophilic shell ofmicelles would fast shed from the hydrophobic core, resulting in the bigger aggregates and theaccumulation of hydrophobic polymers in cytosol. Therefore, we reason that, if the disulfide bondis positioned in the core within multiarmed amphiphilic copolymers, both the drug-release andmechanical properties of the micelles and hydrogels might be tuned in a dynamic manner. Themulti-armed star biodegradable block copolymers mPEO-b-PCL were designed and synthesizedby thiol-yne click chemistry. They self-assembled into bioreducible micelles and hydrogels inaqueous solution. The DTT addition reduced the micelles to their half size without changing themorphology. Copolymer1formed hydrogels with a higher mechanical strength (8times) than thelinear precursor, and the DTT addition also reduced the storage modulus. The supramolecularhydrogels have bioreducibility, and both mechanical and drug-release properties are controlled bytopological structure.(3) Synthesis and characterization of NIR-sensitive linear-dendron-like block amphiphilicpolymers by click chemistryIt is known that skin absorbs UV and visible light quite readily, while light between750and1000nm can deeply penetrate the skin with less damage on the irradiated area. Moreover, theefficient and quick drug-release in diseased site can be realized by an external stimulus, such aslight. So we designed and synthesized functional linear-dendron-like amphiphilic polymers withphotosensitive groups (PEO-D3DNQ) by CuAAC. Their structures were characterized by bymeans of FT-IR,1H NMR and GPC. The UV and near-infrared light sensitivity of self-assembled micelles were confirmed by UV-vis, DLS and TEM. The polymers self-assembled into sphericalmicelles and they were dynamically stable over25days in aqueous solution. The DOX-loadednanoparticles of PEO5K-D3DNQ had a higher drug-loading capacity (20.1%). MTT assaysuggested polymers had low cytotoxicity, and the toxicity of the drug-loaded micelles after lightirradiation was higher than those without light irradiation. This also verified the light-sensitivity,and they are hopely applied for photosensitive drug delivery system.(4) Synthesis and characterization of NIR-sensitive and sugar-targeted dendron-dendron-likeblock amphiphilic polymers by click chemistryDespite environment-responsive drug-loaded nanoparticles can quickly release drug,however, these nanoparticles often lack highly efficient tumor-targeting properties, which wouldinduce cytotoxicity. To address these problems, a new concept was introduced to fabricate asugar-triggered targeting and photo sensitivity to afford a dendritic micellar nanocarrier(Dm-Lac-D3DNQ). The UV and near-infrared light sensitivity of self-assembled micelles wereconfirmed by UV-vis, DLS and TEM. The polymers self-assembled into spherical micelles by adialysis method and they were dynamically stable over20days in aqueous solution. TheDOX-loaded nanoparticles of D2-Lac-D3DNQ had a highest drug-loading capacity (15.6%).Dm-Lac-D3DNQ had specific recognition with RCA120by UV-vis and DLS. MTT assaysuggested polymers had low cytotoxicity, and the toxicity of the drug-loaded micelles after lightirradiation was higher than those without light irradiation, also verifying the photo-sensitivity. |
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