波动性温敏核壳智能微凝胶对戒毒药物的承载与释放

According to the characteristic of large fluctuation in body temperature of the drug abusers, fluctuant thermosensitive-driven core-shell microgels will be designed for storage and delivery of the detoxification agents, such as sinomenine, buprenorphine, methadone, etc. The hydrophobic core will be consisted of poly(4-allylanisole) (PAA), while the hydrophilic shell will be consisted of crosslinking copolymer with graft poly(ethylene glycol) structure [copolymer of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) with oligo(ethylene glycol) methyl ether methacrylates (MEOxMA, x is the number of ethylene oxide units)]. Various curves of the fluctuant temperature change will be designed by a simulation of systematic monitoring for the fluctuant body temperature change (for example, intensity, frequency and range etc.) of the drug abusers. The effects of the core structure of the core-shell microgels PAA@P(MEO2MA-co-MEOxMA), combination of the core and the shell, molar ratios of MEO2MA/MEOxMA and different x values on the intelligent loading and releasing of various detoxification agents will be investigated. It can be achieved to provide a matching relationship between the structure optimization, control of drug loading capacity, drug release, and degree, number of times, reversibility of the fluctuant thermosensitive core-shell microgel system. It will be also possible to create an effective synthesis method for the microgel carriers with the feature of loading/release detoxification agents.

针对戒毒人员在毒瘾发作时体温波动大的特点，设计一种承载与释放戒毒药(如青藤碱、丁丙诺啡、美沙酮等)的波动温敏驱动型核壳微凝胶。亲油核拟采用聚(4-烯丙基苯甲醚)(简称PAA)，亲水壳拟采用具有聚(乙二醇)枝化结构的交联共聚物[2-(2-甲氧基乙氧基)甲基丙烯酸乙酯(简称MEO2MA)与各种分子质量不同的低聚(乙二醇)甲醚甲基丙烯酸脂(简称MEOxMA，x为乙氧基片段的个数)的共聚物]。通过系统监测戒毒人员体温波动变化情况(如强度、频率和范围等)，模拟设计各种温度波动曲线，研究各波动曲线下该核壳微凝胶PAA@P(MEO2MA-co-MEOxMA)的核结构、核与壳组合、壳层MEO2MA/MEOxMA摩尔比以及不同x值等因素对各种戒毒药在温敏智能承载与释放时的影响。给出该微凝胶在结构优化、载药量控制、戒毒药释放与波动温敏程度、次数和可逆性之间的匹配关系，创建一种戒毒药微凝胶载体合成的有效方法。

本项目针对吸毒者在毒瘾发作时体温从37.24 ℃上升到40.50 ℃这一个明显特征，设计合成了一类用于承载类戒毒药物的温敏性核-壳微凝胶，并对其影响温敏性能的各种因素进行了系统的研究。分别为：（1）以聚甲基丙烯酸甲酯（PMMA）微球为核，具有低聚(乙二醇) 枝化结构的共聚物[2-(2-甲氧基乙氧基)甲基丙烯酸乙酯( 2-(2-methoxyethoxy) ethyl methacrylate，(MEO2MA))与低聚(乙二醇)甲基丙烯酸甲基醚(oligo(ethylene glycol) methyl ether methacrylate, MEO5MA)组成的共聚物P(MEO2MA-co-MEO5MA)]为壳，合成了在体温波动范围特征内具有明显温敏体积变化的核-壳微凝胶PMMA@P(MEO2MA-co-MEO5MA)。确定了初始构壳摩尔比n(MEO2MA)/n(MEO5MA) = 1:6为最佳配比，微凝胶的大小可以通过核的尺度来加以调节。发现三种类戒毒药（氯丙嗪、青藤碱和地尔硫卓）在该微凝胶上具有理想的承载与释放功能。所合成的PMMA/P(MEO2MA-co-MEO5MA)微凝胶在小于50 ug/mL的浓度范围能表现出对大鼠胸主动脉内皮细胞适宜的生物相容性。（2）以聚苯乙烯（PS）微球为核，具有低聚(乙二醇) 枝化结构的共聚物P(MEO2MA-co-MEO5MA) 为壳，合成了合成了在体温波动范围特征内具有明显温敏体积变化的核-壳微凝胶PS@P(MEO2MA-co-MEO5MA)。确定了初始构壳摩尔比n(MEO2MA)/n(MEO5MA) = 1:3为最佳配比，发现单一组分壳层[P(MEO5MA) 或P(MEO9MA)]与PS核制备的微凝胶也能产生理想的温敏特性，且微凝胶的大小可以通过核的尺度来加以调节。发现三种类戒毒药（氯丙嗪、青藤碱和地尔硫卓）在该微凝胶上具有理想的承载与释放功能。所形成的PS@P(MEO2MA-co-MEO5MA)微凝胶在0.39~50 ug/mL浓度范围表现出对大鼠胸主动脉内皮细胞适宜的生物相容性。（3）以P(MEO2MA)为核，P(MEO2MA-co-MEO5MA)为壳，合成了具有特殊温敏体积变化的P(MEO2MA)/P(MEO2MA-co-MEO5MA)核-壳微凝胶。发现乳化剂SDS的浓度对微凝胶的合成与稳定性影响较大。