【作者】 于姗姗；

【导师】 王晓蕾；

【作者基本信息】 山东师范大学 ， 分析化学， 2020， 硕士

【摘要】 人造微纳米马达是一种将化学能转化为机械能的微型自主运动装置,其具有体积小、比表面积大、运动速度快、制作简单、容易修饰等优点。近年来,随着微纳米技术的不断发展,新型微纳米马达不断被研制的同时,新的驱动方式也不断被发展,产生了以Janus球、管状、棒状等形状为代表的微纳米马达;也开发出了化学、光、磁场、超声场及电场等马达驱动方式。这些微纳米马达在环境检测与修复、生物医学、分析检测、生物传感等领域有较大的应用前景。但是现阶段的微管马达的外层材料主要是聚（3,4-乙烯二氧噻吩）、聚苯胺、还原氧化石墨烯等,这些材料的表面活性基团种类少,运载药物能力有限,生物降解性差等缺点,使其在环境治理和药物运输等方面的应用受到很大的限制。本论文主要研制了新型β-环糊精修饰聚天冬氨酸微米管状马达,并探索其在有机污染物光降解和协同载药方面的应用,主要工作如下:1.基于β-环糊精修饰聚天冬氨酸微管马达光降解有机污染物的应用研究作为最常见的内分泌干扰物之一,双酚A（BPA）被广泛用于阻燃剂,塑料包装和环氧树脂中,由于双酚A中苯环特有的稳定性,使其不易被微生物降解。双酚A会导致内分泌失调,威胁着胎儿和儿童的健康。癌症和新陈代谢紊乱导致的肥胖也被认为与此有关,因此,提高环境中BPA的有效降解是一个亟待解决的问题。在此章研究工作中,我们采用模板电聚合法制备了一种β-环糊精修饰的聚天冬氨酸（CD/PASP/Ni/Pt）微管马达,微管马达内部的Ni层可实现马达的快速回收利用,而内部的Pt层可以催化H₂O₂产生氧气气泡,从而推动微管马达运动,实现其在1.0%H₂O₂溶液中的自驱动。与此同时,微管马达运动产生的氧气,在185 nm紫外光照射时产生臭氧,形成UV-H₂O₂-O₃体系,可实现BPA的光降解。微管马达表面的环糊精空腔的疏水特性,使其可以快速有效地包结BPA,而环糊精在254 nm紫外光照射下,会产生羟基自由基（·OH）并攻击BPA的中间位点以及包结在β-CD外的BPA的苯环,使BPA发生光氧化,进一步加速了BPA的光降解速度。同时,体系中产生的大量气泡和微管马达的快速运动增加了物质的有效传输和混合,使微管马达与BPA之间有更多的相互作用,从而大大提高了BPA光降解的速度和效率。实验结果表明,CD/PASP/Ni/Pt微管马达具有降解时间短（≤12 min）,降解能力强（接近99.5%）等优点。另外,研究表明该微管马达对偶氮染料——亚甲基蓝也有很好的光降解能力。因此,CD/PASP/Ni/Pt微管马达在高效、快速光降解复杂有机污染物方面有很大的应用潜力。2.基于β-环糊精修饰聚天冬氨酸/铁/锌微管马达的制备和协同载药研究传统的给药方法多采用口服或静脉注射法,为达到疗效,用药量往往比较大,会增加不良反应的发生几率。因此选择性地将药物输送到目标组织和病患部位已成为当前科学用药的一个研究热点。在癌症治疗中,靶向给药尤为重要。另外,研究发现单一药物的治疗往往很难有效抑制不断发生异化的肿瘤细胞,而多药联用对肿瘤细胞的抑制作用明显增强。在上章构建的微管马达基础上,我们构建了可在胃酸中快速运动的CD/PASP/Fe/Zn微管马达。利用微管马达表面的β-环糊精的疏水空腔包结具有抗炎作用的姜黄素（CUR）,聚天冬氨酸（PASP）的羧基通过静电作用结合抗癌药物——阿霉素（DOX）,实现了微管马达对DOX和CUR的协同负载。体外实验表明,在胃酸模拟液中,该载药微管马达内部的锌（Zn）会产生氢气气泡,从而促使马达在溶液中快速运动;微管马达中层铁（Fe）单质的存在,使其可在磁场的调控下改变运动方向。小鼠活体实验表明,微管马达在胃中的快速运动可使其嵌入胃粘膜中,因而可实现药物的有效运输和缓慢释放,并有望实现抗癌药物的磁控靶向给药。由于我们采用的微管马达材料——无论是外层的β-环糊精修饰的聚天冬氨酸还是内部的Zn和Fe单质都会在体内分解为无毒的物质,CD/PASP/Fe/Zn微管马达的毒性检测表明,口服该微管马达24小时,小鼠没有出现明显的毒性反应。总之,该微管马达是一种生物相容性好的药物载体,有望实现两种药物的体内靶向协同输送,拓展了微纳米马达在生物医学领域中的应用。更多还原

【Abstract】 Micro/nanomotor is a small autonomous motion device that converts chemical energy into mechanical energy.It has the characteristics of small size,large specific surface area,fast movement speed,simple production,and easy modification.With the development of nanotechnology,the shapes of motors are various,including spherical,rod,and tubular etc.The main driving methods of micro/nanomotors is chemical driving and external energy driving,such as light,magnetic field,ultrasound field,and electronic field.New designs of motors and driving methods are constantly being invented and developed.These small self-driving motors are optimal for a wide range of environmental detection and remediation,biomedical,analytical testing,and biosensing etc.However,the outer layer materials of the microtube motor at this stage are mainly poly（3,4-ethylenedioxythiophene）,polyaniline,and reduced graphene oxide,etc.These materials have few types of surface active groups,limited drug carrying capacity,and biological The shortcomings such as poor degradability limit its application in environmental treatment and drug transportation.In this thesis,microtubular motors withβ-cyclodextrin-functionalized polyaspartic acid membrane were prepared and have been used in the photodegradation of organic pollutants and the collaborative drugs delivery.The main work is outline as following:1.The application ofβ-cyclodextrin functionalized polyaspartic acid microtubular motors for the photodegradation of organic pollutantsAs one of the most common endocrine disruptors,bisphenol A（BPA）is a widely used chemical for flame retardants,plastic packaging,and epoxy resins.Due to the unique stability of the benzene ring in bisphenol A,it is not easily degraded by microorganisms.It has been found that bisphenol A can adversely affect the development of reproductive organs when it accumulates in the human body.Therefore,it is an urgent problem to improve the effective degradation of bisphenol A in the environment.In this chapter,we report the design of a self-propelled tubular micromotor based on a polymer of aspartic acid functionalized by β-cyclodextrin（CD/PASP）for the rapid and efficient removal of organic pollutants.The CD/PASP/Ni/Pt tubular micromotor is fabricated by using an outer CD/PASP layer,a thin nickel interlayer,and an inner platinum layer using template electrodeposition.The oxygen bubbles generated by the catalysis of platinum push them moving quickly in H₂O₂ aqueous solution and the nickel layer can facilitate the collection of tubular micromotors.The oxygen bubbles can be converted into ozone in 185 nm ultraviolet light and then a UV-H₂O₂-O₃ system is formed for the rapid degradation of BPA.Furthermore,the hydrophobic cavity of the cyclodextrin allows the tubular micromotor to quickly and efficiently encapsulate bisphenol A.The inclusion structure makes BPA enough close to the secondary hydroxyl groups of theβ-CD cavity,which can be activated and converted into·OH radicals under 254 nm UV irradiation.It enhances the speed and efficiency of the photodegradation of BPA.The experimental results show that CD/PASP/Ni/Pt tubular micromotors can rapidly degrade 5×10^-4 mol/L BPA in 12 min（close to99.5%in degradation rate）.Compared with other methods,the degradation efficiency of CD/PASP/Ni/Pt tubular micromotors is significantly improved.In addition,the tubular micromotor also has a good ability to remove azo dyes.Therefore,the CD/PASP/Ni/Pt tubular micromotors can achieve the efficient and rapid photodegradation of complex pollutants.2.The preparation and drug delivery ofβ-cyclodextrin functionalized polyaspartic acid/iron/zinc microtubular motorsIn order to achieve the therapeutic effect,the traditional treatment methods are mostly oral or intravenous injection,which often uses a large amount of medicine and increases the incidence of adverse reactions.Therefore,the selective delivery of drugs to target tissues and cellular disease sites has become a research hotspot in current scientific medicine.Targeted drug delivery is particularly important in cancer treatment.Moreover,using a single drug is always hard to inhibit the dissimilation of tumor cells in cancer treatment.More and more multi-drug combination treatments are used to kill and inhibit tumor cells in the recent years.In this chapter,aβ-cyclodextrin-functionalized polyaspartic acid（CD/PASP/Fe/Zn）tubular micromotor is fabricated.Curcumin（CUR）,one of anti-inflammatory drugs,is encapsulated by the hydrophobic cavity ofβ-cyclodextrin on the surface of the tubular micromotor.Then doxorubicin（DOX）,one of the regular anti-cancer drugs,is bonded on the carboxyl group of polyaspartic acid（PASP）through the electrostatic interaction.Therefore,a CD-CUR/PASP-DOX/Fe/Zn tubular micromotor loading with DOX and CUR is achieved.In vitro experiments showed that hydrogen bubbles generated by the zinc（Zn）inside the drug-loaded tubular micromotor promoted the rapid movement of the tubular micromotor in gastric acid simulation fluid.The tubular micromotor could change its direction of movement under the control of a magnetic field due to the presence of a thin layer of iron（Fe）in the tubular micromotor.In vivo experiments indicated that CD-CUR/PASP-DOX/Fe/Zn tubular micromotors could stay in the gel layer of gastric mucosa and increase the release time of DOX and CUR.The preparation materials of the tubular micromotor includingβ-CD functionalized PASP and internal Zn,Fe,will decompose in vivo without any toxic substances.The toxicity test showed that there was no obvious toxic reaction in mice after oral administration of the tubular micromotor.In a word,this micromotor is a kind of drug carrier with good biocompatibility and biodegradation,which can realize the delivery and controlled release of multiple drugs in vivo and is expected to be used in more biomedical field.更多还原