葡聚糖基“智能”纳米凝胶的自组装辅助制备及生物应用研究
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摘要
纳米凝胶是一类由亲水性或两亲性高分子组成的纳米尺度三维互穿网络，由于其具有亲水性、稳定性和可修饰性，在生物显影，药物、基因输运，及生物活性分子检测等生物医用领域具有广阔的应用前景。本文基于葡聚糖这种生物相容性良好的天然大分子多糖，通过硝酸铈铵在葡聚糖链上引发多种功能单体的自由基聚合，并诱发葡聚糖主链与功能单体接枝链自组装形成纳米聚集体，通过在此过程中加入适当交联剂，从而将“聚合”、“组装”、“化学交联”等过程一步完成，高效制得具有环境敏感性的“智能”纳米凝胶（所得纳米凝胶水溶液的浓度可达10mg/mL以上）。在这种自组装辅助的一步法（self-assembly assisted method,SAA method）中，设计并使用具有不同功能性的单体或交联剂，可赋予纳米凝胶对pH、光或特定化学物质的环境敏感性。本研究在对这种自组装辅助一步法研究的基础上，对制备的多种功能性纳米凝胶进行了结构、组成的表征与分析，并探究了其在药物输送、生物标记等领域的生物应用前景。本论文具体开展了以下工作：
（1）利用自组装辅助法通过氢键诱导的自组装合成了葡聚糖-聚丙烯酸纳米凝胶（Dex-PAANGs），并对其合成参数进行了研究，通过控制反应物的投料，可以控制粒子的粒径及表面电荷；对其进行荧光修饰后，制备得到的荧光纳米凝胶（fluorescent nanogels, FNGs）可有效标记脂肪干细胞（adipose-derived stem cells, ADSCs）。实验结果表明，粒径和表面电荷对其进入ADSCs的能力有显著影响，粒径小于200nm的带电粒子更容易进入细胞。此外，FNGs还可用于标记淋巴管内皮细胞（lymphaticendothelial cells, LECs），且不影响LECs的正常功能，具有很好的生物相容性；经皮下注射后，FNGs由于粒径较大（~200nm），不进入血管，而是经淋巴回流进入淋巴管，并在淋巴结部位显影，标记时间可长达2-4h，对淋巴结具有一定的选择性，有十分重要的临床意义。此外，研究表明，Dex-PAA NGs还可负载淋巴水肿治疗药物—血管内皮生长因子C（vascular endothelial growth factor C, VEGF-C），在治疗淋巴水肿中具有应用潜力。
（2）针对肿瘤部位还原性较强、弱酸性的“肿瘤微环境”，通过引入含二硫键的交联剂二烯丙基二硫（diallyl disulfide, DADS），设计并成功制得还原环境敏感的葡聚糖基纳米凝胶，其在还原性环境中可“解交联”。并分别通过“氢键”和“疏水作用力”这两种不同的自组装驱动力，利用自组装辅助一步法制备了由亲水性单体丙烯酸（acrylic acid,AA）或疏水性单体丙烯酸甲酯（methyl acrylate, MA）组成的Dex-SS-PAANGs和Dex-SS-PMA NGs。在制备方法的研究中，本部分将单体由丙烯酸（acrylicacid, AA）这种聚阴离子单体拓展到丙烯酸甲酯（methyl acrylate, MA）这种疏水单体，从而将SAA法合成葡聚糖基纳米凝胶的单体范围从亲水性的阴离子单体推广到疏水性单体，大大提高了该法的普适性。
在成功制备两类还原环境敏感的纳米凝胶，并对其机理进行研究的基础上，本部分对两类纳米凝胶的尺度、形貌、还原环境响应性、特别是抗肿瘤药物输送能力进行了研究。动态光散射（DLS）及静态光散射（SLS）研究发现，两类纳米凝胶均可在还原剂如谷胱甘肽GSH存在下出现一定的粒径和分子量变化，表现出一定的还原性环境“解交联”行为。这种还原性环境敏感的特点在还原性物质过表达的肿瘤部位的药物输送中具有重要意义，因而本研究将这类纳米凝胶用于抗肿瘤药物盐酸阿霉素（DOX）的负载，通过酸敏感的腙键将DOX负载于两类纳米凝胶中，并对药物释放行为及其在宫颈癌及乳腺癌治疗中的应用进行了研究。研究表明，Dex-SS-PMANGs的分布较Dex-SS-PAANGs窄，且粒径较小，分散均匀，性能更加稳定。Dex-SS-PMANGs通过腙键连接DOX的能力较Dex-SS-PAA NGs强，载药量和载药效率均较高。此外，Dex-SS-PMA-DOX载药纳米凝胶对人宫颈癌HeLa细胞和人乳腺癌MCF-7细胞的抑制能力较Dex-SS-PAA-DOX强，能够很好地抑制肿瘤细胞的生长。尤其是当使用还原剂GSH模拟体内环境时，这类二硫键交联的纳米凝胶比碳-碳键交联的载体能够更好地释药并杀死肿瘤细胞，其中对乳腺癌MCF-7细胞的杀伤能力更强一些。后续的在体抑瘤实验中，发现Dex-SS-PMA-DOX保留了DOX的抑制肿瘤生长的能力，同时明显降低了DOX的毒副作用。这表明Dex-SS-PMA-DOX是一种具有良好应用前景的抗肿瘤药物输送体系。
（3）选用pH和葡萄糖双响应的丙烯酰胺基苯硼酸单体，利用疏水力诱导的自组装作用一步制备了具有pH/葡萄糖双响应性的葡聚糖-聚丙烯酰胺基苯硼酸纳米凝胶（Dex-PAAPBANGs, DABANGs）体系。该类纳米凝胶葡萄糖响应性的根源在于当二醇类物质（如葡萄糖等）存在时，PAAPBA链能够发生离解平衡的移动，电离程度增加，亲水性增强。研究发现，DABA NGs在pH=10时具有明显的葡萄糖响应性，当加入葡萄糖时，其粒径增大、Zeta电位变负。为进一步证实该纳米凝胶的葡萄糖响应性，本部分还选用了一种荧光发射光谱对于环境亲/疏水性敏感的荧光素单体2-[4-(3-羟基-4-氧代-4H-苯并吡喃-2-基）苯氧基]乙基丙烯酰胺（2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy] ethylacrylamide,3HF-AM），通过该单体与AAPBA单体的共聚一步制备了具有荧光性能的纳米凝胶FDABA NGs。研究表明，碱性条件下葡萄糖的加入可诱导FDABA NGs水溶液荧光颜色由蓝绿色向纯蓝色转变。这一“可视化”的葡萄糖敏感行为对于环境中的葡萄糖检测非常有利。此外，DABA NGs还能够通过非共价键力负载治疗糖尿病的药物胰岛素（insulin, INS），INS从载体中的释放行为具有一定的葡萄糖响应性，从而为胰岛素的葡萄糖敏感释放提供了可能。
综上所述，本研究提出并实施了一种自组装辅助的一步法（SAA）成功制备了多种具有环境敏感性和良好生物相容性的葡聚糖基“智能”纳米凝胶。本研究主要的创新点在于将这种制备葡聚糖基纳米凝胶的SAA方法由水溶性阴离子单体拓展至疏水性单体，并通过采用二硫键连接的交联剂成功制备了性能可控的还原环境敏感性纳米凝胶，将SAA方法发展成为一定范围内普适的多糖基纳米凝胶制备方法，并为其生物医学应用奠定了基础。
Nanogels are nano-scaled three dimensional interpenetrating networksformed by hydrophilic or amphiphilic polymers, and their excellent stabilityin aqueous solutions and ability to deliver a wide range of cargoes haverendered them very popular in biomedical applications. Nanogels can bemodified with fluorescent or magnetic agents for bio-imaging, or loaded withdrugs, proteins and growth factors for environmental-sensitive release, orused for bioactive molecules detection in complexed system. In this work,we efficiently fabricated several dextran-based smart nanogels with aself-assembly assisted one-pot synthesis method (SAA method). Duringthis process, free radicals were initiated in dextran backbone by using cericammonium nitrate (CAN), afterwards, various functional monomerspolymerized from dextran backbone. With the proceeding of thepolymerization of monomers, the self-assembly between dextran backbonesand polymeric grafts was induced to form nano-aggregates. With theaddition of di-vinyl monomers in this process, the “polymerization”,“self-assembly”, and “crosslinking” were accomplished together with highefficiency. The functional nanogels can be fabricated by this SAA methodat the concentration of as high as10mg/mL. Various monomers andcrosslinkers were utilized for the preparation of nanogels with pH-, reducingenvironment-, or even glucose-responsiveness. The structure andcomposition of the as-prepared nanogels were confirmed and their potentialapplications in biomedical fields were explored. The main contributions inthis thesis are as follows:
(1) Dextran-poly(acrylic acid) nanogels (Dex-PAA NGs) were fabricatedwith hydrogen force-assisted self-assembly, and parameters affectingnanogels size and Zeta potential were studied. Dex-PAA NGs were furtherconjugated with a small fluorescent molecule5-aminofluorescein (5-AF)through amide condensation and the acquired fluorescent NGs (FNGs) wereused for adipose-derived stem cells (ADSCs) imaging. Furtherinvestigations discovered that sizes and Zeta potentials were two importantfactors affecting FNGs ability to enter ADSCs cells, and the results showedthat charged nanogels with a diameter less than200nm could enter cellsmore efficiently. The preferred FNGs were then used for lymphaticendothelial cells (LECs) labeling, and the FNGs-labeled LECs functionssuch as Dil-Ac-LDL ingestion and micro-tube formation ability were notaffected. Owing to their capability of entering lymph vessel by lymphaticdrainage, FNGs could also be used for lymph node imaging when injectedsubcutaneously, and the imaging time lasted for2-4hours which was muchbetter than the currently used imaging agents. What s more, Dex-PAA NGswere used in loading vascular endothelial growth factor C (VEGF-C), a drugwhich has been proven useful for lymphedema treatment. Based on thestudy, Dex-PAA NGs are of potential in lymphedema treatment.
(2) As is well known, the tumor microenvironment is more reductiveand acidic than normal human tissues, we fabricated reduction-sensitivedextran-based nanogels through the SAA method by using the disulfide bond(-SS-) containing diallyl disulfide (DADS) as crosslinker. The disulfidebond in the resultant nanogels could be reduced to thiols when reductant waspresent, as a result, the nanogels were de-crosslinkable in tumormicroenvironments. Here we fabricated Dex-SS-PAA NGs from acrylicacid (AA) based on the self-assembly force of hydrogen bond, andDex-SS-PMA NGs from methyl acrylate (MA) with hydrophobic interactions.The successful fabrication of Dex-SS-PMA NGs greatly expanded the scopeof the SAA method from hydrophilic monomers to hydrophobic ones, thusallowing the fabrication of a diverse range of dextran-based nanogels.
After the successful fabrication of two kinds of reduction-sensitivenanogels and the studies on their fabrication mechanisms, the size,morphology, reduction-sensitiveness and anti-cancer drug delivery abilities ofthese two categories of nanogels were studied. Dynamic light scattering(DLS) and static light scattering (SLS) results showed that the size andmolecular weight (Mw) of the two nanogels changed with the addition ofreductive agent glutathione (GSH), so their reduction-sensitivede-crosslinkage behavior was verified. The reduction-sensitive carrierswere very useful and promising in anti-cancer drug delivery because of thereductive tumor microenvironment. With this in mind, we conjugated aneffective anti-cancer drug doxorubicin hydrochloride (DOX) onto theDex-SS-PAA NGs and Dex-SS-PMA NGs through an acid-labile hydrazonebond, and their release behaviors and anti-cancer effects on human cervicalcancer HeLa cells and human brease cancer MCF-7cells were studied.Compared with Dex-SS-PAA NGs, the Dex-SS-PMA NGs had a narrowersize distribution, smaller size than Dex-SS-PAA NGs, higher loading contentand encapsulation efficiency of DOX when load DOX through the hydrazonebond. Correspondingly, Dex-SS-PMA-DOX NGs also revealed a strongerinhibition ability toward HeLa cells and MCF-7cells. When GSH wasadded to the culture medium to simulate the tumor environment, the DADScrosslinked nanogels showed better anti-cancer performance than theirnon-degradable counterparts, especially toward MCF-7cells. The in vivoexperiments carried out on nude mice with MCF-7tumor xenograft showedthat Dex-SS-PMA-DOX retained the anti-cancer ability of free DOX butsignificantly reduced the side effects. Dex-SS-PMA-DOX was shown to bea very promising anti-cancer drug delivery system.
(3) pH/glucose dual responsive nanogels based on dextran andpoly(3-acrylamidophenylboronic acid)(PAAPBA) were fabricated withhydrophobic force assisted self-assembly strategy. The as-preparedDex-PAAPBA NGs (short for DABA NGs) showed a narrow size dispersity.As the ionization equilibrium shift of the PAAPBA chains would shift to the formation of more negatively charged species when glucose was present,DABA NGs exhibited a volume increase and Zeta potential decrease uponglucose addition at slightly alkaline pH. The glucose sensitivity of DABANGs was visualized by introducing a stimuli-responsive fluorescent agent,2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy]ethylacrylamide (3HF-AM) into the system. The fluorescence color of the resultant FDABA NGschanged from greenish blue to a deeper blue when glucose was added, andthis fluorescence variation upon glucose addition might have potentialapplication for glucose detection. Moreover, DABA NGs could encapsulateinsulin-a drug used for diabetes treatment, and the insulin-loaded nanogelsshowed a glucose-responsive release behavior, which may have potential forin vivo insulin delivery.
In conclusion, we proposed and realized an SAA method for thepreparation of various dextran-based smart nanogels with environmentalsensitiveness and good biocompatibility. The novelty of this thesis lies inthe development and the universal applicability of the SAA method, whichinclude the expandation of the SAA method from hydrophilic polyanionmonomers to hydrophobic ones, the introduction of disulfide-containingcrosslinkers to prepare reduction-sensitive nanogels, and the exploration ofthe biomedical applications of these dextran-based smart nanogels.
（1）利用自组装辅助法通过氢键诱导的自组装合成了葡聚糖-聚丙烯酸纳米凝胶（Dex-PAANGs），并对其合成参数进行了研究，通过控制反应物的投料，可以控制粒子的粒径及表面电荷；对其进行荧光修饰后，制备得到的荧光纳米凝胶（fluorescent nanogels, FNGs）可有效标记脂肪干细胞（adipose-derived stem cells, ADSCs）。实验结果表明，粒径和表面电荷对其进入ADSCs的能力有显著影响，粒径小于200nm的带电粒子更容易进入细胞。此外，FNGs还可用于标记淋巴管内皮细胞（lymphaticendothelial cells, LECs），且不影响LECs的正常功能，具有很好的生物相容性；经皮下注射后，FNGs由于粒径较大（~200nm），不进入血管，而是经淋巴回流进入淋巴管，并在淋巴结部位显影，标记时间可长达2-4h，对淋巴结具有一定的选择性，有十分重要的临床意义。此外，研究表明，Dex-PAA NGs还可负载淋巴水肿治疗药物—血管内皮生长因子C（vascular endothelial growth factor C, VEGF-C），在治疗淋巴水肿中具有应用潜力。
（2）针对肿瘤部位还原性较强、弱酸性的“肿瘤微环境”，通过引入含二硫键的交联剂二烯丙基二硫（diallyl disulfide, DADS），设计并成功制得还原环境敏感的葡聚糖基纳米凝胶，其在还原性环境中可“解交联”。并分别通过“氢键”和“疏水作用力”这两种不同的自组装驱动力，利用自组装辅助一步法制备了由亲水性单体丙烯酸（acrylic acid,AA）或疏水性单体丙烯酸甲酯（methyl acrylate, MA）组成的Dex-SS-PAANGs和Dex-SS-PMA NGs。在制备方法的研究中，本部分将单体由丙烯酸（acrylicacid, AA）这种聚阴离子单体拓展到丙烯酸甲酯（methyl acrylate, MA）这种疏水单体，从而将SAA法合成葡聚糖基纳米凝胶的单体范围从亲水性的阴离子单体推广到疏水性单体，大大提高了该法的普适性。
在成功制备两类还原环境敏感的纳米凝胶，并对其机理进行研究的基础上，本部分对两类纳米凝胶的尺度、形貌、还原环境响应性、特别是抗肿瘤药物输送能力进行了研究。动态光散射（DLS）及静态光散射（SLS）研究发现，两类纳米凝胶均可在还原剂如谷胱甘肽GSH存在下出现一定的粒径和分子量变化，表现出一定的还原性环境“解交联”行为。这种还原性环境敏感的特点在还原性物质过表达的肿瘤部位的药物输送中具有重要意义，因而本研究将这类纳米凝胶用于抗肿瘤药物盐酸阿霉素（DOX）的负载，通过酸敏感的腙键将DOX负载于两类纳米凝胶中，并对药物释放行为及其在宫颈癌及乳腺癌治疗中的应用进行了研究。研究表明，Dex-SS-PMANGs的分布较Dex-SS-PAANGs窄，且粒径较小，分散均匀，性能更加稳定。Dex-SS-PMANGs通过腙键连接DOX的能力较Dex-SS-PAA NGs强，载药量和载药效率均较高。此外，Dex-SS-PMA-DOX载药纳米凝胶对人宫颈癌HeLa细胞和人乳腺癌MCF-7细胞的抑制能力较Dex-SS-PAA-DOX强，能够很好地抑制肿瘤细胞的生长。尤其是当使用还原剂GSH模拟体内环境时，这类二硫键交联的纳米凝胶比碳-碳键交联的载体能够更好地释药并杀死肿瘤细胞，其中对乳腺癌MCF-7细胞的杀伤能力更强一些。后续的在体抑瘤实验中，发现Dex-SS-PMA-DOX保留了DOX的抑制肿瘤生长的能力，同时明显降低了DOX的毒副作用。这表明Dex-SS-PMA-DOX是一种具有良好应用前景的抗肿瘤药物输送体系。
（3）选用pH和葡萄糖双响应的丙烯酰胺基苯硼酸单体，利用疏水力诱导的自组装作用一步制备了具有pH/葡萄糖双响应性的葡聚糖-聚丙烯酰胺基苯硼酸纳米凝胶（Dex-PAAPBANGs, DABANGs）体系。该类纳米凝胶葡萄糖响应性的根源在于当二醇类物质（如葡萄糖等）存在时，PAAPBA链能够发生离解平衡的移动，电离程度增加，亲水性增强。研究发现，DABA NGs在pH=10时具有明显的葡萄糖响应性，当加入葡萄糖时，其粒径增大、Zeta电位变负。为进一步证实该纳米凝胶的葡萄糖响应性，本部分还选用了一种荧光发射光谱对于环境亲/疏水性敏感的荧光素单体2-[4-(3-羟基-4-氧代-4H-苯并吡喃-2-基）苯氧基]乙基丙烯酰胺（2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy] ethylacrylamide,3HF-AM），通过该单体与AAPBA单体的共聚一步制备了具有荧光性能的纳米凝胶FDABA NGs。研究表明，碱性条件下葡萄糖的加入可诱导FDABA NGs水溶液荧光颜色由蓝绿色向纯蓝色转变。这一“可视化”的葡萄糖敏感行为对于环境中的葡萄糖检测非常有利。此外，DABA NGs还能够通过非共价键力负载治疗糖尿病的药物胰岛素（insulin, INS），INS从载体中的释放行为具有一定的葡萄糖响应性，从而为胰岛素的葡萄糖敏感释放提供了可能。
综上所述，本研究提出并实施了一种自组装辅助的一步法（SAA）成功制备了多种具有环境敏感性和良好生物相容性的葡聚糖基“智能”纳米凝胶。本研究主要的创新点在于将这种制备葡聚糖基纳米凝胶的SAA方法由水溶性阴离子单体拓展至疏水性单体，并通过采用二硫键连接的交联剂成功制备了性能可控的还原环境敏感性纳米凝胶，将SAA方法发展成为一定范围内普适的多糖基纳米凝胶制备方法，并为其生物医学应用奠定了基础。
Nanogels are nano-scaled three dimensional interpenetrating networksformed by hydrophilic or amphiphilic polymers, and their excellent stabilityin aqueous solutions and ability to deliver a wide range of cargoes haverendered them very popular in biomedical applications. Nanogels can bemodified with fluorescent or magnetic agents for bio-imaging, or loaded withdrugs, proteins and growth factors for environmental-sensitive release, orused for bioactive molecules detection in complexed system. In this work,we efficiently fabricated several dextran-based smart nanogels with aself-assembly assisted one-pot synthesis method (SAA method). Duringthis process, free radicals were initiated in dextran backbone by using cericammonium nitrate (CAN), afterwards, various functional monomerspolymerized from dextran backbone. With the proceeding of thepolymerization of monomers, the self-assembly between dextran backbonesand polymeric grafts was induced to form nano-aggregates. With theaddition of di-vinyl monomers in this process, the “polymerization”,“self-assembly”, and “crosslinking” were accomplished together with highefficiency. The functional nanogels can be fabricated by this SAA methodat the concentration of as high as10mg/mL. Various monomers andcrosslinkers were utilized for the preparation of nanogels with pH-, reducingenvironment-, or even glucose-responsiveness. The structure andcomposition of the as-prepared nanogels were confirmed and their potentialapplications in biomedical fields were explored. The main contributions inthis thesis are as follows:
(1) Dextran-poly(acrylic acid) nanogels (Dex-PAA NGs) were fabricatedwith hydrogen force-assisted self-assembly, and parameters affectingnanogels size and Zeta potential were studied. Dex-PAA NGs were furtherconjugated with a small fluorescent molecule5-aminofluorescein (5-AF)through amide condensation and the acquired fluorescent NGs (FNGs) wereused for adipose-derived stem cells (ADSCs) imaging. Furtherinvestigations discovered that sizes and Zeta potentials were two importantfactors affecting FNGs ability to enter ADSCs cells, and the results showedthat charged nanogels with a diameter less than200nm could enter cellsmore efficiently. The preferred FNGs were then used for lymphaticendothelial cells (LECs) labeling, and the FNGs-labeled LECs functionssuch as Dil-Ac-LDL ingestion and micro-tube formation ability were notaffected. Owing to their capability of entering lymph vessel by lymphaticdrainage, FNGs could also be used for lymph node imaging when injectedsubcutaneously, and the imaging time lasted for2-4hours which was muchbetter than the currently used imaging agents. What s more, Dex-PAA NGswere used in loading vascular endothelial growth factor C (VEGF-C), a drugwhich has been proven useful for lymphedema treatment. Based on thestudy, Dex-PAA NGs are of potential in lymphedema treatment.
(2) As is well known, the tumor microenvironment is more reductiveand acidic than normal human tissues, we fabricated reduction-sensitivedextran-based nanogels through the SAA method by using the disulfide bond(-SS-) containing diallyl disulfide (DADS) as crosslinker. The disulfidebond in the resultant nanogels could be reduced to thiols when reductant waspresent, as a result, the nanogels were de-crosslinkable in tumormicroenvironments. Here we fabricated Dex-SS-PAA NGs from acrylicacid (AA) based on the self-assembly force of hydrogen bond, andDex-SS-PMA NGs from methyl acrylate (MA) with hydrophobic interactions.The successful fabrication of Dex-SS-PMA NGs greatly expanded the scopeof the SAA method from hydrophilic monomers to hydrophobic ones, thusallowing the fabrication of a diverse range of dextran-based nanogels.
After the successful fabrication of two kinds of reduction-sensitivenanogels and the studies on their fabrication mechanisms, the size,morphology, reduction-sensitiveness and anti-cancer drug delivery abilities ofthese two categories of nanogels were studied. Dynamic light scattering(DLS) and static light scattering (SLS) results showed that the size andmolecular weight (Mw) of the two nanogels changed with the addition ofreductive agent glutathione (GSH), so their reduction-sensitivede-crosslinkage behavior was verified. The reduction-sensitive carrierswere very useful and promising in anti-cancer drug delivery because of thereductive tumor microenvironment. With this in mind, we conjugated aneffective anti-cancer drug doxorubicin hydrochloride (DOX) onto theDex-SS-PAA NGs and Dex-SS-PMA NGs through an acid-labile hydrazonebond, and their release behaviors and anti-cancer effects on human cervicalcancer HeLa cells and human brease cancer MCF-7cells were studied.Compared with Dex-SS-PAA NGs, the Dex-SS-PMA NGs had a narrowersize distribution, smaller size than Dex-SS-PAA NGs, higher loading contentand encapsulation efficiency of DOX when load DOX through the hydrazonebond. Correspondingly, Dex-SS-PMA-DOX NGs also revealed a strongerinhibition ability toward HeLa cells and MCF-7cells. When GSH wasadded to the culture medium to simulate the tumor environment, the DADScrosslinked nanogels showed better anti-cancer performance than theirnon-degradable counterparts, especially toward MCF-7cells. The in vivoexperiments carried out on nude mice with MCF-7tumor xenograft showedthat Dex-SS-PMA-DOX retained the anti-cancer ability of free DOX butsignificantly reduced the side effects. Dex-SS-PMA-DOX was shown to bea very promising anti-cancer drug delivery system.
(3) pH/glucose dual responsive nanogels based on dextran andpoly(3-acrylamidophenylboronic acid)(PAAPBA) were fabricated withhydrophobic force assisted self-assembly strategy. The as-preparedDex-PAAPBA NGs (short for DABA NGs) showed a narrow size dispersity.As the ionization equilibrium shift of the PAAPBA chains would shift to the formation of more negatively charged species when glucose was present,DABA NGs exhibited a volume increase and Zeta potential decrease uponglucose addition at slightly alkaline pH. The glucose sensitivity of DABANGs was visualized by introducing a stimuli-responsive fluorescent agent,2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy]ethylacrylamide (3HF-AM) into the system. The fluorescence color of the resultant FDABA NGschanged from greenish blue to a deeper blue when glucose was added, andthis fluorescence variation upon glucose addition might have potentialapplication for glucose detection. Moreover, DABA NGs could encapsulateinsulin-a drug used for diabetes treatment, and the insulin-loaded nanogelsshowed a glucose-responsive release behavior, which may have potential forin vivo insulin delivery.
In conclusion, we proposed and realized an SAA method for thepreparation of various dextran-based smart nanogels with environmentalsensitiveness and good biocompatibility. The novelty of this thesis lies inthe development and the universal applicability of the SAA method, whichinclude the expandation of the SAA method from hydrophilic polyanionmonomers to hydrophobic ones, the introduction of disulfide-containingcrosslinkers to prepare reduction-sensitive nanogels, and the exploration ofthe biomedical applications of these dextran-based smart nanogels.
引文
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