葡聚糖基纳米抗癌药物载体的设计与应用
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摘要
现今，癌症已经成为人类健康的最大威胁之一。在癌症的诸多治疗方法之中，化疗依然是主要的治疗方法之一。然而常用的小分子化疗药物存在着水溶性差，体内半衰期短，没有靶向性，药物利用率低，毒副作用较大和面临癌细胞多药耐药性等严峻挑战。为克服这些问题，我们针对性的设计了一系列的可降解的葡聚糖基纳米载药体系。并分别对它们在增加药物溶解性，增加药物半衰期，降低毒副作用，靶向能力等方面的作用进行了评估。具体如下
（1）通过高效的点击反应合成了一系列的葡聚糖-聚己内酯两嵌段共聚物。考察了共聚物的胶束行为，通过透射电镜和动态光散射测定了胶束的粒径大小。并以阿霉素作为药物模型制备了载药胶束，考察了载药胶束的体外模拟释放及抑制癌细胞增殖的效果。通过激光共聚焦和流式细胞实验评价了载药胶束的细胞内吞效率和细胞内释放情况。实验结果表明：葡聚糖-聚己内酯共聚物有很好的球形形貌，粒径可调。而载药胶束有很好的增加药物溶解性，增加药物半衰期，降低毒副作用的效果，对癌细胞增殖有一定的抑制作用。
（2）为克服小分子药物靶向性差，毒副作用大的缺陷，进一步将靶向小分子叶酸和半乳糖键合在葡聚糖-聚己内酯共聚物上。进而考察了靶向葡聚糖-聚己内酯载药胶束的体外释放行为及抑制癌细胞增殖的效果。随后通过激光共聚焦和流式细胞实验评价了载药胶束的细胞内吞效率和细胞内释放情况。结果表明：靶向载药胶束在其对应受体过表达的细胞中，有较好的抑制癌细胞增殖的效果，细胞内吞效率和细胞内释放速率。
（3）化疗治疗中提高药物的利用率和治疗效果十分重要。环境响应性纳米载体可以根据人体微环境的变化控制载体在指定的部位迅速释放，增加药物局部浓度，提高药物利用率。我们设计了两种基于葡聚糖的细胞微环境pH响应的两嵌段共聚物并以其包载阿霉素。通过透射电镜和动态光散射测定了胶束在不同pH下的粒径变化。结果表明：胶束有很好的pH响应性。pH载药胶束有较快的释放速率和较好的抑制癌细胞增殖的效果，并且细胞内吞效率高，细胞内释放迅速。因此，这两种能在细胞内加速释放的载药胶束有作为抗癌药物载体的应用前景。
（4）近年来，多功能化纳米抗癌药物载体发展迅速。多功能纳米载体被寄望于能有效增加药物疗效，提高癌症治疗的实际效果。多功能纳米载体主要包括具有增加药物肿瘤部位识别和富集的靶向基团，可以追踪载体的成像因子，智能性的释放行为等等。然而成本和回报的比率可能限制多功能化纳米抗癌药物载体的发展。多功能化意味着更复杂，更高的成本及更难体内的安全评估。为克服这一问题，我们设计了一种基于主客体作用的模块化的多功能纳米载体，苯并咪唑接枝在葡聚糖侧基作为骨架，同时预先合成很多基于环糊精的多功能模块，针对不同的治疗需求，选择对应的模块与骨架组成响应的纳米载体。这种模块化的载体给设计多功能化的纳米载体提供了新的思路。
通过本文的研究，希望能够对葡聚糖基抗癌药物载体设计与应用的基本科学问题，新型策略等提供基础性的实验依据和新思路，为抗癌药物载体的设计与应用奠定基础。
Cancer has increased to be the most serious thereaten for human health.Chemotherapy plays an important role in cancer therapy. However, commonly usedchemotherapy drugs always suffer from non-specific interaction, short half-life, lowdrug efficiency, severe toxicity and multi-drug resistance. To solve these problems, wedesigned novel biodegradable nanocarriers based on dextran for anticancer drugdelivery, and the effects on reducing toxicity, enhancing drug efficiency, targeteddelivery and multifunctionality were evaluated.
(1) Dextran-b-poly (ε-caprolactone)(Dex-PCL) diblock copolymers was preparedvia “click” reaction. The obtained Dex-PCL diblock copolymers were furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The DOX-loadedDex-PCL nanoparticles were characterized by transmission electron microscopy(TEM) and dynamic light scattering (DLS). In vitro drug release and cytotoxicity ofthe DOX-loaded Dex-b-PCL micelles were examined. The cellular uptake andintracellular release behaviors of micelles were followed with CLSM and flowcytometry. The micelles provide a promising candidate to overcome the problems ofshort half-life and low drug efficiency for small molecule drugs.
(2) To overcome the non-specific interaction and severe toxicity for normal tissue ofsmall molecule drugs, dextran-b-poly (ε-caprolactone)(Dex-PCL) diblockcopolymers with folic acid or galactose were designed and prepared. In vitro drugrelease and cytotoxicity of targeted micelles were examined. The cellular uptake andintracellular release behaviors of targeted micelles were observes by CLSM and flowcytometry. All the results exhibited targeted Dex-PCL micelles can effectivelyenhance the cytotoxicity, cellular uptake and intracellular release behaviors forreceptor overexpressed cells.
(3) Major challenge in chemotherapy is linked to multidrug resistance (MDR)against anticancer drugs. The stimuli responsive carriers are noted for theirsite-specific targeting release of payloads modulated by the specificmicroenvironments of intracellular space, leading to aggressive anticancer activityand maximal chemotherapeutic efficacy. So they are hopeful to overcoming multidrugresistance. Two pH-sensitive copolymers based on dextran were designed and furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The pH-sensitive micelles were characterized by transmission electron microscopy (TEM) and dynamiclight scattering (DLS). Both the two DOX-loaded pH-sensitive micelles shownincreasing release in acid conditions mimicking the endosomal/lysosomalcompartments. The enhanced intracellular DOX release was observed in cells.DOX-loaded intracelluar pH-sensitive micelles showed higher cellular proliferationinhibition towards cancer cells than pH-insensitive micelles. Therefore, with the goodbiocompatibility and accelerated intracellular drug release, the two type of micellesprovide an efficient platform to build intelligent drug delivery systems.(4) The design and development of “multifunctional” nanoparticles intended toimprove delivery, therapeutic efficacy, and ultimately patient outcome.Multifunctional nanoparticles have been devised with targeting moieties to improvespecificity and tumor accumulation, imaging agents to assess delivery and dosing,endosome escape mechanisms, target-dependent assembly or disassembly to controldrug release, and so on. However, the cost/benefit ratio of these modifications inimproving the delivery of many small-molecule drugs is less certain. Each newfunctionality elevates complexity, cost and regulatory barriers arise. To solve thesebarriers, we design a kind of modular multifunctional nano delivery systems usinghost-guest recognition as the driving force for macromolecular self-assembly.Benzimidazole linked on dextran acts as backbone, while pre-synthesizedmultifunctional polymers with cyclodextrin act as changeable modules. For differenttumor therapeutic applications, different modules are chosen and inserted in the maincase to achive a multifunctional delivery system. These modular delivery systemsprovided a promising multifunctional carrier for cancer therapy.
The above result would be expected to provide basic knowledge on theapplication of biodegradable polymers for anticancer drug delivery, and also providesome new strategies for nanocarrier of cancer therapy.
（1）通过高效的点击反应合成了一系列的葡聚糖-聚己内酯两嵌段共聚物。考察了共聚物的胶束行为，通过透射电镜和动态光散射测定了胶束的粒径大小。并以阿霉素作为药物模型制备了载药胶束，考察了载药胶束的体外模拟释放及抑制癌细胞增殖的效果。通过激光共聚焦和流式细胞实验评价了载药胶束的细胞内吞效率和细胞内释放情况。实验结果表明：葡聚糖-聚己内酯共聚物有很好的球形形貌，粒径可调。而载药胶束有很好的增加药物溶解性，增加药物半衰期，降低毒副作用的效果，对癌细胞增殖有一定的抑制作用。
（2）为克服小分子药物靶向性差，毒副作用大的缺陷，进一步将靶向小分子叶酸和半乳糖键合在葡聚糖-聚己内酯共聚物上。进而考察了靶向葡聚糖-聚己内酯载药胶束的体外释放行为及抑制癌细胞增殖的效果。随后通过激光共聚焦和流式细胞实验评价了载药胶束的细胞内吞效率和细胞内释放情况。结果表明：靶向载药胶束在其对应受体过表达的细胞中，有较好的抑制癌细胞增殖的效果，细胞内吞效率和细胞内释放速率。
（3）化疗治疗中提高药物的利用率和治疗效果十分重要。环境响应性纳米载体可以根据人体微环境的变化控制载体在指定的部位迅速释放，增加药物局部浓度，提高药物利用率。我们设计了两种基于葡聚糖的细胞微环境pH响应的两嵌段共聚物并以其包载阿霉素。通过透射电镜和动态光散射测定了胶束在不同pH下的粒径变化。结果表明：胶束有很好的pH响应性。pH载药胶束有较快的释放速率和较好的抑制癌细胞增殖的效果，并且细胞内吞效率高，细胞内释放迅速。因此，这两种能在细胞内加速释放的载药胶束有作为抗癌药物载体的应用前景。
（4）近年来，多功能化纳米抗癌药物载体发展迅速。多功能纳米载体被寄望于能有效增加药物疗效，提高癌症治疗的实际效果。多功能纳米载体主要包括具有增加药物肿瘤部位识别和富集的靶向基团，可以追踪载体的成像因子，智能性的释放行为等等。然而成本和回报的比率可能限制多功能化纳米抗癌药物载体的发展。多功能化意味着更复杂，更高的成本及更难体内的安全评估。为克服这一问题，我们设计了一种基于主客体作用的模块化的多功能纳米载体，苯并咪唑接枝在葡聚糖侧基作为骨架，同时预先合成很多基于环糊精的多功能模块，针对不同的治疗需求，选择对应的模块与骨架组成响应的纳米载体。这种模块化的载体给设计多功能化的纳米载体提供了新的思路。
通过本文的研究，希望能够对葡聚糖基抗癌药物载体设计与应用的基本科学问题，新型策略等提供基础性的实验依据和新思路，为抗癌药物载体的设计与应用奠定基础。
Cancer has increased to be the most serious thereaten for human health.Chemotherapy plays an important role in cancer therapy. However, commonly usedchemotherapy drugs always suffer from non-specific interaction, short half-life, lowdrug efficiency, severe toxicity and multi-drug resistance. To solve these problems, wedesigned novel biodegradable nanocarriers based on dextran for anticancer drugdelivery, and the effects on reducing toxicity, enhancing drug efficiency, targeteddelivery and multifunctionality were evaluated.
(1) Dextran-b-poly (ε-caprolactone)(Dex-PCL) diblock copolymers was preparedvia “click” reaction. The obtained Dex-PCL diblock copolymers were furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The DOX-loadedDex-PCL nanoparticles were characterized by transmission electron microscopy(TEM) and dynamic light scattering (DLS). In vitro drug release and cytotoxicity ofthe DOX-loaded Dex-b-PCL micelles were examined. The cellular uptake andintracellular release behaviors of micelles were followed with CLSM and flowcytometry. The micelles provide a promising candidate to overcome the problems ofshort half-life and low drug efficiency for small molecule drugs.
(2) To overcome the non-specific interaction and severe toxicity for normal tissue ofsmall molecule drugs, dextran-b-poly (ε-caprolactone)(Dex-PCL) diblockcopolymers with folic acid or galactose were designed and prepared. In vitro drugrelease and cytotoxicity of targeted micelles were examined. The cellular uptake andintracellular release behaviors of targeted micelles were observes by CLSM and flowcytometry. All the results exhibited targeted Dex-PCL micelles can effectivelyenhance the cytotoxicity, cellular uptake and intracellular release behaviors forreceptor overexpressed cells.
(3) Major challenge in chemotherapy is linked to multidrug resistance (MDR)against anticancer drugs. The stimuli responsive carriers are noted for theirsite-specific targeting release of payloads modulated by the specificmicroenvironments of intracellular space, leading to aggressive anticancer activityand maximal chemotherapeutic efficacy. So they are hopeful to overcoming multidrugresistance. Two pH-sensitive copolymers based on dextran were designed and furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The pH-sensitive micelles were characterized by transmission electron microscopy (TEM) and dynamiclight scattering (DLS). Both the two DOX-loaded pH-sensitive micelles shownincreasing release in acid conditions mimicking the endosomal/lysosomalcompartments. The enhanced intracellular DOX release was observed in cells.DOX-loaded intracelluar pH-sensitive micelles showed higher cellular proliferationinhibition towards cancer cells than pH-insensitive micelles. Therefore, with the goodbiocompatibility and accelerated intracellular drug release, the two type of micellesprovide an efficient platform to build intelligent drug delivery systems.(4) The design and development of “multifunctional” nanoparticles intended toimprove delivery, therapeutic efficacy, and ultimately patient outcome.Multifunctional nanoparticles have been devised with targeting moieties to improvespecificity and tumor accumulation, imaging agents to assess delivery and dosing,endosome escape mechanisms, target-dependent assembly or disassembly to controldrug release, and so on. However, the cost/benefit ratio of these modifications inimproving the delivery of many small-molecule drugs is less certain. Each newfunctionality elevates complexity, cost and regulatory barriers arise. To solve thesebarriers, we design a kind of modular multifunctional nano delivery systems usinghost-guest recognition as the driving force for macromolecular self-assembly.Benzimidazole linked on dextran acts as backbone, while pre-synthesizedmultifunctional polymers with cyclodextrin act as changeable modules. For differenttumor therapeutic applications, different modules are chosen and inserted in the maincase to achive a multifunctional delivery system. These modular delivery systemsprovided a promising multifunctional carrier for cancer therapy.
The above result would be expected to provide basic knowledge on theapplication of biodegradable polymers for anticancer drug delivery, and also providesome new strategies for nanocarrier of cancer therapy.
引文
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