【作者】 陈超；

【导师】 杨显珠；

【作者基本信息】 合肥工业大学 ， 制药工程（专业学位）， 2018， 硕士

【摘要】 聚合物纳米载体作为活性化合物,比如小分子药物,多肽或者基因的递送载体引起了科学家的广泛关注。这些纳米载体不仅能够显著增强治疗药物的一些性质,比如水溶性,生物相容性以及可以增加长循环等等,而且它们能够通过合理的化学设计,在特点组织、部位或细胞中,通过特异性刺激因子,实现智能药物递送和释放,这又被称为智能响应性药物递送系统。这些特异性刺激因子包括p H,温度,酶,光和超声等,可分为内源性和外源性,这些反应中部分是在体内自然发生的。内源性刺激包括、还原环境、酶等;外源性刺激包括光,超声,磁场等。这些内源性或外源性响应的纳米载体递送药物具有很好的应用潜力。但是目前尚未有响应性纳米载体能够应用到临床,原因包括设计复杂,难以放大生成,部分纳米载体生物相容性有待提高。开发具有前景的响应性纳米载体成为迫切需求。在本文中,我们主要研究胞内微环境响应的纳米载体。结合超支化聚磷酸酯纳米载体的优势,比如磷酸酯的生物可降解性,超支化材料的支化特性能够更好地负载纳米药物,并赋予其响应性,我们将敏感化学键引入到聚乙二醇修饰的超支化聚磷酸酯体系,并不断对载体进行改良。我们主要根据如下肿瘤微环境特点选择性引入响应性化学键。其一,二硫键,可以快速被谷胱甘肽(GSH)或者是还原性的酶所断裂,在细胞外氧化状态下仍然稳定,能够被用来实现还原性敏感。胞内药物释放能够被不同浓度的谷胱甘肽靶向,目前已知肿瘤组织内细胞外谷胱甘肽浓度(~2-10 u M),细胞内(~2-10 m M)。其二,由于内涵体,溶酶体内环境(~5.4),出现了大量的抗癌药物递送系统。而光敏剂治疗由于其时空的可选择性和非侵入性,具有较好的应用前景。有一些光敏剂已经走向临床。而高浓度光敏剂或者ROS高产率的光敏剂具有更好的抑制肿瘤增长的能力,但是避免不了产生光毒性,我们设计合成了酸响应超支化纳米材料,通过在p H(5.4)条件下颗粒较快的崩解,体外药物释放递送药物验证了材料的良好响应能力,并且通过包载光敏剂Ce6检测荧光发现材料具有较好的淬灭Ce6荧光特点,因此我们设想包载较高浓度Ce6而不会对正常细胞产生光毒,肿瘤内涵体酸度释放后,定点光照肿瘤部位,产生高浓度ROS高效杀伤肿瘤细胞。更多还原

【Abstract】 Polymer nanocomposites carrier as active compounds like small drug molecules,peptides or gene delivery carrier,has attracted wide attention of scientists.The nanometer carrier can significantly enhance not only some properties of drugs,such as water soluble,biocompatibility,and can increase the long cycle,and so on,and they can through reasonable chemical design,the characteristics of the organization,parts,or cells,through specific stimulating factor,intelligent drug delivery and release,this is also known as intelligent responsive drug delivery system.These specific stimulation factors including p H,temperature,enzyme,light and ultrasonic,etc.,can be divided into endogenous and exogenous,some of these reactions is naturally occurring in the body.Endogenous stimuli including,reductive environment,enzymes,etc;Exogenous stimuli including light,ultrasound,magnetic field,etc.The response of endogenous or exogenous nanometer carrier delivery drugs has very good application potential.But has yet to have a responsive nanometer carrier can be applied to clinical,causes include design complex,difficult to enlarge,part of the nanometer carrier biocompatibility remains to be improved.Development of promising responsiveness nanometer carrier become urgent needs.In this article,we mainly study intracellular micro nanometer carrier of environmental response.Combining the advantage of the hyperbranched poly phosphate nanometer carrier,such as phosphate biodegradable,branched properties of the hyperbranched nanodrugs are better able to load,and give its responsiveness,we will be introduced to the sensitive chemical bonds of polyethylene glycol modified hyperbranched poly phosphate system,and continuously modified to carrier.We mainly according to the following characteristics of the tumor microenvironment selective introduction of responsiveness chemical bonds.First,disulfide bond,can quickly be glutathione(GSH)fracture,or reducing the enzyme outside the cell oxidation conditions remain stable,can be used to realize reducing sensitivity.Intracellular drug release can be targeted by different concentration of GSH,known in the tumor tissue extracellular GSH concentration(~ 2-10 u M),cells(~ 2-10 m M).Secondly,due to the endosome,dissolving enzyme in vivo environment(~ 5.4),emerged a large number of anticancer drug delivery system.And photosensitizer treatment due to its selectivity of space-time and non-invasive,has good application prospect.There are some photosensitizer has to clinical.And high concentration of photosensitizer or ROS productivity of photosensitizer has better ability to suppress tumor growth,but avoid the produce light toxicity,we designed and synthesized acid response of hyperbranched nano materials,in the p H(5.4)particles under the condition of rapid disintegration,in vitro drug release good responsiveness of delivering drugs to verify the material,and through the package carrier photosensitizer Ce6 inspection of fluorescent material has good found the Ce6 fluorescence quenching characteristic,so we assume package load with high Ce6 and won’t produce light toxicity to normal cells,the connotation of the tumor body acidity released,tumor site,fixed point light produce high concentrations of Ce6 efficient killing tumor cells.更多还原