含儿茶酚基团聚合物胶束对硼替佐米的控制释放研究

发布时间：2018-03-05 03:06

本文选题：儿茶酚基团　切入点：两亲性聚合物　出处：《河南大学》2016年硕士论文　论文类型：学位论文

【摘要】：近年来,癌症的发病率逐渐升高,成为威胁人类健康的疾病之一。而聚合物胶束除了可以增加药物溶解度之外,还可以提高药物稳定性、降低毒性、延缓释放、提高疗效和靶向性,成为抗肿瘤药物载体的研究热点。而多功能聚合物胶束体系由于其能更好的控制药物的释放,因此备受关注。儿茶酚类物质具有很好的生物相容性和降解性,可以通过邻苯二酚基团共价连接抗肿瘤药物硼替佐米。本文就是利用儿茶酚类衍生物多巴胺先合成一种功能性单体多巴胺丙烯酰胺(DMA),进而利用可逆加成-断裂链转移(RAFT)聚合法成功合成了三种具有不同功能性的聚合物胶束体系,提高了药物的负载率和稳定性,硼酸酯键还具有pH控制药物释放的特点。主要结论如下:1、P(DMA-co-IBA)聚合物胶束的制备及载药研究本章通过可逆加成-断裂链转移(RAFT)聚合法合成了一种无规共聚物P(DMA-co-IBA),用红外光谱(FT-IR)、核磁共振氢谱(1HNMR)、凝胶渗透色谱(GPC)对其结构与形成进行表征。共聚物在水溶液中可自组装形成以聚丙烯酸异丁酯(PIBA)为内核、聚多巴胺丙烯酰胺(PDMA)为外壳的胶束体系,临界胶束浓度约为2.51 mg/L。用扫描电镜(SEM)、透射电镜(TEM)和动态光散射(DLS)表征可知聚合物胶束成球形,粒径约100 nm,且粒径分布均一,PDI为0.034。通过共价连接和物理包覆抗肿瘤药物硼替佐米(BTZ),使其具有更大的载药量,减少了突释现象的发生。研究载药胶束在体外的控释行为及细胞抗肿瘤活性。结果表明:两亲性聚合物P(DMA-co-PIBA)具有良好的细胞相容性,材料本身没有细胞毒性,载药胶束能有效的杀死肿瘤细胞,并且成明显的pH依赖性。2、P(DMA-co-IBA)-b-PAA聚合物胶束的制备及载药研究通过可逆加成-断裂链转移(RAFT)聚合法,以多巴胺丙烯酰胺(DMA)和丙烯酸异丁酯(IBA)合成无规共聚物与丙烯酸(AA)反应,成功制备出具有pH敏感性的两亲性嵌段共聚物(P(DMA-co-IBA)-b-PAA)。用红外光谱(FT-IR)、核磁共振氢谱(1HNMR)、凝胶渗透色谱(GPC)对其结构与形成进行表征。由扫描电镜(SEM)、动态光散射(DLS)表征可观察到呈球形的聚合物胶束,聚合物临界胶束浓度约为3.98mg/L。以硼替佐米为模型药物,研究载药胶束在体外的控释行为。结果表明:P(DMA-co-IBA)-b-PAA嵌段共聚物比无规共聚物体系具有更大的载药量,载药后体外释药实验明显呈pH依赖性,有望成为理想的药物载体。3、P(DMA-co-NIPAM)-b-(VK-co-IBA)聚合物胶束的制备及载药研究本章采用RAFT聚合的方法合成了一种含儿茶酚基团的新型荧光嵌段聚合物P(DMA-co-NIPAM)-b-(VK-co-IBA)。用红外光谱(FT-IR)、核磁共振氢谱(1HNMR)、凝胶渗透色谱(GPC)对其结构与形成进行表征。聚合物在水溶液中能自组装形成乙烯基咔唑(VK)和丙烯酸异丁酯(IBA)在内部,多巴胺丙烯酰胺(DMA)和N-异丙基丙烯酰胺(NIPAM)在外部的核壳结构的胶束,临界胶束浓度约为0.39 mg/L。由扫描电镜(SEM)、透射电镜(TEM)和动态光散射(DLS)表征可观察到明显球形结构的聚合物胶束,且粒径比较均一,约为100 nm。以抗癌药物硼替佐米作为模型药物,研究载药胶束在体外的控释行为及细胞抗肿瘤活性。结果表明:P(DMA-co-NIPAM)-b-(VK-co-IBA)载药胶束具有良好的抗肿瘤效果,可作为一个潜在的荧光材料用于生物领域的荧光标记和成像。
[Abstract]:In recent years, the incidence rate of cancer increased gradually, become one of the threats to human health. The polymer micelles in addition to increase drug solubility, but also can improve the stability of drugs, reduce toxicity, delayed release, improve the curative effect and targeting, become a research hotspot in anticancer drug carrier. The multifunctional polymeric micelles due to it can better control of drug release, so much attention. Catechol material has good biocompatibility and degradability of the organisms, through the catechol group covalently linked to antitumor drug bortezomib. This paper is the use of catechol derivatives to dopamine synthesis of a functional monomer acrylamide (DMA), and dopamine the reversible addition fragmentation chain transfer (RAFT) polymerization has been successfully synthesized with three different functional polymer micelles, improve the drug loading rate and The stability of the borate ester bonding also has the characteristics of pH control of drug release. The main conclusions are as follows: 1, P (DMA-co-IBA) polymer micelle preparation and drug loading of this chapter through reversible addition fragmentation chain transfer (RAFT) a random copolymer of P polymerization (DMA-co-IBA), infrared spectra (FT-IR), nuclear magnetic resonance spectroscopy (1HNMR), gel permeation chromatography (GPC) to characterize the structure and form. The copolymers can self assemble to form acrylic acid isobutyl ester in aqueous solution (PIBA) as the core, poly acrylamide (PDMA) as dopamine micelle shell, critical micelle concentration is about 2.51 mg/L. by using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS) characterization of the polymer micelles into a spherical particle size of about 100 nm, and the particle size distribution is uniform, PDI 0.034. by covalent modification and physical coating antitumor drug bortezomib (BTZ), which has a greater load The dosage, reduce the occurrence of burst release phenomenon. Research on micelle release behavior and control cells in vitro antitumor activity. The results showed that: two amphiphilic polymer P (DMA-co-PIBA) has good biocompatibility, the material itself has no cytotoxicity, drug loaded micelles can effectively kill tumor cells, and significantly pH dependent.2 P (DMA-co-IBA) and preparation of drug loaded -b-PAA polymeric micelles by reversible addition fragmentation chain transfer (RAFT) polymerization with acrylamide (DMA) and dopamine (IBA) synthesis of isobutyl acrylate copolymer with acrylic acid (AA) was prepared successfully with pH sensitivity the two amphiphilic copolymers (P (DMA-co-IBA) -b-PAA). By infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (1HNMR), gel permeation chromatography (GPC) to characterize the structure and form. By scanning electron microscopy (SEM), dynamic light scattering (DLS) characterization can be observed in spherical The polymer polymer micelles, critical micelle concentration is about 3.98mg/L. with bortezomib as a model drug to study the drug loaded micelles in vitro release behavior of the control. The results showed that P (DMA-co-IBA) -b-PAA copolymers than random copolymer system has greater loading, loading after the in vitro release experiments showed obvious pH dependence that is expected to become the ideal drug carrier.3, P (DMA-co-NIPAM) -b- (VK-co-IBA) polymer micelle preparation and drug loading of this chapter a new fluorescence with catechol group P triblock copolymer was synthesized by the polymerization of RAFT (DMA-co-NIPAM) -b- (VK-co-IBA). By infrared spectroscopy (FT-IR). Nuclear magnetic resonance spectroscopy (1HNMR), gel permeation chromatography (GPC) to characterize the structure and form. The polymer can self assemble into vinyl carbazole in aqueous solution (VK) and isobutyl methacrylate (IBA) inside, dopamine (DMA) and acrylamide N- isopropyl Based on acrylamide (NIPAM) core-shell structure outside the micelles, critical micelle concentration is about 0.39 mg/L. by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS) characterization of polymer micelles can be observed obviously the spherical structure, and the particle size is uniform, about 100 nm. to anticancer drugs bortezomib as a model drug to study the drug loaded micelles release and control cells in vitro antitumor activity. The results showed that P (DMA-co-NIPAM) -b- (VK-co-IBA) micelles has good anti-tumor effect, can be used as a potential fluorescent materials for fluorescence labeling and imaging of biological field.

【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943

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