近红外光响应的纳米复合物的制备及其药物控释性能研究

发布时间：2018-01-20 17:26

本文关键词： 近红外光敏感纳米复合物药物载体控制释放　出处：《苏州大学》2015年硕士论文　论文类型：学位论文

【摘要】：近红外光相比于紫外光和可见光具有更好的组织穿透性和较低的细胞伤害性,而且可以控制药物释放的位置和时间,因而在生物医药的材料领域受到了广泛的关注,本文主要展开了以下三个方面的工作:(1)采用香豆素光致断裂引发体系,将香豆素基团修饰上长烷基链的疏水基团(DDACMM)并与聚乙二醇甲醚甲基丙烯酸酯(PEG,Mn=950)和N-羟基琥珀酰亚胺丙烯酸酯(NSA)共聚后,通过NSA上的琥珀酰亚胺基团与叶酸(FA)反应从而得到具有叶酸靶向基团的两亲性共聚物。合成的两亲性聚合物通过自组装形成胶束的过程中包裹上阿霉素(DOX),在光照下,由于香豆素基团的双光子吸收导致胶束降解从而释放出DOX。在体外细胞实验中,在808 nm的光照下胶束能够在细胞中成功的释放出DOX,且未经光照的胶束表现出很好的生物相容性。(2)在修饰了十八烷基三甲氧基硅烷(C18)的中空介孔硅球(HMS@C18)的表面通过自组装的方法包裹一层近红外光敏感的聚合物(HAMAFA-b-DDACMM)。这个近红外靶向的多嵌段聚合物是由[7-(didodecylamino)coumarin-4-yl]methyl methacrylate、丙烯酸羟乙酯(HEA)和N-(3-氨基丙基)甲基丙烯酸盐盐酸盐(APMA)RAFT活性聚合后接枝上靶向基团叶酸(FA)而成。由于香豆素基团有很高的双光子吸收率,该共聚物在飞秒脉冲的近红外激光(808 nm)的刺激下进行双光子吸收过程后降解。通过自组装过程得到了核-壳‖结构的纳米粒子(HMS@C18@HAMAFA-b-DDACMM)。在808 nm的近红外光照射下,由于外层光敏聚合物降解,导致预先负载了药物的纳米粒子释放出药物。在体外实验中,该纳米粒子能够很容易的精确进入对叶酸受体的肿瘤细胞(KB细胞)内部。此外,该纳米粒子有很高的荧光强度,这可以用来观察细胞内部药物摄入情况。(3)设计合成了一种近红外和p H双重响应纳米药物载体,可用于磁共振和荧光造影造影。一方面,中空多孔的四氧化铁(HPFe3O4,~20 nm)在到达肿瘤部位时能够被刻蚀使得空隙变大从而加快药物释放;另一方面,近红外光敏感的聚合物(DDACMM-PEG-FA)通过香豆素单体(DDACMM)与聚乙二醇(PEG)聚合后修饰靶向基团叶酸(FA)。这个核-壳‖结构的纳米粒子(HPFe3O4@DDACMM-PEG-FA)是通过在中空核‖上包裹两亲性聚合物而成,受到近红外光刺激后大约65-80%的药物会从中释放出来。而且肿瘤部位的酸性条件会使得四氧化三铁进一步腐蚀而提高释放效率。此外,由于四氧化三铁的超顺磁性和香豆素的荧光性,磁共振造影和荧光造影可用于观察药物释放的过程。光敏感的药物载体在远程精确控制药物释放具有优势,其中近红外光良好的生物相容性和组织穿透性是理想的光敏感的光源。另外引入无机纳米粒子,提高药物载体的载药量和稳定性,同时还能引入其他的功能。因此该近红外敏感的纳米复合药物载体在临床治疗和诊断上具有非常广阔的前景。
[Abstract]:Near-infrared light has better tissue penetration and lower cellular nociceptivity than ultraviolet and visible light, and it can control the location and time of drug release. Therefore, in the field of biomedical materials has been widely concerned. In this paper, the following three aspects of work: 1) the use of coumarin photoinduced fracture initiation system. The coumarin group was modified with the hydrophobic group (DDACMM) of the alkyl chain and was modified with polyethylene glycol methyl ether methacrylate (PEG). Mn-950) was copolymerized with N-hydroxysuccinimide acrylate (NSA). Study on the relationship between succinimide group and folate in NSA. Amphiphilic copolymers with folic acid targeting groups were obtained by reaction. The synthesized amphiphilic polymers were encapsulated with doxorubicin (DOX) in the process of self-assembly to form micelles. In vitro, DOX. was released due to the degradation of micelles due to the two-photon absorption of coumarin groups. Under 808 nm illumination, the micelles can release DOX successfully in the cells. And the unilluminated micelles showed good biocompatibility.) the hollow mesoporous silica spheres modified with 18 alkyl trimethoxy silane (C18) were modified by HMS C18). A near-infrared photo-sensitive polymer, HAMAFA-b-DDACMM, is encapsulated by self-assembly. The near-infrared targeted multiblock polymer is composed of. [Methyl methacrylate. Hydroxyethyl acrylate (HEAA) and N-butadiene-3-aminopropyl) methacrylate hydrochloride were polymerized with APMA-RAFT and then grafted onto the target group folate. Because the coumarin group has a very high two-photon absorptivity. The copolymer was degraded by two-photon absorption under the stimulation of femtosecond pulse near infrared laser (808 nm). The nanocrystalline particles with core-shell structure were obtained by the self-assembly process. HMS @ C18 @ HAMAFA-b-DDACMM. Irradiated by near infrared light at 808 nm. Due to the degradation of the outer Guang Min polymer, the nanoparticles preloaded with the drug were released from the drug. The nanoparticles can easily and accurately enter the tumor cells of folic acid receptors (KB cells). In addition, the nanoparticles have high fluorescence intensity. This can be used to observe the uptake of drugs in cells.) designed and synthesized a NIR and pH dual response drug carrier, which can be used in magnetic resonance and fluorescence imaging. On the one hand. The hollow porous ferric oxide (HPFe _ 3O _ 4) can be etched to the tumor site to enlarge the void and accelerate the release of the drug. On the other hand. The near-infrared sensitive polymer DDACMM-PEG-FAA was polymerized with coumarin monomers (DDACMM) and polyethylene glycol (PEG) to modify the targeted group folic acid (FAA). The core-shell structure nano-particle HPFe _ 3O _ 4 @ DDACMM-PEG-FAA was formed by encapsulating amphiphilic polymers in hollow core. About 65-80% of the drugs released from the drug were stimulated by near-infrared light, and the acidic condition of the tumor site would further corrode iron tetroxide and improve the release efficiency. Due to the superparamagnetism of Fe _ 2O _ 4 and the fluorescence of coumarin, magnetic resonance imaging and fluorescence imaging can be used to observe the process of drug release. Photo-sensitive drug carriers have advantages in remote and accurate control of drug release. Good biocompatibility and tissue penetrability of near-infrared light are ideal light sources. In addition, inorganic nanoparticles are introduced to improve the drug load and stability of drug carriers. Therefore, the NIR sensitive nanocomposite drug carrier has a broad prospect in clinical treatment and diagnosis.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TB33;TQ460.1

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