阿霉素磁靶向光敏脂质体的制备及其在肿瘤光热—化疗联合治疗中的应用

发布时间：2018-01-10 17:02

本文关键词：阿霉素磁靶向光敏脂质体的制备及其在肿瘤光热—化疗联合治疗中的应用　出处：《江苏大学》2017年硕士论文　论文类型：学位论文

【摘要】：脂质体作为一种常见的药物载体,能够有效地增强药物的稳定性,降低毒副作用。然而,常规的脂质体往往不能实现药物在病理部位的定点和定位释放。光热治疗(Photothermal therapy,PTT)是一种新型的治疗手段,在肿瘤的治疗方面具有良好的应用前景。Fe_3O_4纳米粒具有低毒性、超顺磁性以及良好的光热转换特性,可以作为一种理想的光敏剂应用于肿瘤的光热治疗。在本研究中,我们基于Fe_3O_4纳米粒和热敏脂质体(thermosensitive liposomes,TSL),构建了一种兼具了磁靶向、光热以及热敏释放等特性的多功能药物载体,又称为磁靶向光敏脂质体(Fe_3O_4-TSL)。选用阿霉素(Doxorubicin,DOX)作为模板药物,通过硫酸铵梯度法进行了药物的负载,构建了阿霉素磁靶向光敏脂质体(DOXFe_3O_4-TSL),并将其应用于体内外光热-化疗协同治疗肿瘤的研究。具体内容如下:一、分别采用高温热分解法和逆向蒸发法制备了油溶性的Fe_3O_4磁性纳米粒和Fe_3O_4-TSL药物载体,并对其进行了表征。结果显示所制得的Fe_3O_4纳米粒,具有近红外吸收特性并表现出超顺磁性和磁性。该纳米粒被包裹在脂质双分子层中,其负载会使得脂质体的粒径有所增大,但是不会对其相变温度产生影响。此外,该Fe_3O_4-TSL表现出良好的体外磁共振响应性和近红外(near-infrared,NIR)光热升温效果。选择MCF-7细胞为模型,考察了Fe_3O_4-TSL的细胞毒性,结果表明Fe_3O_4-TSL毒性较低、生物相容性较好。二、采用硫酸铵梯度法对TSL及Fe_3O_4-TSL进行了DOX的负载。通过比较DOXFe_3O_4-TSL与DOX-TSL的NIR光控释放效果,结果表明Fe_3O_4的负载使得脂质体中的DOX可通过NIR光触发释放。细胞实验结果表明DOXFe_3O_4-TSL可以被肿瘤细胞摄取,在NIR激光触发下,DOX从DOXFe_3O_4-TSL中释放出来并进入细胞核。对DOXFe_3O_4-TSL的体外抗肿瘤效果进行评价,结果发现单纯的光热治疗抗肿瘤效果有限,而光热治疗结合化疗则能大大增强肿瘤的治疗效果。三、构建S180荷瘤小鼠模型,研究了DOXFe_3O_4-TSL的体内肿瘤靶向性及抗肿瘤效果。尾静脉注射后,Fe_3O_4-TSL能够逐渐靶向聚集于肿瘤部位,并表现出良好的体内磁共振成像效果和光热效应。体内抗肿瘤结果显示,DOXFe_3O_4-TSL的光热-化疗抗肿瘤效果明显优于单纯的光热治疗或化疗,且组织病理学检查表明其在治疗过程中并没有对正常组织造成损伤。
[Abstract]:Liposomes as a drug carrier common, can effectively enhance the stability of drugs, reduce side effects. However, conventional liposomes often cannot achieve drug release in point and positioning. Pathology of photothermal therapy (Photothermal therapy PTT) is a new type of treatment, it has a good application prospect.Fe_3O_4 nanoparticles in the treatment of tumors with low toxicity, superparamagnetism and good thermal properties, thermal treatment can be used as a kind of ideal photosensitizer used in tumor. In this study, we based on nanoparticles and thermal Fe_3O_4 of liposome (thermosensitive liposomes, TSL), constructed a with magnetic targeting multifunctional drug carrier, and the thermal characteristics of photothermal release, also known as magnetic targeting photosensitive liposomes (Fe_3O_4-TSL) with adriamycin (Doxorubicin, DOX) as a template by drugs The ammonium sulfate gradient method for drug loading, constructed adriamycin magnetic targeting photosensitive liposomes (DOXFe_3O_4-TSL), and study its application in vivo photothermal chemotherapy synergistic. The specific contents are as follows: first, using high temperature oil soluble Fe_3O_4 magnetic nanoparticles and Fe_3O_4-TSL of the prepared drug carrier and method reverse evaporation method for decomposition and characterized. The results showed that the prepared Fe_3O_4 nanoparticles with near infrared absorption properties and show superparamagnetic and magnetic nanoparticles. It was wrapped in the lipid bilayer, the load will make the liposome size increased, but it does not influence the phase transition temperature. In addition, the Fe_3O_4-TSL showed good in vitro magnetic resonance response and near infrared (near-infrared, NIR). Select the MCF-7 photothermal heating effect cells as a model, effects of cytotoxic Fe_3O_4-TSL And the results show that Fe_3O_4-TSL has low toxicity, good biocompatibility. Two, the load on the DOX on TSL and Fe_3O_4-TSL were studied by means of ammonium sulfate gradient method. The effect of release by NIR light control comparison of DOXFe_3O_4-TSL and DOX-TSL, the results show that the Fe_3O_4 load makes the liposomes DOX by NIR light triggered release. The experimental results show that the cell DOXFe_3O_4-TSL can be cancer cells in NIR laser triggered, DOX released from DOXFe_3O_4-TSL and enter the nucleus. Evaluation of antitumor effect of DOXFe_3O_4-TSL in vitro, the results found that light heat treatment of the simple anti-tumor effect is limited, and photothermal therapy combined with chemotherapy can greatly enhance the effect of tumor therapy. Three, the construction of S180 bearing mice were studied in vivo tumor targeting of DOXFe_3O_4-TSL and anti tumor effect. After intravenous injection, Fe_3O_4-TSL can gradually gathered in the target The tumor site, and demonstrated in vivo magnetic resonance imaging and photothermal effect. Good antitumor results showed antitumor effect was better than photothermal therapy or chemotherapy DOXFe_3O_4-TSL photothermal chemotherapy, and histopathological examination showed that the treatment process does not cause damage to normal tissue.

【学位授予单位】：江苏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96

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