聚多巴胺相关纳米粒在前列腺癌治疗中的研究

发布时间：2018-03-19 02:31

本文选题：前列腺癌　切入点：纳米粒子　出处：《南京大学》2017年博士论文　论文类型：学位论文

【摘要】：前列腺癌是泌尿系统最常见肿瘤之一,严重威胁着男性健康,在美国其发病率位于男性恶性肿瘤之首,死亡率仅次于肺癌位于第二。在我国前列腺癌发病率虽低于发达国家,但也呈现明显增长趋势。前列腺癌的治疗目前仍是临床诊治中的难题,特别是进展到去势抵抗性前列腺癌阶段的治疗更是目前世界各国泌尿外科医生关注的重点。目前,越来越多的纳米材料被应用在肿瘤治疗的研究中,纳米材料的增强透过性与保留(EPR)效应使得纳米粒易于富集在实体肿瘤部位。具有光敏作用的纳米材料由于其激发后的光热效应可产生极强的肿瘤杀伤作用,因而逐渐受到人们的关注。相较于常见的金属和半导体纳米粒,新型有机材料的光敏剂,由于其有着良好的生物相容性光学稳定性,低毒副作用及较高的光热转化效率等优点,越来越受到研究者的欢迎。多巴胺是一种医学中常见的神经传导物质,在神经疾病的治疗中具有很好的疗效。聚多巴胺(Polydopamine,PDA)具有良好的组织相容性和生物体内的安全性,并且可以极高效地将近红外光转化为热能,从而在体内和体外杀死肿瘤细胞。聚多巴胺是一种优秀的光敏材料。本研究将聚多巴胺纳米粒作为载体,分别构建多巴胺-顺铂纳米粒及pH敏感应答型聚多巴胺-聚烯丙胺-柠康酸酐-阿霉素纳米粒,将光热治疗与化疗联合起来,作用于前列腺癌细胞及动物模型,探究其对前列腺癌肿瘤的杀伤作用。主要工作如下:(1)构建聚多巴胺-顺铂纳米粒[Pt(Ⅳ)-PDA NP]。顺铂是临床和研究中常使用的抗肿瘤药物,并且易于修饰,其可以通过氧化达到四价的状态,而进入细胞内后四价铂又可以被还原为具有抗肿瘤效用的二价铂,从而在胞内产生抗肿瘤效应。此纳米载药系统通过聚乙二醇(PEG)将PDA与四价铂连接,产物粒径为70nm左右。我们表征了纳米粒的特性,以及体外近红光照射下温度升高的情况,评估了对前列腺癌细胞系PC3,DU145和LnCap的杀伤情况及纳米粒在PC3细胞中的细胞摄取情况。最后通过PC3细胞构建动物模型,探究Pt(Ⅳ)-PDANP在裸鼠体内的各器官分布情况及光热治疗-化疗联合下对肿瘤的抑制作用。(2)构建聚多巴胺-聚烯丙胺-柠康酸酐-阿霉素pH敏感型纳米粒(Dox@PAH-cit/PDANP)。聚烯丙胺-柠康酸酐(PAH-cit)是一种pH敏感应答型聚合物,其可以在酸性条件下侧链水解,从而使表面从负电位转变为正电位。其可附着在纳米粒表面。当pH降低时,PAH-cit的酰胺水解,使得阿霉素在酸性环境中达到有效释放。而在肿瘤细胞质溶酶体中为弱酸性环境,因此达到阿霉素药物在细胞和动物中肿瘤部位有效释放的作用。我们制备了 Dox@PAH-cit/PDANP,其粒径为80nm左右,随后评估其在不同pH,不同近红外光照射时间体外药物释放情况,以及体外前列腺癌细胞系和裸鼠体内对肿瘤的杀伤作用。结果显示,两种以聚多巴胺为载体的载药体系都有着极佳的光热转换效率,在近红外光(808nm)的照射下可产生热量,温度升高,体外实验中均可以有效杀死前列腺癌肿瘤细胞。并且相对游离药物,有着更好的细胞摄取能力。通过构建裸鼠的前列腺癌皮下瘤模型,聚多巴胺相关纳米粒在肿瘤部位有着很高的蓄积,尾静脉注射药物后,通过近红外光对肿瘤部位的照射,可以极强地抑制肿瘤的生长,达到杀伤肿瘤的目的。综上所述,我们构建了成熟的光热转换的以多巴胺纳米粒为载体的药物递送体系,有很强的临床应用前景。
[Abstract]:Prostate cancer is one of the most common tumor in urinary system, a serious threat to men's health in the United States, the incidence of malignant tumors in men, after lung cancer mortality in second. The incidence of prostate cancer in China is lower than that of the developed countries, but also a significant growth trend. The treatment of prostate cancer is still in the clinical diagnosis and treatment the problem, especially to the progress in the treatment of castration resistant prostate cancer stage is currently the focus of the world attention of all urologists. At present, nano materials are used more and more in the study of tumor treatment, nano materials to enhance the transmission and retention (EPR) effect of the nanoparticles is easy to concentrate in tumor site. Nano materials have photosensitization due to the photothermal effect after the excitation can produce a strong tumor killing effect, thus gradually attracted people's attention. Compared to the common The metal and semiconductor nanoparticles, new organic material photosensitizer, because it has good biological compatibility and optical stability, photothermal conversion efficiency has the advantages of low toxicity and high, more and more researchers welcome. Dopamine is a common medical nerve conduction material, it has good curative effect in the treatment of neural diseases. Polydopamine (Polydopamine, PDA) has good biocompatibility and safety of organisms, and can be extremely efficient nearly infrared light into heat, thus killing the tumor cells in vivo and in vitro. Polydopamine is a kind of excellent photosensitive materials. This study will polydopamine nanoparticles as carrier, were constructed dopamine - and pH sensitive nanoparticles with a poly dopamine - polyallylamine - citraconic anhydride - adriamycin nanoparticles, the photothermal therapy combined with chemotherapy, acting in front of Column cell and animal model of adenocarcinoma, explore its killing effect on prostate cancer. The main work is as follows: (1) construction of polydopamine cisplatin nanoparticles [Pt (IV) -PDA NP]. cisplatin is often used clinically and in research of antitumor drugs, and easy modification, it can achieve the tetravalent state through oxidation, and enter the cell after platinum can be reduced to two valent platinum has anti-tumor effects, resulting in the anti-tumor effect in cell. The drug loaded nano system by polyethylene glycol (PEG) to connect PDA and platinum, the particle size is about 70nm. We characterize the properties of nanoparticles, as well as in in vitro red light irradiation temperature increase, the evaluation of prostate cancer cell line PC3 cell uptake and destruction of nanoparticles DU145 and LnCap in PC3 cells. Finally, the construction of animal model by PC3 cells, explore Pt (IV) -PDANP in the nude Inhibition of tumor organ distribution and photothermal therapy - in vivo chemotherapy. (2) Gou Jianju dopamine - polyallylamine - citraconic anhydride - adriamycin pH sensitive nanoparticles (Dox@PAH-cit/PDANP). Polyallylamine - citraconic anhydride (PAH-cit) is a pH sensitive polymer type A, the in acidic conditions side chain hydrolysis, so that the surface change from negative potential for positive potential. The nanoparticles can be attached to the surface. When pH decreases, hydrolysis of the amide PAH-cit, which effectively release doxorubicin in the acidic environment. And in the cytoplasm of tumor lysosomes in weak acidic environment, so as to achieve the doxorubicin of tumor in animal cells and in part of the effective release. We prepared Dox@PAH-cit/PDANP, the grain size is about 80nm, then evaluate the in vitro drug release in different pH, different near infrared irradiation time and in vitro The killing effect of prostate cancer cell lines and tumor of nude mice. The results showed that two kinds of poly dopamine as the carrier of drug delivery system has excellent thermal conversion efficiency, in the near infrared (808nm) can produce heat, irradiation temperature, in vitro can effectively kill prostate cancer cells. And relatively free drug, has a better ability of cell uptake. The prostate cancer subcutaneous tumor model in nude mice, the polydopamine nanoparticles at the tumor site related with the accumulation of very high, intravenous injection of drugs, through the near infrared light irradiation on the site of the tumor, can strongly inhibit the growth of tumor, achieve the purpose of killing the tumor. In summary, we constructed a mature photothermal conversion to dopamine nanoparticles as carrier of drug delivery system, clinical application is very strong.

【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.25

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