PEG-IR-780-C13胶束体内成像和肿瘤治疗及DOX-HSA-NPs心脏毒性研究

发布时间：2019-02-09 19:22

【摘要】：IR-780是一种可以用于体内外荧光成像和光热治疗的疏水性近红外荧光小分子染料。但是,其在药用溶剂中的溶解度极低,这限制了其在医药上的应用。通过对IR-780分子进行分子修饰,合成了可以自组装形成PEG-IR-780-C13胶束的新分子,达到提高IR-780的溶解度的目的。PEG-IR-780-C13胶束在在静脉注射后可以靶向到肿瘤部位,从而应用于肿瘤的成像。体内光热治疗实验表明PEG-IR-780-C13胶束在808nm激光激发后可以有效的熔蚀CT26移植瘤。更重要的是,形成胶束后进行静脉注射没有出现明显的毒性。综上所述,我们的胶束在产生优秀治疗效果的同时毒性小,因此其具有成为临床应用的光热治疗媒介的发展潜力。阿霉素是一种高效的广谱抗癌药物。然而,阿霉素的临床应用却受到其心脏毒性的限制。为了降低其心脏毒性,我们以一种新的分子开关法制备白蛋白为载体的纳米粒,实现阿霉素的肿瘤靶向给药。我们所制备的DOX-HSA-NPs载药量和粒径分别为4.3%和120.1±26nm。纳米粒体外摄取实验和体外药效实验表明,阿霉素在制成纳米粒后可以更加高效的被细胞摄取,并且保留了其细胞毒性。体内组织分布和药效学研究向我们展示了纳米粒优秀的肿瘤蓄积能力和肿瘤生长抑制效果。在经过白蛋白包载后,阿霉素的最大耐受量由10mg/kg提升到30mg/kg,这说明阿霉素的系统毒性大幅降低了。给予ICR小白鼠DOX-HSA-NPs后所得的小白鼠的左室射血分数和左室短径收缩率与生理盐水组的相比几乎没有什么差别,此外其他的一些心脏毒性检测指标比如肌酸激酶,乳酸脱氢酶,超氧化物歧化酶和丙二醛均没有太大的改变。这些结果表明DOX-HSA-NPs没有引起心脏组织的组织学病变。此外,在组织学切片中也得到了验证相似的结论。因此,此白蛋白纳米载药系统可能是阿霉素药物肿瘤靶向输送颇具前景的给药方式之一。
[Abstract]:IR-780 is a hydrophobic near infrared fluorescent small molecule dye which can be used for in vivo and in vitro fluorescence imaging and photothermal therapy. However, its solubility in pharmaceutical solvents is extremely low, which limits its application in medicine. By modifying IR-780 molecules, a new molecule which can self-assemble to form PEG-IR-780-C13 micelles was synthesized. In order to improve the solubility of IR-780, PEG-IR-780-C13 micelles can be targeted to the tumor site after intravenous injection, which can be used in tumor imaging. Photothermal therapy in vivo showed that PEG-IR-780-C13 micelles could be effectively etched into CT26 xenografts after stimulated by 808nm laser. More importantly, micelles were formed without apparent toxicity after intravenous injection. To sum up, our micelles have the potential to become the photothermal therapy medium for clinical application because of their low toxicity and excellent therapeutic effect. Adriamycin is an effective broad-spectrum anticancer drug. However, the clinical use of adriamycin is limited by its cardiac toxicity. In order to reduce its cardiac toxicity, a new molecular switch method was used to prepare albumin nanoparticles, which could be used to target adriamycin (adriamycin) tumor. The drug loading and particle size of DOX-HSA-NPs were 4.3% and 120.1 卤26 nm, respectively. The results of in vitro uptake and in vitro pharmacodynamics of nanoparticles showed that doxorubicin could be more efficiently ingested by cells and retained its cytotoxicity after the preparation of nanoparticles. The study of tissue distribution and pharmacodynamics showed us the excellent tumor accumulation ability and tumor growth inhibition effect of nanoparticles. After albumin loading, the maximum tolerance of adriamycin was increased from 10mg/kg to 30 mg / kg, which indicated that the systemic toxicity of adriamycin was significantly reduced. The left ventricular ejection fraction (LVEF) and left ventricular short diameter contraction rate of ICR mice after DOX-HSA-NPs were almost no different from those of normal saline group, and some other cardiac toxicity indicators such as creatine kinase, Lactate dehydrogenase, superoxide dismutase and malondialdehyde did not change significantly. These results suggest that DOX-HSA-NPs does not cause histological changes in heart tissue. In addition, a similar conclusion was obtained in histologic sections. Therefore, this system may be one of the promising drug delivery methods for adriamycin tumor targeting delivery.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96;O648.1

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