【摘要】：IR-780是一種可以用于體內(nèi)外熒光成像和光熱治療的疏水性近紅外熒光小分子染料。但是,其在藥用溶劑中的溶解度極低,這限制了其在醫(yī)藥上的應(yīng)用。通過對IR-780分子進(jìn)行分子修飾,合成了可以自組裝形成PEG-IR-780-C13膠束的新分子,達(dá)到提高IR-780的溶解度的目的。PEG-IR-780-C13膠束在在靜脈注射后可以靶向到腫瘤部位,從而應(yīng)用于腫瘤的成像。體內(nèi)光熱治療實驗表明PEG-IR-780-C13膠束在808nm激光激發(fā)后可以有效的熔蝕CT26移植瘤。更重要的是,形成膠束后進(jìn)行靜脈注射沒有出現(xiàn)明顯的毒性。綜上所述,我們的膠束在產(chǎn)生優(yōu)秀治療效果的同時毒性小,因此其具有成為臨床應(yīng)用的光熱治療媒介的發(fā)展?jié)摿Α０⒚顾厥且环N高效的廣譜抗癌藥物。然而,阿霉素的臨床應(yīng)用卻受到其心臟毒性的限制。為了降低其心臟毒性,我們以一種新的分子開關(guān)法制備白蛋白為載體的納米粒,實現(xiàn)阿霉素的腫瘤靶向給藥。我們所制備的DOX-HSA-NPs載藥量和粒徑分別為4.3%和120.1±26nm。納米粒體外攝取實驗和體外藥效實驗表明,阿霉素在制成納米粒后可以更加高效的被細(xì)胞攝取,并且保留了其細(xì)胞毒性。體內(nèi)組織分布和藥效學(xué)研究向我們展示了納米粒優(yōu)秀的腫瘤蓄積能力和腫瘤生長抑制效果。在經(jīng)過白蛋白包載后,阿霉素的最大耐受量由10mg/kg提升到30mg/kg,這說明阿霉素的系統(tǒng)毒性大幅降低了。給予ICR小白鼠DOX-HSA-NPs后所得的小白鼠的左室射血分?jǐn)?shù)和左室短徑收縮率與生理鹽水組的相比幾乎沒有什么差別,此外其他的一些心臟毒性檢測指標(biāo)比如肌酸激酶,乳酸脫氫酶,超氧化物歧化酶和丙二醛均沒有太大的改變。這些結(jié)果表明DOX-HSA-NPs沒有引起心臟組織的組織學(xué)病變。此外,在組織學(xué)切片中也得到了驗證相似的結(jié)論。因此,此白蛋白納米載藥系統(tǒng)可能是阿霉素藥物腫瘤靶向輸送頗具前景的給藥方式之一。
[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 鹵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.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R96;O648.1

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