發(fā)布時間：2019-02-09 19:22

【摘要】：IR-780是一種可以用于體內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)藥上的應用。通過對IR-780分子進行分子修飾,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,從而應用于腫瘤的成像。體內光熱治療實驗表明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,我們的膠束在產生優(yōu)秀治療效果的同時毒性小,因此其具有成為臨床應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胞攝取,并且保留了其細胞毒性。體內組織分布和藥效學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數(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。這些結果表明DOX-HSA-NPs沒有引起心臟組織的組織學病變。此外,在組織學切片中也得到了驗證相似的結論。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.
【學位授予單位】：南京大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R96;O648.1

【相似文獻】

相關期刊論文 前10條

1 王佩,李玉珍,劉恩生;大環(huán)內酯類抗生素的心臟毒性[J];藥物不良反應雜志;2000年02期

2 丘懿,郭笑如,黎碧云;大環(huán)內酯類抗生素的心臟毒性與預防措施[J];海峽藥學;2001年02期

3 廖子君,余國政,陳曉泉;抗腫瘤細胞毒藥物所致心臟毒性發(fā)生機制及處理對策[J];臨床腫瘤學雜志;2004年04期

4 倫新強;大環(huán)內酯類抗生素心臟毒性防治[J];中國藥物應用與監(jiān)測;2005年03期

5 陳一堅;孔繁智;;中藥心臟毒性的研究概況[J];浙江中醫(yī)雜志;2008年08期

6 余薇;吳基良;汪暉;;阿霉素心臟毒性防治研究進展[J];咸寧學院學報(醫(yī)學版);2008年04期

7 蘇崢;張超;梁玉翠;;中西醫(yī)結合對抗阿霉素心臟毒性的療效觀察[J];實用心電學雜志;2002年01期

8 何曉華;何并文;唐步堅;;阿霉素心臟毒性的藥物防護[J];中國癌癥防治雜志;2010年01期

9 李崇慧;;中醫(yī)藥防治化療后心臟毒性研究進展[J];中醫(yī)藥臨床雜志;2012年07期

10 郭英;甄珍;邊育紅;張艷軍;;藥物心臟毒性評價方法的研究進展[J];毒理學雜志;2013年04期

相關會議論文 前10條

1 張婧;王金華;胡寶榮;;β-內酰胺類抗生素的心臟毒性[A];第四屆全國藥物性損害與安全用藥學術會議、心血管藥物安全應用與藥源性心血管疾病防治專題研討會會刊[C];2012年

2 李楊;許頂立;孫競;;抗胸腺細胞免疫球蛋白所致心臟毒性及影響因素[A];中華醫(yī)學會心血管病學分會第十次全國心血管病學術會議匯編[C];2008年

3 張越;楊吉利;;腫瘤治療藥物的心臟毒性[A];吉林省中醫(yī)藥學會心病專業(yè)委員會成立暨第一次學術研討會論文集[C];2007年

4 石遠凱;;抗腫瘤藥物的心臟毒性[A];第四屆全國藥物性損害與安全用藥學術會議、心血管藥物安全應用與藥源性心血管疾病防治專題研討會會刊[C];2012年

5 譚初兵;劉巍;呂超君;徐為人;湯立達;;藥物心臟毒性預測和早期發(fā)現(xiàn)[A];新藥研發(fā)暨新藥發(fā)現(xiàn)學術研討會會議論文集[C];2010年

6 金承遠;周歧新;;蒽環(huán)類抗腫瘤藥物對心臟的毒性作用及其防治[A];第四屆中國腫瘤學術大會暨第五屆海峽兩岸腫瘤學術會議論文集[C];2006年

7 王淑顏;汪溪潔;馬t，

本文編號：2419313