基于QDs和DOX的靶向诊疗体系的制备与表征
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摘要
通过酰胺化反应在聚甲基丙烯酸环氧丙酯-g-聚乙二醇聚合物(PGMA-g-PEG)上修饰叶酸靶分子(FA).核磁共振(1H-NMR)和红外光谱(FTIR)测试表明成功合成了PGMA-g-(PEG)(FA)聚合物.利用该聚合物对量子点(QDs)进行配体交换形成水溶性量子点,再通过戊二醛及亚胺键键连的方式在水溶性量子点表面连接抗癌药物阿霉素(DOX)形成叶酸靶向的诊疗一体体系.紫外-可见光谱(UV-Vis)谱图显示该体系具有量子点和阿霉素的特征吸收峰,同时还出现了叶酸的特征吸收峰,由此说明了叶酸靶向的诊疗一体体系的成功制备.通过体外药物释放研究表明该体系具有较好的p H敏感性,在p H为5.0时具有较大的药物释放率,而在p H为7.4时较稳定,药物几乎得不到释放.通过He La细胞实验研究表明相比于诊疗体系,带有叶酸靶向的诊疗体系具有更大的细胞毒性,可以更好的被细胞所摄取,在细胞内形成较高浓度的量子点和阿霉素,可以更好的实现细胞的成像和肿瘤的治疗.
By amidation reaction,folic acid( FA) was grafted to hydrophilic polymer poly( glycidyl methacrylate)-g-poly( ethylene glycol))( PGMA-g-PEG). Nuclear magnetic resonance( NMR) and infrared spectroscopy( FTIR) tests showed that polymer PGMA-g-( PEG)( FA) was successfully synthesized and the grafting level of FA was 1. 7%. In order to prepare water-soluble quantum dots,the polymer PGMA-g-( PEG)( FA) was used to modify quantum dots( QDs) by ligand exchange. And using glutaraldehyde,the anti-cancer drug doxorubicin( DOX) was attached to the surface of the water-soluble quantum dots by the imine groups to form the final folic acid targeted theranostics system QDs@ PGMA-g-( PEG)( FA)( DOX). UV-Visible spectra( UV-Vis) showed that the folic acid targeted theranostics system had the characteristic absorption peaks of QDs,DOX,and FA. The result illustrated that the folic acid targeted theranostics system was successfully prepared. The drug release study showed that the system was p H sensitive,had large drug release amount at p H5. 0,and was stable at p H = 7. 4. Hela cells experimental studies showed that compared with the theranostics system,the folic acid targeted theranostics system had greater cytotoxicity and higher concentrations of QDs in the cytoplasm and higher concentrations of DOX in the nucleus. All above,compared with the theranostics system,folic acid targeted theranostics system can be better applied to cell imaging and tumor treatment in the future.
By amidation reaction,folic acid( FA) was grafted to hydrophilic polymer poly( glycidyl methacrylate)-g-poly( ethylene glycol))( PGMA-g-PEG). Nuclear magnetic resonance( NMR) and infrared spectroscopy( FTIR) tests showed that polymer PGMA-g-( PEG)( FA) was successfully synthesized and the grafting level of FA was 1. 7%. In order to prepare water-soluble quantum dots,the polymer PGMA-g-( PEG)( FA) was used to modify quantum dots( QDs) by ligand exchange. And using glutaraldehyde,the anti-cancer drug doxorubicin( DOX) was attached to the surface of the water-soluble quantum dots by the imine groups to form the final folic acid targeted theranostics system QDs@ PGMA-g-( PEG)( FA)( DOX). UV-Visible spectra( UV-Vis) showed that the folic acid targeted theranostics system had the characteristic absorption peaks of QDs,DOX,and FA. The result illustrated that the folic acid targeted theranostics system was successfully prepared. The drug release study showed that the system was p H sensitive,had large drug release amount at p H5. 0,and was stable at p H = 7. 4. Hela cells experimental studies showed that compared with the theranostics system,the folic acid targeted theranostics system had greater cytotoxicity and higher concentrations of QDs in the cytoplasm and higher concentrations of DOX in the nucleus. All above,compared with the theranostics system,folic acid targeted theranostics system can be better applied to cell imaging and tumor treatment in the future.
引文
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2 Barick K,Singh S,Bahandur D,Lawane M,Patkar D,Hassan P.J Coll Int Sci,2014,418:120~125
3 Wu W,Aiello M,Zhou T,Berliner A,Banerjee P,Zhou S.Biomaterials,2010,163(22):3023~3031
4 Wu Zhanyu(吴战宇),Sa Zongpeng(撒宗朋),Qiu Fangping(邱芳萍),Zhao Yili(赵义丽),Li Yapeng(李亚鹏),Wang Shuwei(王书唯),Wang Jingyuan(王静媛).Acta Polymerica Sinica(高分子学报),2010,(5):516~521
5 Sideratou Z,Tsiourvas D,Paleos C M.Langmuir,2000,16(4):1766~1769
6 Ganta S,Devalapally H,Shahiwala A,Amiji M.J Control Release,2008,126(3):187~204
7 Chen Jingxiao(陈荆晓),Wang Huiyuan(王慧媛),Xu Xiaoding(许小丁),Chen Weihai(陈巍海),Zhang Xianzheng(张先正).Acta Polymerica Sinica(高分子学报),2011,(8):799~811
8 Johnson K A,Brown P H.Semin Oncol,2010,37(4):345~358
9 Minko T,Dharap S S,Pakunlu R I.Curr Drug Targets,2004,5(4):389~406
10 Russel-Jones G,Mctavish K,Mcewan J,Rice J,Nowotnik D.J Inorg Biochem,2004,98(10):1625~1633
11 Mahon E,Salvati A,Bombelli F B.J Control Release,2012,162(2):164~174
12 Liu Y,Chen Z,Liu C.Biomaterials,2011,32(22):5167~5176
13 Low P,Henne W,Doorneweerd D.Acc Chem Res,2008,41(1):120~129
14 Dong Dan(董丹),Chen Feng(陈凤),Fu Yan(付艳),Wang Rui(王瑞),Zheng Yonghui(郑勇辉),Jing Xiabin(景遐斌).Acta Polymerica Sinica(高分子学报),2012,(8):915~922
15 Andresen T L,Jensen S S.Jorgensen K.Prog Lipid Res,2005,44(1):68~97
16 Wang Y Z,Zhang X N,Xu Z L,Huang H L,Li Y P,Wang J Y.J Mater Sci,2014,49(21):7539~7546
17 Grabe M,Oater G.J Gen Physiol,2001,117(4):329~344
18 Gerweck L E,Seetharaman K.Cancer Res,1996,56(6):1194~1198
19 Robert J L,Philip S L.Biochim Biophys Acta,1995,1233(2):134~144