叶酸修饰的具有靶向功能的Mn_3O_4造影剂的制备及其在核磁共振成像中的应用
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摘要
通过高温热解的方法制备出Mn3O4纳米粒子,再利用正硅酸四乙酯(TEOS)包硅改善其水溶性和稳定性,通过加入3-氨基丙基三乙氧基硅烷(APTES)使纳米粒子表面接入大量氨基,最后再连接增加磁性纳米粒子生物相容性的有机分子聚乙二醇(PEG)和靶向分子叶酸(FA),得到Mn3O4靶向造影剂.体外实验表明,该造影剂具有低的细胞毒性,并对宫颈癌细胞具有较好的磁共振增强成像效果以及主动靶向作用.
The monodisperse silica-coated manganese oxide nanoparticles(NPs) were synthesized via a thermal decomposition approach and were aminated through silanization. The amine-functionalized core-shell NPs enabled the covalent conjugation of organic hydrophilic PEG and folate(FA) onto their surfaces. The formed Mn3O4@SiO2-PEG-FA core-shell nanocomposites are water-dispersible, stable, and biocompatible. Furthermore, we demonstrate that Mn3O4@SiO2-PEG-FA NPs as a T1 contrast agent display effective targeting ability, and lower toxicity in vitro, enabling them to be developed as multimodel nanoplatform for long-term targeted imaging.
The monodisperse silica-coated manganese oxide nanoparticles(NPs) were synthesized via a thermal decomposition approach and were aminated through silanization. The amine-functionalized core-shell NPs enabled the covalent conjugation of organic hydrophilic PEG and folate(FA) onto their surfaces. The formed Mn3O4@SiO2-PEG-FA core-shell nanocomposites are water-dispersible, stable, and biocompatible. Furthermore, we demonstrate that Mn3O4@SiO2-PEG-FA NPs as a T1 contrast agent display effective targeting ability, and lower toxicity in vitro, enabling them to be developed as multimodel nanoplatform for long-term targeted imaging.
引文
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27 Yang H,Zhuang Y,Hu H,Du X,Zhang C,Shi X,Wu H,Yang S.Silica-coated manganese oxide nanoparticles as a platform for targeted magnetic resonance and fluorescence imaging of cancer cells.Adv Funct Mater,2010,20:1733–1741
28 Lu Y,Yin Y,Mayers BT,Xia Y.Modifying the surface properties of superparamagnetic iron oxide nanoparticles through a sol-gel approach.Nano lett,2001,2:183–186
29 Yang H,Zhuang Y,Sun Y,Dai A,Shi X,Wu D,Li F,Hu H,Yang S.Targeted dual-contrast T1-and T2-weighted magnetic resonance imaging of tumors using multifunctional gadolinium-labeled superparamagnetic iron oxide nanoparticles.Biomaterials,2011,32:4584–4593
30 Kohler N,Sun C,Fichtenholtz A,Gunn J,Fang C,Zhang M.Methotrexate-immobilized poly(ethylene glycol)magnetic nanoparticles for MR imaging and drug delivery.Small,2006,2:785–792
31 Kumagai M,Sarma TK,Cabral H,Kaida S,Sekino M,Herlambang N,Osada K,Kano MR,Nishiyama N,Kataoka K.Enhanced in vivo magnetic resonance imaging of tumors by PEGylated iron-oxide-gold core-shell nanoparticles with prolonged blood circulation properties.Macromol Rapid Comm,2010,31:1521–1528
32 Zhang WL,Li N,Huang J,Luo SF,Fan MX,Liu SY,Muir B,Yu JH.Gadolinium-conjugated folate-poly(ethylene glycol)-polyamidoamine dendrimer-carboxyl nanoparticles as potential tumor-targeted,circulation-prolonged macromolecular magnetic resonance imaging contrast agents.II.J Appl Polym Sci,2011,121:3175–3184
33 Peng YK,Lai CW,Hsiao YH,Tang KC,Chou PT.Multifunctional mesoporous silica-coated hollow manganese oxide nanoparticles for targeted optical imaging,T1magnetic resonance imaging and photodynamic therapy.Mater Express,2011,1:136–143
34 Yang JJ,Yang J,Wei L,Zurkiya O,Yang W,Li S,Zou J,Zhou Y,Maniccia ALW,Mao H,Zhao F,Malchow R,Zhao S,Johnson J,Hu X,Krogstad E,Liu Z-R.Rational design of protein-based MRI contrast agents.J Am Chem Soc,2008,130:9260–9267
35 Chou SW,Shau YH,Wu PC,Yang YS,Shieh DB,Chen CC.In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging.J Am Chem Soc,2010,132:13270–13278
2 Kim J,Piao Y,Hyeon T.Multifunctional nanostructured materials for multimodal imaging,and simultaneous imaging and therapy.Chem Soc Rev,2009,38:372–390
3 Kang WJ,Chae JR,Cho YL,Lee JD,Kim S.Multiplex imaging of single tumor cells using quantum-dot-conjugated aptamers.Small,2009,5 :2519–2522
4 于艳蓉,谭蓉,杨红,杨仕平.纳米多功能磁共振造影剂的合成、修饰及其生物应用.上海师范大学学报(自然科学版),2012,41:419 –431
5 张崇琨,陈冬梅,李向远,杨仕平.磁性纳米材料在磁传感和生物探针中的应用.上海师范大学学报(自然科学版),2012,41:203 –210
6 Yang H,Li X,Zhou H,Zhuang Y,Hu H,Wu H,Yang S.Monodisperse water-soluble Fe-Ni nanoparticles for magnetic resonance imaging.J Alloys Compd,2011,509:1217–1221
7 Gao J,Gu H,Xu B.Multifunctional magnetic nanoparticles:design,synthesis,and biomedical applications.Acc Chem Res,2009,42:1097–1107
8 Morawski AM,Lanza GA,Wickline SA.Targeted contrast agents for magnetic resonance imaging and ultrasound.Curr Opin Bitechnol,2005,16:89–92
9 Wu H,Liu G,Zhuang Y,Wu D,Zhang H,Yang H,Hu H,Yang S.The behavior after intravenous injection in mice of multiwalled carbon nanotube/Fe3O4hybrid MRI contrast agents.Biomaterials,2011,32:4867–4876
10 Yang H,Zhang C,Shi X,Hu H,Du X,Fang Y,Ma Y,Wu H,Yang S.Water-soluble superparamagnetic manganese ferrite nanoparticles for magnetic resonance imaging.Biomaterials,2010,31:3667–3673
11 Yang H,Tian Z,Wang J,Yang S.A magnetic resonance imaging nanosensor for Hg(II)based on thymidine-functionalized supermagnetic iron oxide nanoparticles.Sens Actu B Chem,2012,161:429–433
12 Jun Y-w,Huh Y-M,Choi J-s,Lee J-H,Song H-T,Kim S,Yoon S,Kim K-S,Shin J-S,Suh J-S,Cheon J.Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging.J Am Chem Soc,2004,5732–5733
13 Na HB,Lee JH,An K,Park YI,Park M,Lee IS,Nam D-H,Kim ST,Kim S-H,Kim S-W,Lim K-H,Kim K-S,Kim S-O,Heyon T.Development of a T1contrast agent for magnetic resonance imaging using MnO nanoparticles.Angew Chem Int Ed,2007,46:5397–5401
14 Saini S,Nelson RC.Technique for MR imaging of the liver.Radiology,1995,195:575–577
15 Lim K,Stark DD,Leese PT,Pfefferbaum A,Rocklage SM,Quay SC.Hepatobiliary MR imaging:first human experience with MnDPDP.Radiology,1991,178:79–82
16 Cheng Z,Thorek DL,Tsourkas A.Gadolinium-conjugated dendrimer nanoclusters as a tumor-targeted T1magnetic resonance imaging contrast agent.Angew Chem Int Ed,2010,49:346–350
17 Shin J,Anisur RM,Ko MK,Im GH,Lee JH,Lee IS.Hollow manganese oxide nanoparticles as multifunctional agents for magnetic resonance imaging and drug delivery.Angew Chem Int Ed,2009,48:321–324
18 Shukoor MI,Natalio F,Tahir MN,Wiens M,Tarantola M,Therese HA,Barz M,Weber S,Tererkhov M,Schroder HC,Muller WEG,Janshoff A,Theato P,Zentel R,Schreiber LM,Tremel W.Pathogen-mimicking MnO nanoparticles for selective activation of the TLR9pathway and imaging of cancer cells.Adv Funct Mater,2009,19:3717–3725
19 Weitman SD,Lark RH,Coney LR,Fort DW,Frasca V,Zurawski VR Jr,Kamen BA.Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.Cancer Res,1992,52:3396–3401
20 B.S JFR,Chaudhuri PK,Ratnam M.Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines.Physiologic and clinical implications.Cancer,2006,73:2432–2443
21 Zhang Y,Kohler N,Zhang M.Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake.Biomaterials,2002,23:1553–1561
22 Sun C,Sze R,Zhang M.Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI.J Biomed Mater Res A,2006,78:550–557
23 Li K,Wen S,Larson AC,Shen M,Zhang Z,Chen Q,Shi X,Zhang G.Multifunctional dendrimer-based nanoparticles for in vivo MR/CT dual-modal molecular imaging of breast cancer.Int J Nanomed,2013,8:2589–2600
24 Salazar-Alvarez G,Sort J,Suriac S,BaróMD,Nogués J.Synthesis and size-dependent exchange bias in inverted core-shell MnO|Mn3O4nanoparticles.J Am Chem Soc,2007,129:9102–9108
25 Seo WS,Jo HH,Lee K,Kim B,Oh SJ,Park JT.Size-dependent magnetic properties of colloidal Mn3O4and MnO nanoparticles.Angew Chem Int Ed,2004,43:1115–1117
26 Kee D,Lee SS,Papaefthymiou GC,Ying JY.Nanoparticle architectures templated by SiO2/Fe2O3nanocomposites.Chem Mater,2006,18:614 –619
27 Yang H,Zhuang Y,Hu H,Du X,Zhang C,Shi X,Wu H,Yang S.Silica-coated manganese oxide nanoparticles as a platform for targeted magnetic resonance and fluorescence imaging of cancer cells.Adv Funct Mater,2010,20:1733–1741
28 Lu Y,Yin Y,Mayers BT,Xia Y.Modifying the surface properties of superparamagnetic iron oxide nanoparticles through a sol-gel approach.Nano lett,2001,2:183–186
29 Yang H,Zhuang Y,Sun Y,Dai A,Shi X,Wu D,Li F,Hu H,Yang S.Targeted dual-contrast T1-and T2-weighted magnetic resonance imaging of tumors using multifunctional gadolinium-labeled superparamagnetic iron oxide nanoparticles.Biomaterials,2011,32:4584–4593
30 Kohler N,Sun C,Fichtenholtz A,Gunn J,Fang C,Zhang M.Methotrexate-immobilized poly(ethylene glycol)magnetic nanoparticles for MR imaging and drug delivery.Small,2006,2:785–792
31 Kumagai M,Sarma TK,Cabral H,Kaida S,Sekino M,Herlambang N,Osada K,Kano MR,Nishiyama N,Kataoka K.Enhanced in vivo magnetic resonance imaging of tumors by PEGylated iron-oxide-gold core-shell nanoparticles with prolonged blood circulation properties.Macromol Rapid Comm,2010,31:1521–1528
32 Zhang WL,Li N,Huang J,Luo SF,Fan MX,Liu SY,Muir B,Yu JH.Gadolinium-conjugated folate-poly(ethylene glycol)-polyamidoamine dendrimer-carboxyl nanoparticles as potential tumor-targeted,circulation-prolonged macromolecular magnetic resonance imaging contrast agents.II.J Appl Polym Sci,2011,121:3175–3184
33 Peng YK,Lai CW,Hsiao YH,Tang KC,Chou PT.Multifunctional mesoporous silica-coated hollow manganese oxide nanoparticles for targeted optical imaging,T1magnetic resonance imaging and photodynamic therapy.Mater Express,2011,1:136–143
34 Yang JJ,Yang J,Wei L,Zurkiya O,Yang W,Li S,Zou J,Zhou Y,Maniccia ALW,Mao H,Zhao F,Malchow R,Zhao S,Johnson J,Hu X,Krogstad E,Liu Z-R.Rational design of protein-based MRI contrast agents.J Am Chem Soc,2008,130:9260–9267
35 Chou SW,Shau YH,Wu PC,Yang YS,Shieh DB,Chen CC.In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging.J Am Chem Soc,2010,132:13270–13278