基于树形聚合物的靶向磁共振造影剂的合成及生物学评价
|
摘要
核磁共振造影剂自从20世纪80年代被发现和应用以来,在核磁共振成像中有着独特的位置,对现代医学检测的发展起着重要的作用。为了实现早检测、早发现,本文在树形大分子基础上合成了一种新型的靶向性大分子造影剂FA-PEG (4000Da) PAMAM-Gds,初步了研究了其体外细胞毒性(MTT、FCM实验),组织急慢性毒性(组织切片),细胞靶向性(cell-TEM);体内MR成像,在MR试验中研究了大分子造影剂的驰预率,最佳成像浓度,最佳成像时间以及其在裸鼠体内的代谢等。具体内容如下：
第一章绪论
核磁共振造影剂是用来缩短成像时间、提高成像对比度和清晰度的一种成像增强对比剂。它能改变体内局部组织中水质子的驰预速率,提高正常与患病部位的成像对比度,从而显示体内器官的功能状态。核磁共振造影剂的繁荣发展,使得目前存在的MR造影剂多种多样,其分类方法亦然。四氧化三铁等超顺磁性造影剂、水溶性顺磁钆螯合物磁共振造影剂等都得到深入的研究和发展。新型的靶向大分子造影剂一般指分子量大于20000Da的造影剂复合物,是一类非常具有研究前景的MR造影剂。我们合成并研究了,树形大分子(PAMAM)为载体主体的,聚乙二醇(PEG)调控分子粒径,叶酸组织靶向型,水溶性顺磁性钆螯合物磁共振造影剂：FA-PEG-PAMAM-Gds.
第二章靶向大分子造影剂(FA-PEG-PAMAM-Gds)的合成
采用传统的发散法,以乙二胺为核多步迈克尔加成制备了4.0G的树形大分子聚合物聚酰-胺胺(PAMAM)。将此大分子与丁二酸酐反应得到端基为羧基的PAMAM-COOH。叶酸与聚乙二醇反应制得一端为氨基的分子量不同的叶酸靶向缩合物：H2N-PEG(1000 Da)-NH-FA, H2N-PEG (2000 Da)-NH-FA和H2N-PEG (4000 Da)-NH-FA.靶向缩合物与端基为羧基的PAMAM-COOH部分缩合反应,制备得到靶向大分子载体PAMAM-PEG-FA,同时制备了两种不具靶向性的大分子载体mPEG (5000 Da)-PAMAM和mPEG (2000 Da)-PAMAM。大分子载体与GdCl3·6H2O螯合,得靶向型大分子造影剂复合物FA-PEG-PAMAM-Gds和无靶向性的造影剂复合物Gds-PAMAM-PEG。1H-NMR、FT-IR等表征了酰胺键缩合等反应,证明了合成实验的成功实现。SEM、TEM、DLS等手段对大分子造影剂复合物进行了分子形貌和粒径表征。
第三章靶向大分子造影剂的体外实验研究
本章主要研究靶向型造影剂复合物FP (4000 Da) PGds的体外细胞毒性、生物相容性和细胞表面的靶向性富集。KB、L929、7702等6种细胞的MTT实验,以及辅助性的A549细胞的FCM实验,结果表明了大分子造影剂复合物FP (4000 Da) PGds的基本无细胞毒性、生物相容性高。’心脏、肺部,等组织器官的切片观察,表明大分子造影剂复合物FP (4000 Da) PGds的无急性和慢性组织毒性。细胞株KB和L929的cell-TEM观察结果,表明大分子造影剂复合物FP (4000 Da) PGds在叶酸受体表达成阳性的细胞表面靶向性富集的良好效果。
第四章靶向大分子造影剂的MRI效果评价
FA-PEG(4000 Da)-PAMAM-Gds造影剂复合物的MR实验均在西门子3.0T Trio Tim磁共振成像仪上完成了。完成动物体内/皮下肿瘤接种的基础上,设计并完成了驰预率的测定、体内最佳成像时间确定、代谢规律初步研究和肿瘤处靶向富集成像等实验,对造影剂复合物FA-PEG (4000 Da)-PAMAM-Gds的一些基本性质做了初步的研究。
Magnetic resonance imaging contrast agents have played an important role in medical development, and also have been further developed and studied since its born. In order to develop potential tumor-targeted circulation-prolonged macromolecular magnetic resonance imaging (MRI) contrasts agent without the use of low molecular gadolinium (Gd) ligands, a new macromolecular contrast targeting agent (FP (4oooDa) P-Gds),based on the dendritic polymer, was synthesized. We did lots of vitro and vivo experiments to test the quality of MR contrast agent:FP (4000Da) P-Gds.In vitro cytotoxicity (MTT, FCM test), tissue toxicity (biopsy)and so on,we carried out to prove its none cell toxicity. In vivo experiments, the MR was used to study the relaxation rate of the macromolecular contrast agent. Additionly, a series of tests were taken out to find its best imaging concentration, optimal imaging time and so on. so,we got a few initial knowledge about the metabolizability of the macromolecular contrast agent.
Chapter 1:Introduction
Magnetic resonance imaging contrast agents are used to improve MR image which can reduce the proton’relaxation time in an organization. If also can increase MR image distinctness between the normal and diseased organs, which make the disease found earlier and easier. Till now, tens of and hundreds of MRI contrast agents have been synthesized and tested, There're many classification methods about the MRI contrast agents,such as the superparamagnetic Fe3O4 contrast agents, water-soluble paramagnetic gadolinium chelate agent and so on. Macromolecular MR contrast agents refers to a new kind of MRI contrast agents,whose molecular weight are generally bigger than 20000Da. In our study, we designed and synthesized a dendrimer (PAMAM) based, as a polymer carrier, water-soluble paramagnetic gadolinium chelate magnetic resonance contrast agent:FA-PEG-PAMAM-Gds,whose molecular size wased controlled by polyethylene glycol(PEG).With conjugated folate, FA-PEG-PAMAM-Gds could be used as a tumor targeted MR contrast agents.
Chapter 2:Synthesis of Dendrimer-based tumor targeted Macromolecular MR contrast agent (FA-PEG-PAMAM-Gds)
Based on the traditional tracing method, through multi-step Michael addition, the dendritic polymer with ethylenediamine core was synthesized. We got PAMAM-COOH as a result of carboxyl reaction which refers to succinic anhydride and polymer polyamidoamine(PAMAM, dendrimer) 4.0G. H2N-PEG(1000Da)-NH-FA、H2N-PEG (2oooDa)-NH-FA and H2N-PEG (4oooDa)-NH-FA were synthesized from FA and H2N-PEG-NH2 through the acylation reaction. And according to the condensation reaction, H2N-PEG (n)-NH-FA reacted with PAMAM-COOH, formed a tumor targeted carrier PAMAM-PEG(1000Da)-FA. In the same way, another two tumor targeted carrier:PAMAM-PEG(2oooDa)-FA and PAMAM-PEG(4oooDa)-FA were also prepared. Two different types of non-targeted molecular carrier:mPEG (2oooDa)-PAMAM, and mPEG (5000Da)-PAMAM were also prepared. Then all the five macromolecular carriers were chelated with GdCl3·6H2O. So,we got dendrimer-based tumor targeted Macromolecular MR contrast agent FA-PEG(1000Da)-PAMAM-Gds、FA-PEG(2000Da)-PAMAM-Gds and FA-PEG(4oooDa)-PAMAM-Gds and non-targeted MR contrast agents mPEG(2oooDa)-PAMAM-Gds、mPEG(5oooDa)-PAMAM-Gds. The chemical structure of the Synthetic compounds all were confirmed by nuclear magnetic resonance ('H-NMR) or Fourier transform infrared (FT-IR) spectra etc,and the mass percentage content of Gd (Ⅲ) in FA-PEG-PAMAM-Gd was measured by inductively coupled plasma-atomic emission spectrometer (ICP-AES). SEM, TEM and so on were used to describe the surface characters of the macromolecular MR contrast agents.
Chapter 3:The vitro study of the macromolecular MR contrast agents
Our vitro studies focuses on the drug cytotoxicity and biocompatibility of the MR contrast agents, as while we studied its enrichment on the surface of the target cellulars. KB, L929,7702 and other three kinds of cells were taken out in MTT test,together with A549 cells'FCM experiments, macromolecular MR contrast agent FP (4oooDa) PGds were proved has no cell toxicity no matter to tumor or normal calls. Preliminary study on the organization'toxicity,reflects the macromolecular MR contrast agent FP (4oooDa)PGds of non-acute and chronic tissue toxicity,"The vitro tumor targeted enrichment of MR contrast agent FP (4000Da)PGds " refers to KB and L929 two kinds of cells'cell-TEM experimentation, which reflects the high tumor targeted ability of the macromolecular MR contrast agent. That little cytotoxicity-. high mass percentage of Gd and enough enrichment in tumor surface, suggestted its great potential as a tumor-targeted macromolecular MRI contrast agent.
Chapter 4:The vivo MR evaluation of the macromolecular MRI contrast agents
MR experiments were carried out on the Siemens 3.0T Trio Tim magnetic resonance image system which is the most advanced examine instruments in ShangHai.In this chapter,we found, of all the five MR contrast agents contrast agent,FP (4000Da)PGds had the highest relaxation rate. The the best injection concentration of the FA-PEG(4oooDa)-PAMAM-Gds contrast agent was 6.2266g/L.The best body imaging time was 50min later after the injection of FA-PEG(4oooDa)-PAMAM-Gds. About the tumor targeted and metabolism of the FA-PEG(4oooDa)-PAMAM-Gds agent, we do a preliminary study and characterization through nude mice and normal white mice.MR results displayed that it can targeted enrich around the tumor,and make its MR imaging more legible.
第一章绪论
核磁共振造影剂是用来缩短成像时间、提高成像对比度和清晰度的一种成像增强对比剂。它能改变体内局部组织中水质子的驰预速率,提高正常与患病部位的成像对比度,从而显示体内器官的功能状态。核磁共振造影剂的繁荣发展,使得目前存在的MR造影剂多种多样,其分类方法亦然。四氧化三铁等超顺磁性造影剂、水溶性顺磁钆螯合物磁共振造影剂等都得到深入的研究和发展。新型的靶向大分子造影剂一般指分子量大于20000Da的造影剂复合物,是一类非常具有研究前景的MR造影剂。我们合成并研究了,树形大分子(PAMAM)为载体主体的,聚乙二醇(PEG)调控分子粒径,叶酸组织靶向型,水溶性顺磁性钆螯合物磁共振造影剂：FA-PEG-PAMAM-Gds.
第二章靶向大分子造影剂(FA-PEG-PAMAM-Gds)的合成
采用传统的发散法,以乙二胺为核多步迈克尔加成制备了4.0G的树形大分子聚合物聚酰-胺胺(PAMAM)。将此大分子与丁二酸酐反应得到端基为羧基的PAMAM-COOH。叶酸与聚乙二醇反应制得一端为氨基的分子量不同的叶酸靶向缩合物：H2N-PEG(1000 Da)-NH-FA, H2N-PEG (2000 Da)-NH-FA和H2N-PEG (4000 Da)-NH-FA.靶向缩合物与端基为羧基的PAMAM-COOH部分缩合反应,制备得到靶向大分子载体PAMAM-PEG-FA,同时制备了两种不具靶向性的大分子载体mPEG (5000 Da)-PAMAM和mPEG (2000 Da)-PAMAM。大分子载体与GdCl3·6H2O螯合,得靶向型大分子造影剂复合物FA-PEG-PAMAM-Gds和无靶向性的造影剂复合物Gds-PAMAM-PEG。1H-NMR、FT-IR等表征了酰胺键缩合等反应,证明了合成实验的成功实现。SEM、TEM、DLS等手段对大分子造影剂复合物进行了分子形貌和粒径表征。
第三章靶向大分子造影剂的体外实验研究
本章主要研究靶向型造影剂复合物FP (4000 Da) PGds的体外细胞毒性、生物相容性和细胞表面的靶向性富集。KB、L929、7702等6种细胞的MTT实验,以及辅助性的A549细胞的FCM实验,结果表明了大分子造影剂复合物FP (4000 Da) PGds的基本无细胞毒性、生物相容性高。’心脏、肺部,等组织器官的切片观察,表明大分子造影剂复合物FP (4000 Da) PGds的无急性和慢性组织毒性。细胞株KB和L929的cell-TEM观察结果,表明大分子造影剂复合物FP (4000 Da) PGds在叶酸受体表达成阳性的细胞表面靶向性富集的良好效果。
第四章靶向大分子造影剂的MRI效果评价
FA-PEG(4000 Da)-PAMAM-Gds造影剂复合物的MR实验均在西门子3.0T Trio Tim磁共振成像仪上完成了。完成动物体内/皮下肿瘤接种的基础上,设计并完成了驰预率的测定、体内最佳成像时间确定、代谢规律初步研究和肿瘤处靶向富集成像等实验,对造影剂复合物FA-PEG (4000 Da)-PAMAM-Gds的一些基本性质做了初步的研究。
Magnetic resonance imaging contrast agents have played an important role in medical development, and also have been further developed and studied since its born. In order to develop potential tumor-targeted circulation-prolonged macromolecular magnetic resonance imaging (MRI) contrasts agent without the use of low molecular gadolinium (Gd) ligands, a new macromolecular contrast targeting agent (FP (4oooDa) P-Gds),based on the dendritic polymer, was synthesized. We did lots of vitro and vivo experiments to test the quality of MR contrast agent:FP (4000Da) P-Gds.In vitro cytotoxicity (MTT, FCM test), tissue toxicity (biopsy)and so on,we carried out to prove its none cell toxicity. In vivo experiments, the MR was used to study the relaxation rate of the macromolecular contrast agent. Additionly, a series of tests were taken out to find its best imaging concentration, optimal imaging time and so on. so,we got a few initial knowledge about the metabolizability of the macromolecular contrast agent.
Chapter 1:Introduction
Magnetic resonance imaging contrast agents are used to improve MR image which can reduce the proton’relaxation time in an organization. If also can increase MR image distinctness between the normal and diseased organs, which make the disease found earlier and easier. Till now, tens of and hundreds of MRI contrast agents have been synthesized and tested, There're many classification methods about the MRI contrast agents,such as the superparamagnetic Fe3O4 contrast agents, water-soluble paramagnetic gadolinium chelate agent and so on. Macromolecular MR contrast agents refers to a new kind of MRI contrast agents,whose molecular weight are generally bigger than 20000Da. In our study, we designed and synthesized a dendrimer (PAMAM) based, as a polymer carrier, water-soluble paramagnetic gadolinium chelate magnetic resonance contrast agent:FA-PEG-PAMAM-Gds,whose molecular size wased controlled by polyethylene glycol(PEG).With conjugated folate, FA-PEG-PAMAM-Gds could be used as a tumor targeted MR contrast agents.
Chapter 2:Synthesis of Dendrimer-based tumor targeted Macromolecular MR contrast agent (FA-PEG-PAMAM-Gds)
Based on the traditional tracing method, through multi-step Michael addition, the dendritic polymer with ethylenediamine core was synthesized. We got PAMAM-COOH as a result of carboxyl reaction which refers to succinic anhydride and polymer polyamidoamine(PAMAM, dendrimer) 4.0G. H2N-PEG(1000Da)-NH-FA、H2N-PEG (2oooDa)-NH-FA and H2N-PEG (4oooDa)-NH-FA were synthesized from FA and H2N-PEG-NH2 through the acylation reaction. And according to the condensation reaction, H2N-PEG (n)-NH-FA reacted with PAMAM-COOH, formed a tumor targeted carrier PAMAM-PEG(1000Da)-FA. In the same way, another two tumor targeted carrier:PAMAM-PEG(2oooDa)-FA and PAMAM-PEG(4oooDa)-FA were also prepared. Two different types of non-targeted molecular carrier:mPEG (2oooDa)-PAMAM, and mPEG (5000Da)-PAMAM were also prepared. Then all the five macromolecular carriers were chelated with GdCl3·6H2O. So,we got dendrimer-based tumor targeted Macromolecular MR contrast agent FA-PEG(1000Da)-PAMAM-Gds、FA-PEG(2000Da)-PAMAM-Gds and FA-PEG(4oooDa)-PAMAM-Gds and non-targeted MR contrast agents mPEG(2oooDa)-PAMAM-Gds、mPEG(5oooDa)-PAMAM-Gds. The chemical structure of the Synthetic compounds all were confirmed by nuclear magnetic resonance ('H-NMR) or Fourier transform infrared (FT-IR) spectra etc,and the mass percentage content of Gd (Ⅲ) in FA-PEG-PAMAM-Gd was measured by inductively coupled plasma-atomic emission spectrometer (ICP-AES). SEM, TEM and so on were used to describe the surface characters of the macromolecular MR contrast agents.
Chapter 3:The vitro study of the macromolecular MR contrast agents
Our vitro studies focuses on the drug cytotoxicity and biocompatibility of the MR contrast agents, as while we studied its enrichment on the surface of the target cellulars. KB, L929,7702 and other three kinds of cells were taken out in MTT test,together with A549 cells'FCM experiments, macromolecular MR contrast agent FP (4oooDa) PGds were proved has no cell toxicity no matter to tumor or normal calls. Preliminary study on the organization'toxicity,reflects the macromolecular MR contrast agent FP (4oooDa)PGds of non-acute and chronic tissue toxicity,"The vitro tumor targeted enrichment of MR contrast agent FP (4000Da)PGds " refers to KB and L929 two kinds of cells'cell-TEM experimentation, which reflects the high tumor targeted ability of the macromolecular MR contrast agent. That little cytotoxicity-. high mass percentage of Gd and enough enrichment in tumor surface, suggestted its great potential as a tumor-targeted macromolecular MRI contrast agent.
Chapter 4:The vivo MR evaluation of the macromolecular MRI contrast agents
MR experiments were carried out on the Siemens 3.0T Trio Tim magnetic resonance image system which is the most advanced examine instruments in ShangHai.In this chapter,we found, of all the five MR contrast agents contrast agent,FP (4000Da)PGds had the highest relaxation rate. The the best injection concentration of the FA-PEG(4oooDa)-PAMAM-Gds contrast agent was 6.2266g/L.The best body imaging time was 50min later after the injection of FA-PEG(4oooDa)-PAMAM-Gds. About the tumor targeted and metabolism of the FA-PEG(4oooDa)-PAMAM-Gds agent, we do a preliminary study and characterization through nude mice and normal white mice.MR results displayed that it can targeted enrich around the tumor,and make its MR imaging more legible.
引文
[1].姚桢现代医学成像技术概要[J]影响科学学与实践1993,3,50-54.
[2].王毅翔沈天真陈星荣新型磁共振造影剂研究动态[J]国外医学临床放射学分册1995,1,p20-22.
[3]. Lauterbur P C. Image formation by induced local interactions:Examples employing nuclear magnetic resonance[J]. Nature,1973,242:p190-191.
[4].陈星荣,沈天真,段新祥等.全身CT和MRI [M].上海：上海医科大学出版社.1993.p73-80.
[5].赵喜平.磁共振成像系统的原理及其应用[M].北京：科学出版社,2000.
[6]. Caravan P,Ellison J J,McMurry T J,et al. Gadolinium (Ⅲ)chelates as MRI contrast agents:Structure、 dynamics and applications[J].Chem.Rev.1999,99:2293-2352.
[7].鄢国平,卓仁禧.磁共振成像造影剂的研究进展[J].科学通报,2001,4,Vol.46,No.7：p531-538.
[8].张善荣,任吉民,裴奉奎*.磁共振造影剂的一些进展[J].化学进展1995,7(2)：p98-112.
[9].王劲武黄其鎏许乙凯磁共振成像(MRI)靶向造影剂的发展现状[J].影像诊断与介入放射学1997,6,1,p47-48.
[10].王雨青,李铁福,马红岩,邓英杰,王峥,磁共振造影剂的处方筛选和稳定性研究[J].沈阳药科大学学报Nov.2002,Vol19,No16,p395-406.
[11].Ehrlich P. Collected Studies on Immunity. [J].New York:Pergamon Press,1906. 442-447.
[12].俞开潮,万福贤,杨献,张焱 靶向性磁共振成像造影剂的研究进展[J].化学试剂,2004,26(6),329-332；352.
[13]. Aime S, Barge A, Cabella C, Crich SG, Gianolio E. Targeting cells with MR imaging probes based on paramagnetic Gd(III) chelates. [J].Curr Pharm Biotechnol 2004: 5:509-518.
[14].KimYetal. [J].CurrOpinChemBiol,1998; 2(6):733-742.
[15].何国祥,王毅翔.造影剂药理学及临床应用[M].上海：上海科学技术出版社.
[16].KellarKEetal. [J].MagnResonMed,1997; 38(5):712.716.
[17].RebizakR et al. [J].EurJPhamlSci,1999; 7(3):243-248.
[18].Martin QPomper MD. Molecular imaging:an overview. [J].Academic Radiology 2001:8:1141-1153.
[19].Haustein J,Niedorf H,Krestin G,et al. Renal tolerance of gadolinium-DTPA dimeglumine inpatients with chronic renalfailure[J]. Invest Radiol,1992,27:153-156.
[20].卓仁禧,吕正荣,魏俊发合成环状多氨多羧酸螯合物造影剂的方法[P].ZL：95119302.3.1995-11-14.
[21].Chang C A.Magnetic resonance imaging contrast agents:design and physiphysicochemical properties of gadodiamide [J].Invest Radiol,1993,28(suppl,1): 22-27.
[22].Masui T,Saeed M,Wendland M F,et al. Occlusive and reperfused myocardial infacts:MR imaging differentiation with nonionic Gd-DTPA-BAM [J]. Radio logy, 1991,181:72-83.
[23].Wedeking P,Sotak C H,Teleser J,et al. Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP2DO3A) in the nephrectomized rat [J].Magn. Reson.Imag.,1992,10:97-108.
[24].Feng Jiang-hua,SUN Guo-ying,PEI Feng-kui,et al. Comparison between Gd-DTPA and Several Bisamide Derivatives as Potential MRI Contrast Agents[J]. Bioorganic & Medicinal Chemistry,2003,11:3359-3366.
[25].SESSLER J. Red light for Photodynamics[J]. Chemistry in Britan,1998,(5): 18-25.
[26].Wallace R A,HAAR J P,MILLER D B,et al. Synthesis and preliminary evaluation of MP-2269:a novel nonaromatic small-molecule blood-pool MR contrast agent Magn.Reson[J]. Med,1998,40:733-739.
[27].Marc P,CLAIRE C,OLIVER R,et al. a rapid clearance blood pool agent for magnetic resonance imaging:preliminary results[J]. Magnetic Resonance Materials in Physics,Biology and Medicine,2001,12:121-127.
[28].ANELLI P L,BELTRAMI A,UGGERI F,et al. Chelating compounds,their chelates with paramagnetic metal ions,their preparation and use[P]. Eur pat Appl EP 822 180,1998; Chem.Abstr.1998,128,75-95.
[29].Anellip L, Beltrami A, Franzini M,et al. Gd(Ⅲ) complexes of poly(hydroxymethyl) substituted derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [J]. Inorganica Chimica Acta, 2001,317:218-229.
[30].CAVAGNA F M,LORUSSO V,ANELLI P L,et al. Preclinical profile and clinical potential of gadocoletic acidtrisodium salt (B22956/1),a new intravascular contrast medium for MRI[J]. Acad Radiol,2002,2(9):491-494.
[31].罗丽,郑书展,张世平,常建华磁共振成像造影剂的研究进展[J].西北大学学报(自然科学网络版),2004,Vol.2.No.11.
[32].Missel Witz B,Schmitt-willlich H,Ebert W,et al. Pharmacokinetics of Gadomer-17,a new dendritic magnetic resonance contrast agent[J].Magma,2001, 12(2-3):128-34.
[33].Tomalia D A,Baker H,Dewald J,et al. A new class of polymers: Starburst-dendritic macromolecules. Polym J,1985,17 (1):117.
[34].Wiener EC, Brechbiel MW, Brothers H, Magin RL, Gansow OA, Tomalia DA, Lauterbur PC. Dendrimer-based metal chelates:a new class of magnetic imaging contast agents[J]. Magn Reson Med,1994,31:1-8.
[35].翁博丰,郭秀生,于德梅,乔春苗,高战聚酰胺—胺(PAMAM)树枝形高分子的的合成及其与金属配合物的应用[J].功能材料2007年增刊(38)卷2195-2200.
[36].Tom alia D.A. NaylorA.M, Goddard Ⅲ W,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:p138-175.
[37].Kobayashi H, Brechbiel H W. Nano2sized MRI contrast agents with dendrimer cores. [J].Adv Drug Delivery Rev,2005,57 (15):271.
[38].刘晶莹,郑玉峰PAMAM树状大分子磁共振成像造影剂的研究进展[J].材料导报2007,5,vol:21,No.5 p69-72.
[39].王金凤贾欣茹金钟等聚酰胺-胺型树枝状化合物与四氯化钛的配合及其催化作用初步研究高等学校化学学报,2001,4,Vol.22 No.4 p709-711.
[40].俞开潮,万福贤,杨献,张焱 靶向性磁共振成像造影剂的研究进展[J].化学试剂,2004,26(6),329-332,352.
[41].Garin-chesa P. Campbell I.Saigo PE. et al. Trophoblast and ovarian cancer antigen I,K26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein[J]. Am J Pathol.1993.142(2):557-567.
[42]. Cancer Facts and Figures 2002. American Cancer Society. Inc. Atlanta. Georgia,USA (www. cancer. org).
[43]. Bueno R,Appasani K,Mercer H.etal. The alpha folate recaptor is highly activated in malignant pleural mesothelioma:[J]. Thorac.Cardiovasc Surg.2001,121(2): 225-233.
[44].Oung S W,Wright M,Sessler J L,et al. Texaphyrinlipophilic molecular-vesicle complexes,membrane incorporation of texaphyrins,and use in diagnosis and therapy [P].WO:9746262,1997-12-11.
[45]. Wiener E C,Konda S,Shadron A,et al. Targeting dendrimerchelates to tumors and tumor cells expressing the high affinity folate receptor [J].Invest Radiol,1997,32: 748-754.
[46].Kim S H,J eong J H,Cho K C, et al. Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly (et hylenimine). J Cont rol Release,2005,104 (1):223-232.
[47].Chen W-T,Mahmood U,Weissleder R,et al. Arthritis imaging using a near-infrared fluorescence folate-targeted probe [J].Art hritis Res & Ther,2004,7 (2):310-317.
[48].Yoo H S,Park T G. Folate-receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugate[J]. J Control Release, 2004,100 (2):247-256.
[49].林凤云,朱照静叶酸受体介导的靶向给药研究进展[J]中国医院药学杂志2006 Oct,Vol 26,No.10.p1281-1284.
[50].Wang X,Shen F,Freisheim J H,et al. Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and anti-folates [J]. Biochem Pharmacol,1992,44 (9):1898-1901.
[51].Leamon C P, Reddy J A. Folate-targeted chemotherapy [J]. Adv Drug Deliv Rev,2004,56 (8),1127-1141.
[52].Aronov O,Horowitz A T,Gabizon A,et al. Folate targeted PE G as a potential carrier for carboplatin analogs. Synthesis and in vitro studies [J]. Bioconjug Chem,2003,14 (3):563-574.
[53].Paranjpea P V, Chena Y, Kholodovychb V, et al. Tumor-targeted bioconjugate based delivery of camptot hecin:design synthesis and in vitro evaluation [J].J Control Release,2004,100 (2):275-292.
[54].张寿春,李惠敏,王柯敏叶酸-聚合物靶向载药系统研究进展[J].中国医药工业杂志2007,38(9),p676-680.
[55].Lauffer RE. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging:theory and design. J.Chem Rev 1987:87:901-927.
[56]. Weissleder R, Mahmood U.Molecular imaging. [J].Radiology 2001:219: 316-333.
[57].Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium (Ⅲ) chelates as MRI contrast agents:structure, dynamics, and applications. [J].Chem Rev 1999:99: 2293-2352.
[58].Edelman RR, Warach S. Magnetic resonance imaging (1). New England J Med 1993:328:708-716.
[1]. Atsusi M orikawa,Katsum ichi.M acromo lecu les[J],1999,32:1062-1068.
[2]. N ew kom e G.R. Pu re & A pp 1.Chem.[J],998,70 (12):2337-2343.
[3]. Long Fei(龙飞),Fan Yu(范瑜),Ding H ui Jun(丁慧君)et al.Chem.J.(高等学校化学学报),1999,20(3)：495-497
[4]. Fischer M, Vogtle F. Dendrimers:from design to application-a progress report. [J].Angew Chem Int Ed 1999:38:885-905.
[5]. Stiriba SE, Frey H, Haag R. Dendritic polymers in biomedical applications, from potential to clinical use in diagnostics and therapy. [J].Angew Chem Int Ed 2002:41: 1329-1334.
[6]. Labieniec M, Watala C. PAMAM dendrimers-diverse biomedical applications. Facts and unresolved questions. [J].Cent Eur J Biol 2009:4:434-451.
[7]. Calabretta MK, Kumar A, McDermott AM, Cai CZ, Antibacterial activities of poly(amidoamine) dendrimers terminated with amino and poly(ethylene glycol) groups. [J].Biomacromolecules 2007:8:1807-1811.
[8]. Tomalia D.A., J. Am. Chem. Soc. [J].1987,109(5):1601.
[9]. Maiti P. K, Cagin T., Wang G. F. et al. Macromolecules [[J].2004,37(16):6236.
[10].Sui G. D,Mabrouki M., Ma Y. Q. et al.[J].Journal of Colloid and Interface Science [J],2002,250(2):364.
[11].Lei Z Q,YANG Z W,HAN Q R,et al. Oxidation of cyclohexene catalyzed by PAMAM-SAM dendrimers [J].Chinese Chemical L etters,2002,(6):491-494.
[12].王金凤,贾欣茹,金钟等聚酰胺2胺型树枝状化合物与四氯化钛的配合及其催化作用初步研究[J].高等学校化学学报,2001,(4)：709-711.
[13].鄢国平,卓仁禧.磁共振成像造影剂的研究进展[J].科学通报,2001,4,Vo1.46,No.7：p531-538.
[14]. Tom alia D.A. NaylorA.M, GoddardⅢW,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:p138-175.
[15].王俊,李杰,杨锦宗.树枝状大分子催化剂的合成与应用研究进展[J].化工进展,2002,21(10),723.
[16].刘安军,强西怀,田灵,胡智锋,章川波,聚酰胺-胺型树枝状大分子的合成及应用[J].高分子学报,2006,19(4)：66.
[17].王冰冰,罗宇飞,贾欣茹,龚泳梅,吉岩,杨岭,危岩.扇形PAMAM树枝状高分子的合成与表征.[J].高分子学报2004,4(2)：304.
[18].王俊,李杰,杨锦宗.树枝状大分子催化剂的合成与应用研究进展.[J].化工进展,2002,21(10),723.
[19].徐敏,谭克,张韬,等,树状高分子的功能化进展.[J].功能高分子学报,2001,14(4)：481.
[20].龙飞,范瑜,丁慧君等.聚酞胺-胺型树枝状高分子水溶液的表面活性[J].高等学校化学学报,999,20(3):495.
[21].王冰冰,罗宇飞,贾欣茹,龚泳梅,吉岩,杨岭,危岩,扇形PAMAM树枝状高分子的合成与表征.[J].功能高分子学报,2004,4(2)：481.
[22].Tom alia D.A. NaylorA.M, GoddardⅢW,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:138-175.
[23].Zalipsky S, Gilon C, Zilkha A. Attachment of drugs to polyethylene glycols. [J].Eur Polym J 1983:19:1177-1181.
[24].Kono K, Kojima C, Hayashi N, Nishisaka E, Kiura K, Watarai S, Harada A. Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin. [J].Biomaterials 2008:29:1664-1675.
[25].Wang W, Xiong W, Wan JL, Sun XH, Xu HB, Yang XL. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress.[J].Nanotechnology 2009:20:105103-105110.
[26].Tingjun Hou, Junmei Wang, et al. ADME Evaluation in Drug Discovery.7. Prediction of Oral Absorption by Correlation and Classification J. Chem. Inf. Model. 2007,47,208-218.
[27].Kun Zou, Shu Zhu, et al. Dammarane-Type Saponins from Panax japonicus and Their Neurite Outgrowth Activity in SK-N-SH Cells J. Nat. Prod.2002,65,1288-1292.
[28]. Wenyu Huang,John N. Kuhn, et al. Dendrimer Templated Synthesis of One Nanometer Rh and Pt Particles Supported on Mesoporous Silica:Catalytic Activity for Ethylene and Pyrrole Hydrogenation [J].Nano Lett.,2008, Vol.8, No.7,2027-2034.
[29].Hong Zhang, and Naifei Hu. Conductive Effect of Gold Nanoparticles Encapsulated Inside Polyamidoamine (PAMAM) Dendrimers on Electrochemistry of Myoglobin (Mb) in{PAMAM-Au/Mb}nLayer-by-Layer Films J. Phys. Chem. B 2007, 111,10583-10590.
[30].Qing Cai, Youliang Zhao, et al. Synthesis and Properties of Star-Shaped Polylactide Attached to Poly(Amidoamine) Dendrimer, [J].Biomacromolecules 2003,4,828-834.
[31].Bing-Bing Wang, Xin Zhang, et al. Fluorescence and Aggregation Behavior of Poly(amidoamine) Dendrimers Peripherally Modified with Aromatic Chromophores: the Effect of Dendritic Architectures J. AM. CHEM. SOC.2004,126,15180-15194.
[32].Yongwen Zhang, Wei Huang,* Yongfeng Zhou, and Deyuan Yan*Complex Self-Assembly of Hyperbranched Polyamidoamine/Linear Polyacrylic Acid in Water and Their Functionalization J. Phys. Chem. B 2009,113,7729-7736.
[33].Kobayashi H, Brechbiel MW. Nano-sized MRI contrast agents with dendrimer cores. [J].Adv Drug Deliv Rev 2005,57,2271-2286.
[1]. Masoud M. Qazen and Samuel Zalipsky, et al. Targeting Folate Receptor with Folate Linked to Extremities of Poly(ethylene glycol)-Grafted Liposomes:In Vitro Studies.[J]. Bioconjugate Chem.1999,10,289-298.
[2]. Olga Aronov, Aviva T. Horowitz, Alberto Gabizon, and Dan Gibson Folate-Targeted PEG as a Potential Carrier for Carboplatin Analogs. Synthesis and in Vitro Studies.[J]. Bioconjugate Chem.2003,14,563-574.
[3].方尚玲叶酸及其检测[J].武汉工业学院学报2000 p8-11.
[4].龙娜项光亚等叶酸介导的靶向性钆造影剂的制备及驰预性能研究[J].无机化学学报2007,5,Vol.23 No.5 p759-764.
[5]. Wiener EC, Konda S, Shadron A, Brechbiel M, Gansow O. Targeting dendrimer-chelates to tumors and tumor cells expressing the high-affinity folate receptor. [J].Invest Radiol 1997:32:748-754.
[6]. Konda SD, Aref M, Wang S, Brechbiel M, Wiener EC. Specific targeting of folate-dendrimer MRI contrast agents to the high affinity folate receptor expressed in ovarian tumor xenografts. [J].MAGMA 2001:12:104-113.
[7]. Lu Y, Low PS, Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. [J].Cancer Immunol Immunother 2002:51: 153-162.
[8]. Bueno R, Appasani K, Mercer H, Lester S, Sugarbaker D. The folate receptor is highly activated in malignant pleural mesothelioma.[J].Thorac Cardiovasc Surg 2001: 121:225-233.
[9]. Reddy JA, Low PS. Folate-mediated targeting of theraputic and imaging agents to cancer. [J].Crit Rev Ther Drug Carrier Syst 1998:15:587-627.
[10].Yoo H S, Park T G. Folate-reeeptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubidn-PEG-folate conjugate J.Control Release-2004 (2):247-256.
[11].Yang I . IA J . Zhou W . etal . Targeted delivery of antisense oil-godeoxynucleotides to folate receptor-overexpressing tumor cells J.Control Release。 2004,95:321-331.
[12].Ke CY, Mathias CJ, Green MA. Synthesis and evaluation of an " In-labeled folate conjugate of'octadentate-DTPA'[J].Nucl.Med.2000,41:232.
[13].Mc Hugh M, Cheng YC. Demonstration of a High Affinity Folate Binder in Human Cell Membranes and Its Characterization in Cultured Human KB Cells.[J].J Biol Chem,1979,254:11312-11318.
[14].Holm J, Hansen SI, Hoier-Madsen M, et al. Folate Receptor of Human Mammary Adenocarcinoma[J]. A PMIS,1994,102:413-419.
[15]. Antony AC, Kane MA, Portillo RM, et al. Study of the Role of a Particulate FolatebindingProtein in the Uptake of 5-Methyltetrahydrofolate.J.Biol Chem,1985,260:14911-14917.
[16].Nikki Parkera, Mary Jo Turkb, et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay.[J]. Analytical Biochemistry 338 (2005) 284-293.
[17]. Chandrasekar D,Sistla R,Ahmad FJ,Khar RK,Diwan PV.Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.[J].Biomed Mater Res:Part A 2006:82A: 92-103.
[1]. Lauterbur P C.Image formation by induced local interactions Examples employing nuclear magnetic resonance[J]. Nature,1973,242:1902191.
[2]. Ting-Jung Chen. Tsan-Hwang Cheng,et al.Targeted folic acid-PEG nanoparticles for noninvasive imaging of folate receptor by MRI.[J].CHEN ET AL.2007,11,17, p165-175
[3]. Dennis L.Parker,Zheng-Rong Lu,et al. PEG-g-poly(GdDTPA-co-L-cystine): Effect of PEG Chain Lengthon in Vivo Contrast Enhancement in MRI [J].Biomacromolecules 2005,6,p2305-2311.
[4]. Singh P,Gupta U,Asthana A(?)Jain NK.Folate and Folate-PEG-PAMAM dendrimers:synthesis,characterization,and targeted anticancer drug delivery potential in tumor bearing mice. [J].Bioconjugate Chem 2008:19:2239-2252.
[5]. Barrett T,Kobayashi H,Brechbiel M,Choyke PL. Macromolecular MRI contrast agents for imaging tumor angiogenesis. [J].Eur J of Radiology 2006:60:353-366.
[6]. Langereis S,de Lussanet QQvan Genderen MHP,Meijer EW,Beets-Tan RGH, Griffioen AW, van Engelshoven JMA et al. Evaluation of Gd(Ⅲ)DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging. [J].NMR Biomed 2006:19:133-141.
[7]. Wu PC,Su CH,Cheng FY,Weng JC,Chen JH,Tsai TL,Yeh CS et al. Modularly assembled magnetite nanoparticles enhance in vivo targeting for magnetic resonance cancer imaging. [J].Bioconjugate Chem 2008:19:1972-1979.
[8].田雪莲,王莎莉《建立移植型肺癌动物模型的最新方法和进展》[J].重庆医科大学学报,2007年第32卷12期p1337-1339.
[9]. Mathias CJ,Wang S,Lee RJ,et al.Tumor selective Radiopharmaceutica Targeting Via Re-ceptor-mediated Endocytosis of Gallium-67-Deferoxamine-Folate [J]. J Nucl Med,996,37 (6):1003-1008.
[2].王毅翔沈天真陈星荣新型磁共振造影剂研究动态[J]国外医学临床放射学分册1995,1,p20-22.
[3]. Lauterbur P C. Image formation by induced local interactions:Examples employing nuclear magnetic resonance[J]. Nature,1973,242:p190-191.
[4].陈星荣,沈天真,段新祥等.全身CT和MRI [M].上海：上海医科大学出版社.1993.p73-80.
[5].赵喜平.磁共振成像系统的原理及其应用[M].北京：科学出版社,2000.
[6]. Caravan P,Ellison J J,McMurry T J,et al. Gadolinium (Ⅲ)chelates as MRI contrast agents:Structure、 dynamics and applications[J].Chem.Rev.1999,99:2293-2352.
[7].鄢国平,卓仁禧.磁共振成像造影剂的研究进展[J].科学通报,2001,4,Vol.46,No.7：p531-538.
[8].张善荣,任吉民,裴奉奎*.磁共振造影剂的一些进展[J].化学进展1995,7(2)：p98-112.
[9].王劲武黄其鎏许乙凯磁共振成像(MRI)靶向造影剂的发展现状[J].影像诊断与介入放射学1997,6,1,p47-48.
[10].王雨青,李铁福,马红岩,邓英杰,王峥,磁共振造影剂的处方筛选和稳定性研究[J].沈阳药科大学学报Nov.2002,Vol19,No16,p395-406.
[11].Ehrlich P. Collected Studies on Immunity. [J].New York:Pergamon Press,1906. 442-447.
[12].俞开潮,万福贤,杨献,张焱 靶向性磁共振成像造影剂的研究进展[J].化学试剂,2004,26(6),329-332；352.
[13]. Aime S, Barge A, Cabella C, Crich SG, Gianolio E. Targeting cells with MR imaging probes based on paramagnetic Gd(III) chelates. [J].Curr Pharm Biotechnol 2004: 5:509-518.
[14].KimYetal. [J].CurrOpinChemBiol,1998; 2(6):733-742.
[15].何国祥,王毅翔.造影剂药理学及临床应用[M].上海：上海科学技术出版社.
[16].KellarKEetal. [J].MagnResonMed,1997; 38(5):712.716.
[17].RebizakR et al. [J].EurJPhamlSci,1999; 7(3):243-248.
[18].Martin QPomper MD. Molecular imaging:an overview. [J].Academic Radiology 2001:8:1141-1153.
[19].Haustein J,Niedorf H,Krestin G,et al. Renal tolerance of gadolinium-DTPA dimeglumine inpatients with chronic renalfailure[J]. Invest Radiol,1992,27:153-156.
[20].卓仁禧,吕正荣,魏俊发合成环状多氨多羧酸螯合物造影剂的方法[P].ZL：95119302.3.1995-11-14.
[21].Chang C A.Magnetic resonance imaging contrast agents:design and physiphysicochemical properties of gadodiamide [J].Invest Radiol,1993,28(suppl,1): 22-27.
[22].Masui T,Saeed M,Wendland M F,et al. Occlusive and reperfused myocardial infacts:MR imaging differentiation with nonionic Gd-DTPA-BAM [J]. Radio logy, 1991,181:72-83.
[23].Wedeking P,Sotak C H,Teleser J,et al. Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP2DO3A) in the nephrectomized rat [J].Magn. Reson.Imag.,1992,10:97-108.
[24].Feng Jiang-hua,SUN Guo-ying,PEI Feng-kui,et al. Comparison between Gd-DTPA and Several Bisamide Derivatives as Potential MRI Contrast Agents[J]. Bioorganic & Medicinal Chemistry,2003,11:3359-3366.
[25].SESSLER J. Red light for Photodynamics[J]. Chemistry in Britan,1998,(5): 18-25.
[26].Wallace R A,HAAR J P,MILLER D B,et al. Synthesis and preliminary evaluation of MP-2269:a novel nonaromatic small-molecule blood-pool MR contrast agent Magn.Reson[J]. Med,1998,40:733-739.
[27].Marc P,CLAIRE C,OLIVER R,et al. a rapid clearance blood pool agent for magnetic resonance imaging:preliminary results[J]. Magnetic Resonance Materials in Physics,Biology and Medicine,2001,12:121-127.
[28].ANELLI P L,BELTRAMI A,UGGERI F,et al. Chelating compounds,their chelates with paramagnetic metal ions,their preparation and use[P]. Eur pat Appl EP 822 180,1998; Chem.Abstr.1998,128,75-95.
[29].Anellip L, Beltrami A, Franzini M,et al. Gd(Ⅲ) complexes of poly(hydroxymethyl) substituted derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [J]. Inorganica Chimica Acta, 2001,317:218-229.
[30].CAVAGNA F M,LORUSSO V,ANELLI P L,et al. Preclinical profile and clinical potential of gadocoletic acidtrisodium salt (B22956/1),a new intravascular contrast medium for MRI[J]. Acad Radiol,2002,2(9):491-494.
[31].罗丽,郑书展,张世平,常建华磁共振成像造影剂的研究进展[J].西北大学学报(自然科学网络版),2004,Vol.2.No.11.
[32].Missel Witz B,Schmitt-willlich H,Ebert W,et al. Pharmacokinetics of Gadomer-17,a new dendritic magnetic resonance contrast agent[J].Magma,2001, 12(2-3):128-34.
[33].Tomalia D A,Baker H,Dewald J,et al. A new class of polymers: Starburst-dendritic macromolecules. Polym J,1985,17 (1):117.
[34].Wiener EC, Brechbiel MW, Brothers H, Magin RL, Gansow OA, Tomalia DA, Lauterbur PC. Dendrimer-based metal chelates:a new class of magnetic imaging contast agents[J]. Magn Reson Med,1994,31:1-8.
[35].翁博丰,郭秀生,于德梅,乔春苗,高战聚酰胺—胺(PAMAM)树枝形高分子的的合成及其与金属配合物的应用[J].功能材料2007年增刊(38)卷2195-2200.
[36].Tom alia D.A. NaylorA.M, Goddard Ⅲ W,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:p138-175.
[37].Kobayashi H, Brechbiel H W. Nano2sized MRI contrast agents with dendrimer cores. [J].Adv Drug Delivery Rev,2005,57 (15):271.
[38].刘晶莹,郑玉峰PAMAM树状大分子磁共振成像造影剂的研究进展[J].材料导报2007,5,vol:21,No.5 p69-72.
[39].王金凤贾欣茹金钟等聚酰胺-胺型树枝状化合物与四氯化钛的配合及其催化作用初步研究高等学校化学学报,2001,4,Vol.22 No.4 p709-711.
[40].俞开潮,万福贤,杨献,张焱 靶向性磁共振成像造影剂的研究进展[J].化学试剂,2004,26(6),329-332,352.
[41].Garin-chesa P. Campbell I.Saigo PE. et al. Trophoblast and ovarian cancer antigen I,K26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein[J]. Am J Pathol.1993.142(2):557-567.
[42]. Cancer Facts and Figures 2002. American Cancer Society. Inc. Atlanta. Georgia,USA (www. cancer. org).
[43]. Bueno R,Appasani K,Mercer H.etal. The alpha folate recaptor is highly activated in malignant pleural mesothelioma:[J]. Thorac.Cardiovasc Surg.2001,121(2): 225-233.
[44].Oung S W,Wright M,Sessler J L,et al. Texaphyrinlipophilic molecular-vesicle complexes,membrane incorporation of texaphyrins,and use in diagnosis and therapy [P].WO:9746262,1997-12-11.
[45]. Wiener E C,Konda S,Shadron A,et al. Targeting dendrimerchelates to tumors and tumor cells expressing the high affinity folate receptor [J].Invest Radiol,1997,32: 748-754.
[46].Kim S H,J eong J H,Cho K C, et al. Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly (et hylenimine). J Cont rol Release,2005,104 (1):223-232.
[47].Chen W-T,Mahmood U,Weissleder R,et al. Arthritis imaging using a near-infrared fluorescence folate-targeted probe [J].Art hritis Res & Ther,2004,7 (2):310-317.
[48].Yoo H S,Park T G. Folate-receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugate[J]. J Control Release, 2004,100 (2):247-256.
[49].林凤云,朱照静叶酸受体介导的靶向给药研究进展[J]中国医院药学杂志2006 Oct,Vol 26,No.10.p1281-1284.
[50].Wang X,Shen F,Freisheim J H,et al. Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and anti-folates [J]. Biochem Pharmacol,1992,44 (9):1898-1901.
[51].Leamon C P, Reddy J A. Folate-targeted chemotherapy [J]. Adv Drug Deliv Rev,2004,56 (8),1127-1141.
[52].Aronov O,Horowitz A T,Gabizon A,et al. Folate targeted PE G as a potential carrier for carboplatin analogs. Synthesis and in vitro studies [J]. Bioconjug Chem,2003,14 (3):563-574.
[53].Paranjpea P V, Chena Y, Kholodovychb V, et al. Tumor-targeted bioconjugate based delivery of camptot hecin:design synthesis and in vitro evaluation [J].J Control Release,2004,100 (2):275-292.
[54].张寿春,李惠敏,王柯敏叶酸-聚合物靶向载药系统研究进展[J].中国医药工业杂志2007,38(9),p676-680.
[55].Lauffer RE. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging:theory and design. J.Chem Rev 1987:87:901-927.
[56]. Weissleder R, Mahmood U.Molecular imaging. [J].Radiology 2001:219: 316-333.
[57].Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium (Ⅲ) chelates as MRI contrast agents:structure, dynamics, and applications. [J].Chem Rev 1999:99: 2293-2352.
[58].Edelman RR, Warach S. Magnetic resonance imaging (1). New England J Med 1993:328:708-716.
[1]. Atsusi M orikawa,Katsum ichi.M acromo lecu les[J],1999,32:1062-1068.
[2]. N ew kom e G.R. Pu re & A pp 1.Chem.[J],998,70 (12):2337-2343.
[3]. Long Fei(龙飞),Fan Yu(范瑜),Ding H ui Jun(丁慧君)et al.Chem.J.(高等学校化学学报),1999,20(3)：495-497
[4]. Fischer M, Vogtle F. Dendrimers:from design to application-a progress report. [J].Angew Chem Int Ed 1999:38:885-905.
[5]. Stiriba SE, Frey H, Haag R. Dendritic polymers in biomedical applications, from potential to clinical use in diagnostics and therapy. [J].Angew Chem Int Ed 2002:41: 1329-1334.
[6]. Labieniec M, Watala C. PAMAM dendrimers-diverse biomedical applications. Facts and unresolved questions. [J].Cent Eur J Biol 2009:4:434-451.
[7]. Calabretta MK, Kumar A, McDermott AM, Cai CZ, Antibacterial activities of poly(amidoamine) dendrimers terminated with amino and poly(ethylene glycol) groups. [J].Biomacromolecules 2007:8:1807-1811.
[8]. Tomalia D.A., J. Am. Chem. Soc. [J].1987,109(5):1601.
[9]. Maiti P. K, Cagin T., Wang G. F. et al. Macromolecules [[J].2004,37(16):6236.
[10].Sui G. D,Mabrouki M., Ma Y. Q. et al.[J].Journal of Colloid and Interface Science [J],2002,250(2):364.
[11].Lei Z Q,YANG Z W,HAN Q R,et al. Oxidation of cyclohexene catalyzed by PAMAM-SAM dendrimers [J].Chinese Chemical L etters,2002,(6):491-494.
[12].王金凤,贾欣茹,金钟等聚酰胺2胺型树枝状化合物与四氯化钛的配合及其催化作用初步研究[J].高等学校化学学报,2001,(4)：709-711.
[13].鄢国平,卓仁禧.磁共振成像造影剂的研究进展[J].科学通报,2001,4,Vo1.46,No.7：p531-538.
[14]. Tom alia D.A. NaylorA.M, GoddardⅢW,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:p138-175.
[15].王俊,李杰,杨锦宗.树枝状大分子催化剂的合成与应用研究进展[J].化工进展,2002,21(10),723.
[16].刘安军,强西怀,田灵,胡智锋,章川波,聚酰胺-胺型树枝状大分子的合成及应用[J].高分子学报,2006,19(4)：66.
[17].王冰冰,罗宇飞,贾欣茹,龚泳梅,吉岩,杨岭,危岩.扇形PAMAM树枝状高分子的合成与表征.[J].高分子学报2004,4(2)：304.
[18].王俊,李杰,杨锦宗.树枝状大分子催化剂的合成与应用研究进展.[J].化工进展,2002,21(10),723.
[19].徐敏,谭克,张韬,等,树状高分子的功能化进展.[J].功能高分子学报,2001,14(4)：481.
[20].龙飞,范瑜,丁慧君等.聚酞胺-胺型树枝状高分子水溶液的表面活性[J].高等学校化学学报,999,20(3):495.
[21].王冰冰,罗宇飞,贾欣茹,龚泳梅,吉岩,杨岭,危岩,扇形PAMAM树枝状高分子的合成与表征.[J].功能高分子学报,2004,4(2)：481.
[22].Tom alia D.A. NaylorA.M, GoddardⅢW,A..Angew.Chem. Int.Ed.Engl. [J],1990,29:138-175.
[23].Zalipsky S, Gilon C, Zilkha A. Attachment of drugs to polyethylene glycols. [J].Eur Polym J 1983:19:1177-1181.
[24].Kono K, Kojima C, Hayashi N, Nishisaka E, Kiura K, Watarai S, Harada A. Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin. [J].Biomaterials 2008:29:1664-1675.
[25].Wang W, Xiong W, Wan JL, Sun XH, Xu HB, Yang XL. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress.[J].Nanotechnology 2009:20:105103-105110.
[26].Tingjun Hou, Junmei Wang, et al. ADME Evaluation in Drug Discovery.7. Prediction of Oral Absorption by Correlation and Classification J. Chem. Inf. Model. 2007,47,208-218.
[27].Kun Zou, Shu Zhu, et al. Dammarane-Type Saponins from Panax japonicus and Their Neurite Outgrowth Activity in SK-N-SH Cells J. Nat. Prod.2002,65,1288-1292.
[28]. Wenyu Huang,John N. Kuhn, et al. Dendrimer Templated Synthesis of One Nanometer Rh and Pt Particles Supported on Mesoporous Silica:Catalytic Activity for Ethylene and Pyrrole Hydrogenation [J].Nano Lett.,2008, Vol.8, No.7,2027-2034.
[29].Hong Zhang, and Naifei Hu. Conductive Effect of Gold Nanoparticles Encapsulated Inside Polyamidoamine (PAMAM) Dendrimers on Electrochemistry of Myoglobin (Mb) in{PAMAM-Au/Mb}nLayer-by-Layer Films J. Phys. Chem. B 2007, 111,10583-10590.
[30].Qing Cai, Youliang Zhao, et al. Synthesis and Properties of Star-Shaped Polylactide Attached to Poly(Amidoamine) Dendrimer, [J].Biomacromolecules 2003,4,828-834.
[31].Bing-Bing Wang, Xin Zhang, et al. Fluorescence and Aggregation Behavior of Poly(amidoamine) Dendrimers Peripherally Modified with Aromatic Chromophores: the Effect of Dendritic Architectures J. AM. CHEM. SOC.2004,126,15180-15194.
[32].Yongwen Zhang, Wei Huang,* Yongfeng Zhou, and Deyuan Yan*Complex Self-Assembly of Hyperbranched Polyamidoamine/Linear Polyacrylic Acid in Water and Their Functionalization J. Phys. Chem. B 2009,113,7729-7736.
[33].Kobayashi H, Brechbiel MW. Nano-sized MRI contrast agents with dendrimer cores. [J].Adv Drug Deliv Rev 2005,57,2271-2286.
[1]. Masoud M. Qazen and Samuel Zalipsky, et al. Targeting Folate Receptor with Folate Linked to Extremities of Poly(ethylene glycol)-Grafted Liposomes:In Vitro Studies.[J]. Bioconjugate Chem.1999,10,289-298.
[2]. Olga Aronov, Aviva T. Horowitz, Alberto Gabizon, and Dan Gibson Folate-Targeted PEG as a Potential Carrier for Carboplatin Analogs. Synthesis and in Vitro Studies.[J]. Bioconjugate Chem.2003,14,563-574.
[3].方尚玲叶酸及其检测[J].武汉工业学院学报2000 p8-11.
[4].龙娜项光亚等叶酸介导的靶向性钆造影剂的制备及驰预性能研究[J].无机化学学报2007,5,Vol.23 No.5 p759-764.
[5]. Wiener EC, Konda S, Shadron A, Brechbiel M, Gansow O. Targeting dendrimer-chelates to tumors and tumor cells expressing the high-affinity folate receptor. [J].Invest Radiol 1997:32:748-754.
[6]. Konda SD, Aref M, Wang S, Brechbiel M, Wiener EC. Specific targeting of folate-dendrimer MRI contrast agents to the high affinity folate receptor expressed in ovarian tumor xenografts. [J].MAGMA 2001:12:104-113.
[7]. Lu Y, Low PS, Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. [J].Cancer Immunol Immunother 2002:51: 153-162.
[8]. Bueno R, Appasani K, Mercer H, Lester S, Sugarbaker D. The folate receptor is highly activated in malignant pleural mesothelioma.[J].Thorac Cardiovasc Surg 2001: 121:225-233.
[9]. Reddy JA, Low PS. Folate-mediated targeting of theraputic and imaging agents to cancer. [J].Crit Rev Ther Drug Carrier Syst 1998:15:587-627.
[10].Yoo H S, Park T G. Folate-reeeptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubidn-PEG-folate conjugate J.Control Release-2004 (2):247-256.
[11].Yang I . IA J . Zhou W . etal . Targeted delivery of antisense oil-godeoxynucleotides to folate receptor-overexpressing tumor cells J.Control Release。 2004,95:321-331.
[12].Ke CY, Mathias CJ, Green MA. Synthesis and evaluation of an " In-labeled folate conjugate of'octadentate-DTPA'[J].Nucl.Med.2000,41:232.
[13].Mc Hugh M, Cheng YC. Demonstration of a High Affinity Folate Binder in Human Cell Membranes and Its Characterization in Cultured Human KB Cells.[J].J Biol Chem,1979,254:11312-11318.
[14].Holm J, Hansen SI, Hoier-Madsen M, et al. Folate Receptor of Human Mammary Adenocarcinoma[J]. A PMIS,1994,102:413-419.
[15]. Antony AC, Kane MA, Portillo RM, et al. Study of the Role of a Particulate FolatebindingProtein in the Uptake of 5-Methyltetrahydrofolate.J.Biol Chem,1985,260:14911-14917.
[16].Nikki Parkera, Mary Jo Turkb, et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay.[J]. Analytical Biochemistry 338 (2005) 284-293.
[17]. Chandrasekar D,Sistla R,Ahmad FJ,Khar RK,Diwan PV.Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.[J].Biomed Mater Res:Part A 2006:82A: 92-103.
[1]. Lauterbur P C.Image formation by induced local interactions Examples employing nuclear magnetic resonance[J]. Nature,1973,242:1902191.
[2]. Ting-Jung Chen. Tsan-Hwang Cheng,et al.Targeted folic acid-PEG nanoparticles for noninvasive imaging of folate receptor by MRI.[J].CHEN ET AL.2007,11,17, p165-175
[3]. Dennis L.Parker,Zheng-Rong Lu,et al. PEG-g-poly(GdDTPA-co-L-cystine): Effect of PEG Chain Lengthon in Vivo Contrast Enhancement in MRI [J].Biomacromolecules 2005,6,p2305-2311.
[4]. Singh P,Gupta U,Asthana A(?)Jain NK.Folate and Folate-PEG-PAMAM dendrimers:synthesis,characterization,and targeted anticancer drug delivery potential in tumor bearing mice. [J].Bioconjugate Chem 2008:19:2239-2252.
[5]. Barrett T,Kobayashi H,Brechbiel M,Choyke PL. Macromolecular MRI contrast agents for imaging tumor angiogenesis. [J].Eur J of Radiology 2006:60:353-366.
[6]. Langereis S,de Lussanet QQvan Genderen MHP,Meijer EW,Beets-Tan RGH, Griffioen AW, van Engelshoven JMA et al. Evaluation of Gd(Ⅲ)DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging. [J].NMR Biomed 2006:19:133-141.
[7]. Wu PC,Su CH,Cheng FY,Weng JC,Chen JH,Tsai TL,Yeh CS et al. Modularly assembled magnetite nanoparticles enhance in vivo targeting for magnetic resonance cancer imaging. [J].Bioconjugate Chem 2008:19:1972-1979.
[8].田雪莲,王莎莉《建立移植型肺癌动物模型的最新方法和进展》[J].重庆医科大学学报,2007年第32卷12期p1337-1339.
[9]. Mathias CJ,Wang S,Lee RJ,et al.Tumor selective Radiopharmaceutica Targeting Via Re-ceptor-mediated Endocytosis of Gallium-67-Deferoxamine-Folate [J]. J Nucl Med,996,37 (6):1003-1008.