端氨基聚(醚-氨酯-酰胺)配体及磁共振成像造影剂研究

设计合成了一种端氨基聚(醚-氨酯)PEU-((CH2)6NH2)2(Ⅱ),以Ⅱ为原料制备端氨基聚(醚-氨酯-酰胺)PEU/DTPA共聚物造影剂配体(Ⅲ).Ⅲ的特点为(1)大分子配体的端基为—(CH2)6—NH2,柔性间隔基较长,可克服较大的空间位阻,与靶向性物质(如靶向多肽、蛋白质)反应;(2)原料Ⅱ为采用聚氨酯反应制备,亲水亲油链段长短、种类可控性好,实验条件简单;(3)端氨基可以在温和条件下与多肽等反应.大分子配体Ⅲ与Gd3+络合制备了相应的Gd3+配合物(Ⅳ),研究了Ⅳ的弛豫性能,磁共振成像(MRI)结果表明,合成的造影剂Ⅳ纵向弛豫速率(R1)与医用造影剂钆喷酸葡胺Gd-DTPA相比提高了38.40%,在裸鼠肝脏内信号增强率在0.1、6、12、24 h分别是Gd-DTPA最大信号增强的1.5、3、1.8和1.3倍,在体内的半衰期明显延长.用IR、NMR、GPC、官能团滴定、ICP等方法表征产物.

STUDIES ON AMINO GROUP TERMINATED POLY(ETHERURETHANE-AMIDE) LIGAND AND MAGNETIC RESONANCE IMAGING CONTRAST AGENT

To develop and characterize a new class of potential blood pool magnetic resonance(MR) contrast agents which could be used as cancer target gene delivery carrier,novel gadolinium amino group terminated poly(ether-urethane-amide)/diethylenetriamine pentaacetic acid(PEU-Gd-DTPA) polymeric chelate(Ⅳ)was synthesized.The amino group terminated poly(ether-urethane-amide)/diethylenetriamine pentaacetic acid(PEU/DTPA) copolymer ligand(Ⅲ)could be designed and obtained from the reaction of diethylenetriamine pentaacetic acid dianhydride(DTPAA,Ⅰ) with amino group terminated PEU(PEU-((CH_2)_6NH_2)_2)(Ⅱ),which was prepared in high yield by the reaction of polyethylene glycol(PEG) with isophorone diisocyanate(IPDI) and then with hexamethylene diamine.Ligand Ⅲ was then coordinated with Gd~(3+) ion to give the macromolecular contrast agent Ⅳ in water at room temperature.The structure analysis and characterization of DTPAA,Ⅱ,Ⅲ were studied by IR,NMR,GPC,and functional group titration methods.Gadolinium content of the polymeric chelate Ⅳ was 0.88 wt%,which was determined by radio frequency inductively coupled plasma(ICP) spectra.In vitro relaxivity(R_1) studies of Ⅳ showed a 38.40% increase in R_1 relaxivity compared with gadolinium-diethylenetriamine pentaacetic acid dimeglumine(Gd-DTPA) injection.The R_1 values for Gd-DTPA and Ⅳ were 5.93 and 8.21(mmol/L)~(-1)·s~(-1),respectively.In vivo distribution of Gd-DTPA and Ⅳ was studied at magnetic resonance imaging(MRI) before injection,0.1,6,12 and 24 h after injection,with assessment of liver signal intensity(SI) in 10 nude mice.The liver signal enhancement rates of Ⅳ at 0.1,6,12 and 24 h are 1.5,3,1.8 and 1.3 times,respectively,compared with the largest signal intensity 0.33 of Gd-DTPA observed at 0.1 h.The half-life of Ⅳ in liver was as longer as 24 h,while no signal enhancement was observed after 6 hours injection of Gd-DTPA.Ⅳ had also a longer circulation life.