A Biocompatible Gadolinium-Based Amino Acid Copolymer Contrast Agent for Magnetic Resonance Imaging

doi:10.11938/cjmr20160413

Abstract

Abstract: A macromolecular gadolinium complex was prepared as a magnetic resonance imaging (MRI) contrast agent. An ethlendiamine-modified aspartic acid-valine copolymer was synthesized, conjugated with DOTA, and then chelated with Gd³⁺(AI-EDA-DOTA-Gd). T₁-relaxivity of the agent (i.e., 12.6 mmol^-1·L·s^-1) was 2.2 times that of Gd-DOTA (i.e., 5.8 mmol^-1·L·s^-1). Hemolytic tests showed that the macromolecular contrast agent had good blood compatibility. Histological results demonstrated low toxicity of the agent in vivo. MRI experiments on rats demonstrated a prominent enhancement in liver after AI-EDA-DOTA-Gd injection, which persisted longer than that obtained by Gd-DOTA injection. The mean percentage enhancement in liver parenchyma was (55.1±5.7)% at 30~70 min after injection.

Key words: MRI contrast agent, relaxivity, macromolecule, biocompatibility, amino acid copolymer

CLC Number:

O482.53

ZHAN You-yang, XUE Rong, ZHU Yun-long, LI Xiao-jing, PEI Feng-kui, FENG Jiang-hua. A Biocompatible Gadolinium-Based Amino Acid Copolymer Contrast Agent for Magnetic Resonance Imaging[J]. Chinese Journal of Magnetic Resonance, 2016, 33(4): 635-645.

References

[1] Yang Bao-lian(杨保联). Future of ultra high field MRI in basic research and clinical applications(超高场磁共振人体成像应用研究和医学前景)[J]. Chinese J Magn Reson(波谱学杂志), 2015, 32(4):707-714.
[2] Yu Kai-chao(俞开潮), Wang Guo-ping(王国平), Ding Shang-wu(丁尚武), et al. Recent progresses in the development of contrast agents used in magnetic resonance imaging(用于磁共振成像对比增强的造影剂研发进展)[J]. Chinese J Magn Reson(波谱学杂志), 2004, 21(4):505-525.
[3] Chen Y Y, Zhu Q, Hu A G, et al. Preparation of highly efficient MRI contrast agents through complexation of cationic GdⅢ-containing metallosurfactant with biocompatible polyelectrolytes[J]. Chem Eur J, 2014, 20(39):12477-12482.
[4] Pierre V C, Allen M J, Caravan P. Contrast agents for MRI:30+years and where are we going?[J]. J Biol Inorg Chem, 2014, 19(2):127-131.
[5] Gaetano G, Gennara C, Laura M. Synthesis and characterization of novel chemical conjugates based on α,β-polyaspartylhydrazide and β-cyclodextrins[J]. Eur Polym J, 2006, 42(10):2715-2729.
[6] Yang H M, Park C W, Ahn T, et al. A direct surface modification of iron oxide nanoparticles with various poly(amino acid)s for use as magnetic resonance probes[J]. J Colloid Interf Sci, 2013, 391:158-167.
[7] Adel B, Graaf L M, Que I, et al. Contrast enhancement by lipid-based MRI contrast agents in mouse atherosclerotic plaques; a longitudinal study[J]. Contrast Media Mol I, 2013, 8(1):63-71.
[8] Xiao Yan(肖研), Zhan You-yang(湛游洋), Xue Rong(薛蓉), et al. A biocompatible gadolinium (Ⅲ)-poly (aspartic acid-co-phenylalanine) for liver magnetic resonance imaging contrast agent(一种肝脏类生物相容性氨基酸共聚物磁共振成像造影剂)[J]. Chinese J Magn Reson(波谱学杂志), 2015, 32(2):273-282.
[9] Chen X, Park R, Tohme M, et al. Micro PET and autoradiographic imaging of breast cancer alpha(v)-integrin expression using F-18-and Cu-64-labeled RGD peptide[J]. Bioconjugate Chem, 2004, 15(1):41-49.
[10] Werner E J, Datta A, Jocher C I, et al. High-relaxivity MRI contrast agents:where coordination chemistry meets medical imaging[J]. Angew Chem Int Ed Engl, 2008, 47(45):8569-8580.
[11] Yu Kai-chao(俞开潮), Lv Zhi-yong(吕志勇), Yao Yao(姚瑶), et al. Recent progress in development of bio-active MRI contrast agents(生物激活磁共振成像造影剂的研究进展)[J]. Chinese J Magn Reson(波谱学杂志), 2010, 27(3):355-368.
[12] Dekie L, Toncheva V, Dubruel P, et al. Poly-L-glutamic acid derivatives as vectors for gene therapy[J]. J Control Release, 2000, 65(1, 2):187-202.
[13] Dai L L, Liu Y K, Wang Z Q, et al. One-pot facile synthesis of PEGylated superparamagnetic iron oxide nanoparticles for MRI contrast enhancement[J]. Mater Sci Eng C Mater Biol Appl, 2014, 41:161-167.
[14] Xiao Y, Xue R, Li X J, et al. Gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugate of arabinogalactan as a potential liver-targeting magnetic resonance imaging contras tagent[J]. Carbohydr Res, 2014, 395:9-14.
[15] Sun G Y, Feng J H, Pei F K, et al. Synthesis and evaluation of novel polysaccharide-Gd-DTPA compounds as contrast agent for MRI[J]. J Magn Magn Mater, 2003, 265(2):123-129.
[16] Xiao Y, Xue R, Li X J, et al. A new biodegradable and biocompatible gadolinium(Ⅲ)-polymer for liver magnetic resonance imaging contrast agent[J]. Magn Reson Imaging, 2015, 33(6):822-828.
[17] Zhang G D, Zhang R, Melancon M P, et al. The degradation and clearance of Poly (N-hydroxypropy-L-glutamine)-DTPA-Gd as a blood pool MRI contrast agent[J]. Biomaterials, 2012, 33(2):5376-5383.