A Biocompatible Gadolinium (III)-Poly (Aspartic Acid-Co-Phenylalanine) for Liver Magnetic Resonance Imaging Contrast Agent

doi:10.11938/cjmr20150210

Abstract

Abstract:

A new biocompatible gadolinium (III)-macromolecule (AP-EDA-DOTA-Gd) was developed as a magnetic resonance imaging (MRI) contrast agent. Poly (aspartic acid-cophenylalanine) was synthesized, modified via ethylenediamine, conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and finally chelated gadolinium (III), yielding gadolinium (III)-based macromolecule (AP-EDA-DOTA-Gd). The hemolytic tests showed the hemocompatibility of this gadolinium (III)-based macromolecular conjugate. In vitro, AP-EDA-DOTA-Gd could be degraded, when it was incubated with cathepsin B in phosphate buffered solution (pH = 5.5). The T1-relaxivity (15.95 mmol–1·L·s–1) of AP-EDA-DOTA-Gd was 2.9 times of that (5.59 mmol–1·L·s–1) of the clinical MRI contrast agent (Gd-DOTA) at 1.5 T and 25 ℃. The liver enhancement of AP-EDA-DOTA-Gd was 63.5±6.1% during the maximum enhancement time (50-80 min), which was much better than that of Gd-DOTA (24.2±2.9%, 10-30 min). AP-EDA-DOTA-Gd was expected to be a potential liver MRI contrast agent.

Key words: MRI contrast agent, gadolinium (III)-macromolecule, liver, relaxivity

CLC Number:

O482.53

XIAO Yan1，ZHAN You-yang1，XUE Rong1，LI Xiao-jing1*，PEI Feng-kui1，FENG Jiang-hua2*，ZHAN Bo-han2. A Biocompatible Gadolinium (III)-Poly (Aspartic Acid-Co-Phenylalanine) for Liver Magnetic Resonance Imaging Contrast Agent[J]. Chinese Journal of Magnetic Resonance, 2015, 32(2): 273-282.

References

[1] Werner E J, Datta A, Jocher C J, et al. High-relaxivity MRI contrast agents: where coordination chemistry meets medical imaging[J]. Angew Chem, Int Ed, 2008, 47(46): 8 568－8 680.

[2] Yu K C, Lv Z Y, Yao Y, et al. Recent progress in development of bio-active MRI contrast agents[J]. Chinese J Magn Reson, 2010, 27(3): 355－368.

[3] Yu K C, Wang G P, Ding S W, et al. Recent progresses in the development of contrast agents used in magnetic resonance imaging[J]. Chinese J Magn Reson, 2004, 21(4): 505－525.

[4] Major J L, Meade T J. Bioresponsive cell-penetrating and multimeric MR contrast agents[J]. Acc Chem Res, 2009，42(7): 893－903.

[5] Yan G P, Robinson L, Hogg P. Magnetic resonance imaging contrast agents: overview and perspectives[J]. Radiography, 2007, 13: e5－e19.

[6] Chan K W Y, Wong W T. Small molecular gadolinium (III) complexes as MRI contrast agents for diagnostic imaging[J]. Coordin Chem Rev, 2007, 251(17): 2 428－2 451.

[7] Weinmann H J, Ebert W, Misselwitz B, et al. Tissue-specific MR contrast agents[J]. Eur J Radiol, 2003, 46(1): 33－44.

[8] Tsitovich P B, Burns P J, McKay A M, et al. Redox-activated MRI contrast agents based on lanthanide and transition metal ions[J]. J Inorg Biochem, 2014, 133: 143－154.

[9] Jao J C, Lu H C, Lu H Y, et al. The imaging behavior of an MRI contrast agent [Gd (TTDA-BOM)] 2-in a mice liver tumor model at 3 Tesla[J]. J Med Biol Eng, 2010, 30(3): 139－144.

[10] 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(9): 2 293－2 352.

[11] Tang J, Sheng Y, Hu H, et al. Macromolecular MRI contrast agents: Structures, properties and applications[J]. Prog Polym Sci, 2013, 38(3): 462－502.

[12] Li Y, Beija M, Laurent S, et al. Macromolecular ligands for gadolinium MRI contrast agents[J]. Macromolecules, 2012, 45(10): 4 196－4 204.

[13] Nwe K, Milenic D, Bryant L H, et al. Preparation, characterization and in vivo assessment of Gd-albumin and Gd-dendrimer conjugates as intravascular contrast-enhancing agents for MRI[J]. J Inorg Biochem, 2011, 105(5): 722－727.

[14] Fasano M, Curry S, Terreno E, et al. The extraordinary ligand binding properties of human serum albumin[J]. IUBMB Life, 2005, 57(12): 787－796.

[15] Wang S C, Wikström M G, White D L, et al. Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues[J]. Radiology, 1990, 175(2): 483－488.

[16] Rudovský J, Botta M, Hermann P, et al. PAMAM dendrimeric conjugates with a Gd-DOTA phosphinate derivative and their adducts with polyaminoacids: the interplay of global motion, internal rotation, and fast water exchange[J]. Bioconjugate Chem, 2006, 17(4): 975－987.

[17] Pouponneau P, Bringout G, Martel S. Therapeutic magnetic microcarriers guided by magnetic resonance navigation for enhanced Liver chemoembilization: a design review[J]. Ann Biomed Eng, 2014, 42(5): 929－939.

[18] Bryson J M, Reineke J W, Reineke T M. Macromolecular imaging agents containing lanthanides: can conceptual promise lead to clinical potential?[J]. Macromolecules, 2012, 45(22): 8 939－8 952.

[19] Obst M, Steinbüchel A. Microbial degradation of poly(amino acid)s[J]. Biomacromolecules, 2004, 5(4): 1 166－1 176.

[20] Yan G P, Liu M L, Li L Y. Polyaspartamide gadolinium complexes containing sulfadiazine groups as potential macromolecular MRI contrast agents[J]. Bioconjugate Chem, 2005, 16(4): 967－971.

[21] Giammona G, Cavallaro G, Maniscalco L, et al. Synthesis and characterisation of novel chemical conjugates based on α, β-polyaspartylhydrazide and β-cyclodextrins[J]. Eur Poly J, 2006, 42(10): 2 715－2 729.

[22] Oh N M, Oh K T, Youn Y S, et al. Poly (l-aspartic acid) derivative soluble in a volatile organic solvent for biomedical application[J]. Colloid Surface B, 2012, 97: 190－195.

[23] Ferroud C, Borderies H, Lasri E, et al. Synthesis of a novel amphiphilic GdPCTA-[12] derivative as a potential micellar MRI contrast agent[J]. Tetrahedron Lett, 2008, 49(41): 5 972－5 975.

[24] Wojciechowski F, Suchy M, Li A X, et al. A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents[J]. Bioconjugate Chem, 2007, 18(5): 1 625－1 636.

[25] Sprenger G A. From scratch to value: engineering Escherichia coli wild type cells to the production of L-phenylalanine and other fine chemicals derived from chorismate[J]. Appl Microbiol Biotechnol, 2007, 75(4): 739－749.

[26] Akagi T, Higashi M, Kaneko T, et al. Hydrolytic and enzymatic degradation of nanoparticles based on amphiphilic poly (γ-glutamic acid)-graft-l-phenylalanine copolymers[J]. Biomacromolecules, 2006, 7(1): 297－303.

[27] Sage H J, Fasman G D. Conformational studies on poly-L-glutamic acid and copolymers of L-glutamic acid and L-phenylalanine[J]. Biochemistry, 1966, 5(1): 286－296.

[28] Corot C, Schaefer M, Beaute S, et al. Physical, chemical and biological evaluations of CMD-A2-Gd-DOTA. A new paramagnetic dextran polymer[J]. Acta Radiol, 1996, 412: 91－99.

[29] Kishore B K, Lambricht P, Laurent G, et al. Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. II. Comparative in vitro and in vivo studies with poly-L-aspartic, poly-L-glutamic and poly-D-glutamic acids[J]. J Pharm Exper Ther, 1990, 255(2): 875－885.

[30] Lebdušková P, Kotek J, Hermann P, et al. A gadolinium (III) complex of a carboxylic-phosphorus acid derivative of diethylenetriamine covalently bound to inulin, a potential macromolecular MRI contrast agent[J]. Bioconjugate Chem, 2004, 15(4): 881－889.

[31] Chong H S, Garmestani K, Bryant L H, et al. Synthesis and evaluation of novel macrocyclic and acyclic ligands as contrast enhancement agents for magnetic resonance imaging[J]. J Med Chem, 2006, 49(6): 2 055－2 062.

[32] Sun G, Feng J, Jing F, 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.

[33] Zhang G, Zhang R, Melancon M P, et al. The degradation and clearance of Poly (N-hydroxypropyl-L-glutamine)-DTPA-Gd as a blood pool MRI contrast agent[J]. Biomaterials, 2012, 33(21): 5 376－5 383.

[34] Ke T, Feng Y, Guo J, et al. Biodegradable cystamine spacer facilitates the clearance of Gd (III) chelates in poly (glutamic acid) Gd-DO3A conjugates for contrast-enhanced MR imaging[J]. Magn Reson Imaging, 2006, 24(7): 931－940.

[35] Armitage F E, Richardson D E, Li K C P. Polymeric contrast agents for magnetic resonance imaging: synthesis and characterization of gadolinium diethylenetriaminepentaacetic acid conjugated to polysaccharides[J]. Bioconjugate Chem, 1990, 1(6): 365－374.

[36] Secchi F, Di Leo G, Papini G D E, et al. Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial MRI late gadolinium enhancement[J]. Eur J Radiol, 2011, 80(1): 96－102.

[37] Yalkowsky S H, Krzyzaniak J F, Ward G H. Formulation‐related problems associated with intravenous drug delivery[J]. J Pharm Sci, 1998, 87(7): 787－796.

[38] 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): 187－202.