TY - JOUR
T1 - Biodegradable cystamine spacer facilitates the clearance of Gd(III) chelates in poly(glutamic acid) Gd-DO3A conjugates for contrast-enhanced MR imaging
AU - Ke, Tianyi
AU - Feng, Yi
AU - Guo, Junyu
AU - Parker, Dennis L.
AU - Lu, Zheng Rong
N1 - Funding Information:
This research was supported in part by NIH grant R01 CA097465. We thank Dr. Yongen Sun for the technical assistance.
PY - 2006/9
Y1 - 2006/9
N2 - Poly(l-glutamic acid) (PGA)-cystamine-[gadolinium (Gd)-DO3A] was prepared in high yield with a high Gd-DO3A conjugation efficiency. Approximately 55% of the carboxylic groups in PGA were loaded with Gd-DO3A via cystamine as the spacer. Cystamine can be readily cleaved by endogenous thiols to release the Gd(III) chelates from the conjugate facilitating Gd(III) excretion after the magnetic resonance imaging (MRI). The contrast-enhanced MRI with PGA-cystamine-(Gd-DO3A) was investigated in mice bearing MDA-MB-231 breast carcinoma xenografts. PGA-1,6-hexanediamine-(Gd-DO3A), a paramagnetic polymer conjugate of a nondegradable spacer, was used as a control. Both conjugates resulted in similar contrast enhancement in the heart, vasculature, liver and kidneys in the first hour post injection. More substantial signal intensity reduction was observed for PGA-cystamine-(Gd-DO3A) in these organs than PGA-1,6-hexanediamine-(Gd-DO3A) due to release of the Gd chelates from PGA-cystamine-(Gd-DO3A) after the cleavage of the disulfide spacer by the endogenous thiols. Both conjugates resulted in similar tumor enhancement with approximately 70% increased signal intensity in the tumor periphery and 10-40% increased signal intensity in tumor interstitium. No cross-reaction was observed between PGA-cystamine-(Gd-DO3A) and human serum albumin, a plasma protein containing a cysteine residue. PGA-cystamine-(Gd-DO3A) resulted in significantly lower Gd(III) tissue retention than PGA-1,6-hexanediamine-(Gd-DO3A) 10 days after the injection in the mice (P<.05). The conjugation of Gd(III) chelates to biomedical copolymers via the degradable disulfide spacer resulted in significant contrast enhancement in the blood pool and tumor tissue but minimal long-term Gd(III) tissue retention.
AB - Poly(l-glutamic acid) (PGA)-cystamine-[gadolinium (Gd)-DO3A] was prepared in high yield with a high Gd-DO3A conjugation efficiency. Approximately 55% of the carboxylic groups in PGA were loaded with Gd-DO3A via cystamine as the spacer. Cystamine can be readily cleaved by endogenous thiols to release the Gd(III) chelates from the conjugate facilitating Gd(III) excretion after the magnetic resonance imaging (MRI). The contrast-enhanced MRI with PGA-cystamine-(Gd-DO3A) was investigated in mice bearing MDA-MB-231 breast carcinoma xenografts. PGA-1,6-hexanediamine-(Gd-DO3A), a paramagnetic polymer conjugate of a nondegradable spacer, was used as a control. Both conjugates resulted in similar contrast enhancement in the heart, vasculature, liver and kidneys in the first hour post injection. More substantial signal intensity reduction was observed for PGA-cystamine-(Gd-DO3A) in these organs than PGA-1,6-hexanediamine-(Gd-DO3A) due to release of the Gd chelates from PGA-cystamine-(Gd-DO3A) after the cleavage of the disulfide spacer by the endogenous thiols. Both conjugates resulted in similar tumor enhancement with approximately 70% increased signal intensity in the tumor periphery and 10-40% increased signal intensity in tumor interstitium. No cross-reaction was observed between PGA-cystamine-(Gd-DO3A) and human serum albumin, a plasma protein containing a cysteine residue. PGA-cystamine-(Gd-DO3A) resulted in significantly lower Gd(III) tissue retention than PGA-1,6-hexanediamine-(Gd-DO3A) 10 days after the injection in the mice (P<.05). The conjugation of Gd(III) chelates to biomedical copolymers via the degradable disulfide spacer resulted in significant contrast enhancement in the blood pool and tumor tissue but minimal long-term Gd(III) tissue retention.
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U2 - 10.1016/j.mri.2006.03.009
DO - 10.1016/j.mri.2006.03.009
M3 - Article
C2 - 16916710
AN - SCOPUS:33746945447
SN - 0730-725X
VL - 24
SP - 931
EP - 940
JO - Magnetic Resonance Imaging
JF - Magnetic Resonance Imaging
IS - 7
ER -