Poly(l-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging.
The clinical application of macromolecular Gd(III) complexes as MRI contrast agents is impeded by their slow excretion and potential toxicity due to the release of Gd(III) ions caused by the metabolism of the agents. A polymer Gd(III) chelate conjugate with a cleavable spacer has been designed to solve this problem. Poly(l-glutamic acid)-cystamine-[Gd(III)-DOTA] was prepared by the conjugation of DOTA to PGA (MW = 50,000) via cystamine, a cleavable disulfide spacer, followed by the complexation with GdCl(3). A Gd(III) DOTA chelate derivative was readily released from the polymer conjugate in the incubation with cysteine, an endogenous plasma thiol. The conjugate produced significant MRI blood pool contrast enhancement in nude mice bearing OVCAR-3 human ovarian carcinoma xenographs. Less significant contrast enhancement was observed for a small molecular contrast agent, Gd(DTPA-BMA). The pharmacokinetic MRI study showed that the Gd(III) chelate from the conjugate accumulated in the urinary bladder in a similar kinetic pattern to Gd(DTPA-BMA), suggesting that the chelate was released by the endogenous thiols and excreted through renal filtration. The preliminary results suggest that this novel design has a great potential to solve the safety problem of macromolecular MRI contrast agents.
Lu
Zheng-Rong
ZR
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84108, USA. zhengrong.lu@utah.edu
Wang
Xinghe
X
Parker
Dennis L
DL
Goodrich
K Craig
KC
Buswell
Henry R
HR
D000818:Animals; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D019786:Gadolinium DTPA / Q000737:chemistry / Q000493:pharmacokinetics; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011099:Polyglutamic Acid / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013997:Time Factors
D004220:Disulfides; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D011099:Polyglutamic Acid; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D019786:Gadolinium DTPA