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The structural effect of biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents, polydisulfide gadolinium (Gd)(III) chelates, on their in vitro degradability, and cardiovascular and tumor imaging were evaluated in mice. Polydisulfide Gd(III) chelates, Gd-DTPA cystamine copolymers (GDCC), Gd-DTPA l -cystine copolymers (GDCP), Gd-DTPA d -cystine copolymers (dGDCP) and Gd-DTPA glutathione (oxidized) copolymers (GDGP), with different sizes and narrow molecular weight distribution were prepared and evaluated both in vitro and in vivo in mice bearing MDA-MB-231 tumor xenografts. GDGP with large steric hindrance around the disulfide bonds had greater T 1 and T 2 relaxivities than GDCC, GDCP and dGDCP. The degradability of the polydisulfide by the endogenous thiols decreased with increasing steric effects around the disulfide bonds in the order of GDCC>GDCP, dGDCP>GDGP. The size and degradability of the contrast agents had a significant impact on vascular contrast enhancement kinetics. The agents with a large size and low degradability resulted in more prolonged vascular enhancement than the agents with a small size and high degradability. It seems that the size and degradability of the agents did not significantly affect tumor enhancement. All agents resulted in significant contrast enhancement in tumor tissue. This study has demonstrated that the vascular enhancement kinetics of the polydisulfide MRI contrast agents can be controlled by their sizes and structures. The polydisulfide Gd(III) chelates are promising biodegradable macromolecular MRI contrast agents for magnetic resonance angiography and cancer imaging.

The purpose of this study was to investigate the effect of PEGylation of novel biodegradable macromolecular polydisulfide Gd(III) complexes, gadolinium diethylenetriaminepentaacetate (GdDTPA) cystine copolymers (GDCP), on their pharmacokinetics and long-term Gd(III) tissue retention, and to demonstrate the potential application of PEGylated GDCP (PEG-GDCP) for MR angiography (MRA). The pharmacokinetics, biodistribution, and metabolic excretion of PEG(1000)-GDCP (42.1-52.1 kDa; PEG: MW = 1000 Da) with three different PEG grafting degrees and GDCP (43.3 kDa) were investigated in Sprague-Dawley rats. Pharmacokinetic data were analyzed by means of an open two-compartment model. Initially all three PEG(1000)-GDCP contrast agents (CAs) had a higher plasma concentration than GDCP, but after 30 min the Gd(III) concentration from the PEGylated agents rapidly decreased, resulting in significantly lower elimination half-life values. All of the biodegradable macromolecular CAs demonstrated low long-term Gd(III) tissue accumulation, while PEG(1000)-GDCP had significantly lower accumulation in the liver than GDCP. In the rats, all CAs showed excellent vascular contrast enhancement in an MRA protocol with a long image acquisition time. Because PEG(1000)-GDCP remained intravascular for an acceptable period for effective contrast-enhanced (CE)-MRA, and then excreted rapidly from the vasculature with minimal tissue retention, PEG(1000)-GDCP shows a great promise as a blood-pool CA for MRA.

To investigate plasma pharmacokinetics and biodistribution of biodegradable polydisulfide Gd(III) complexes, Gd-DTPA cystine copolymers (GDCP) and Gd-DTPA cystine diethyl ester copolymers (GDCEP) and their efficacy as blood pool MRI contrast agents in comparison with a nondegradable macromolecular agent, Gd-DTPA 1,6-hexanediamine copolymers (GDHC). The pharmacokinetics and biodistribution of GDCP and GDCEP with molecular weight of 35 KDa were investigated in Sprague‐Dawley rats after intravenous administration at a dose of 0.1 mmol Gd/kg. GDHC with the same molecular weight was used as a control. The Gd content in the plasma and various tissues and organs were determined by the ICP-OES. Plasma pharmacokinetic parameters were calculated by using a two-compartment model. The contrast enhanced blood pool MR imaging of the agents was evaluated in Sprague‐Dawley rats on a Siemens Trio 3T MR scanner. The biodegradable macromolecular agents, GDCP and GDCEP, had faster blood pool clearance than the nondegradable GDHC. The long-term Gd(III) tissue retention of the biodegradable polydisulfide agents was substantially lower than the nondegradable macromolecular agent. Both GDCP and GDCEP resulted in significant blood pool enhancement for the first 2 min post-injection and more rapid disappearance of the enhancement over time than GDHC. The negatively charged GDCP had prolonged enhancement duration as compared to GDCEP. The structure and biodegradability of the macromolecular contrast agents significantly affected their pharmacokinetics and blood pool contrast enhancement. Both GDCP and GDCEP provided effective contrast enhancement for MR imaging of the blood pool. The accumulation of toxic Gd(III) ions in the body was greatly reduced with GDCP and GDCEP as compared to the nondegradable control.

Biodegradable macromolecular Gd(III) complexes, Gd-DTPA cystine copolymers (GDCP), were grafted with PEG of different sizes to modify the physicochemical properties and in vivo MRI contrast enhancement of the agents and to study the effect of PEG chain length on these properties. Three new PEG-grafted biodegradable macromolecular gadolinium(III) complexes were synthesized and characterized as blood pool MRI contrast agents. One of three different lengths of MPEG-NH(2) (MW = 550, 1000, and 2000) was grafted to the backbone of GDCP to yield PEG(n)()-g-poly(GdDTPA-co-l-cystine), PEG(n)()-GDCP. The PEG chain length did not dramatically alter the T(1) relaxivity, r(1), of the modified agents. The MRI enhancement profile of PEG(n)()-GDCP with different PEG sizes was significantly different in mice with respect to both signal intensity and clearance profiles. PEG(2000)-GDCP showed more prominent enhancement in the blood pool for a longer period of time than either PEG(1000)-GDCP or PEG(550)-GDCP. In the kidney, PEG(2000)-GDCP had less enhancement at 2 min than PEG(1000)-GDCP, but both PEG(550)-GDCP and PEG(1000)-GDCP showed a more pronounced signal decay thereafter. The three agents behaved similarly in the liver, as compared to that in the heart. All three agents showed little enhancement in the muscle. Chemical grafting with PEG of different chain lengths is an effective approach to modify the physiochemistry and in vivo contrast enhancement dynamics of the biodegradable macromolecular contrast agents. The novel agents are promising for further clinical development for cardiovascular and cancer MR imaging.

Macromolecular gadolinium (Gd)(III) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors, depending on the tumor blood vessel hyperpermeability, resulting in superior contrast enhancement in magnetic resonance (MR) cardiovascular imaging and cancer imaging as shown in animal models. Unfortunately, safety concerns related to these agents’ slow elimination from the body impede their clinical development. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents to facilitate the clearance of Gd(III) complexes from the body after MRI examinations. These novel agents can act as macromolecular contrast agents for in vivo imaging and excrete rapidly as low-molecular-weight agents. The rationale and recent development of the novel biodegradable contrast agents are reviewed here. Polydisulfide Gd(III) complexes have relatively long blood circulation time and gradually degrade into small Gd(III) complexes, which are rapidly excreted via renal filtration. These agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models, yet demonstrate minimal Gd(III) tissue retention as the clinically used low-molecular-weight agents. Structural modification of the agents can readily alter the contrast-enhancement kinetics. Polydisulfide Gd(III) complexes are promising for further clinical development as safe, effective, biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging, and for evaluation of therapeutic response.

The purpose of this study is to investigate how the structures of polydisulfide Gd(III) complexes affect their pharmacokinetics and in vivo contrast enhancement as biodegradable macromolecular MRI contrast agents. A negatively charged polydisulfide Gd(III) complex, (Gd-DTPA)–cystine copolymers (GDCP), and a neutral agent, (Gd-DTPA)–cystine diethyl ester copolymers (GDCEP), with different molecular weights were prepared and characterized. The MRI contrast enhancement of the agents was studied in mice. Neutral GDCEP showed more rapid degradation than negatively charged GDCP in the blood plasma. Consequently, GDCP resulted in more significant and prolonged contrast enhancement in the blood pool and liver than GDCEP. The size of GDCEP did not significantly affect its in vivo contrast enhancement due to rapid degradation and clearance from the blood circulation. The increase in the molecular weight of GDCP resulted in prolonged in vivo contrast enhancement in the blood pool. The structural modification of polydisulfide Gd(III) complexes resulted in biodegradable macromolecular MRI contrast agents with different degradability and in vivo contrast enhancement.

The structures of polydisulfide-based biodegradable macromolecular Gd(III) complexes were modified to improve their in vivo retention time and MRI contrast enhancement. Steric hindrance was introduced around the disulfide bonds to control their access to free thiols in order to alter the degradation rate of the copolymers. Two new macromolecular agents, (Gd-DTPA)-cystine copolymers (GDCP) and (Gd-DTPA)-cystine diethyl ester copolymers (GDCEP), were prepared. Both agents were readily degraded in vitro and in vivo by the disulfide-thiol exchange reaction, but at a slow rate. The introduction of COOH and COOEt groups slowed down the degradation of the copolymers in the incubation with 15 μM cysteine. Metabolic degradation products were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry in the urine samples from rats injected with the agents. The T1 relaxivity (r1) was 5.43 mM−1s−1 for GDCP, and 5.86 mM−1s−1 for GDCEP, respectively, at 3T. MRI contrast enhancement of both agents was studied in nude mice bearing MDA-BM-231 human breast carcinoma xenografts, on a Siemens Trio 3T scanner. The modified agents resulted in more significant contrast enhancement in the blood pool and tumor periphery than (Gd-DTPA)-cystamine copolymers (GDCC) and a low-molecular-weight control agent, Gd-(DTPA-BMA), at a dose of 0.1 mmol-Gd/kg. The results demonstrate that the structural modification of the biodegradable macromolecular Gd(III) complexes resulted in a relatively slow degradation of the macromolecules and significantly improved in vivo contrast enhancement. The modified agents show promise for use in investigations of blood pool and cancer by contrast-enhanced (CE) MRI. Magn Reson Med 53:835–842, 2005. © 2005 Wiley-Liss, Inc.

Biodegradable PEGylated Gd-DTPA l-cystine copolymers, PEG-g-poly(GdDTPA-co-l-cystine), were prepared and tested as a blood pool contrast agent in mice. The biodegradable macromolecular agent was designed to be broken down into smaller Gd complexes by endogenous thiols via the disulfide-thiol exchange reaction to facilitate the clearance of Gd complexes after the contrast-enhanced MRI examination. Gd-DTPA l-cystine copolymers were synthesized by condensation polymerization of l-cystine and DTPA-dianhydride in water followed by chelating with Gd(OAc)(3). MPEG-NH(2) (MW = 2000) was then conjugated to the polymeric backbone in different ratios. The macromolecular contrast agent was readily degraded with the incubation of l-cysteine. It also demonstrated superior contrast enhancement in the heart and blood vessels as compared to a low molecular weight control agent, Gd-(DTPA-BMA). At 1 h postcontrast, the PEGylated macromolecular agent still showed prominent enhancement, while little contrast enhancement was detectable in the blood pool by the control agent. PEG-g-poly(GdDTPA-co-l-cystine) shows promise as an MR blood pool imaging agent.