| Macromolecular Gd3+ complexes for MR imaging have shown prolonged imaging time window and superior imaging quality over clinical contrast agents with small sizes. However, these macromolecular contrast agents are not available in clinics because of Gd3+ accumulation caused by their extended retention in the body. To ameliorate this toxicity concern, biodegradable polydisulfide paramagnetic contrast agents were designed, where the disulfide bonds in these macromolecules degraded via the disulfidethiol exchange reaction in blood plasma. The work in this dissertation involved modification of the polydisulfide agents by introduction of functional moieties around the disulfide bonds. This would optimize the disulfide-thiol exchange reaction rate and consequently the in vivo retention time and MRI contrast enhancement of the agents. Five polydisulfide Gd3+ chelates, Gd-DTPA cystamine copolymers (GDCC), Gd-DTPA L-cystine diethyl ester copolymers (GDCEP), 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 using condensation polymerization and characterized. Large steric hindrance around the disulfide bonds in GDGP resulted in higher T1 and T2 relaxivities than GDCC, GDCP and dGDCP with less steric hindrance. Degradation products identified in in vitro and rat urine samples using mass spectrometry showed that the polydisulfide contrast agents were able to degrade through the disulfide-thiol exchange reactions. The degradability of the polydisulfide by the endogenous thiols decreased with the increase of the steric effects around the disulfide bonds in the order of GDCC > GDCP, dGDCP > GDGP. The size and degradability of the contrast agents had significant impact on vascular contrast enhancement kinetics. The agents with large size and low degradability resulted in more prolonged vascular enhancement than the agents with 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. Polydisulfide contrast agent showed similar cellular toxicity and hemolytic effect as the clinical agents, but presented slightly lower LD 50 in an acute toxicity study in SD rats. Overall, this study has demonstrated that the degradation and vascular enhancement kinetics of the polydisulfide MRI contrast agents can be controlled by side chain modification around disulfide bonds. The polydisulfide Gd3+ chelates are promising biodegradable macromolecular MRI contrast agents for safe and effective MR angiography and cancer imaging. |
