PURPOSE: Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo. METHODS: Intravitreal injections of model contrast agents poly[N-(2-hydroxypropyl)methacrylamide]-GG-1,6-hexanediamine-(Gd-DO3A), biodegradable (Gd-DTPA)-cystine copolymers, and MultiHance were performed in rabbits; their distribution and elimination from the vitreous after injections were determined by MRI. RESULTS: Times for macromolecular contrast agents to decrease to half their initial concentrations in the vitreous ranged from 0.4-1.3 days post-injection. Non-biodegradable polymers demonstrated slower vitreal clearance than those of disulfide-biodegradable polymers. Biodegradable polymers had similar clearance as MultiHance. CONCLUSIONS: Usefulness of T(1) mapping and ms-DSEPI-T12 MRI to study ocular pharmacokinetics was demonstrated. Results suggest an enzymatic degradation mechanism for the disulfide linkage in polymers in the vitreous leading to breakup of polymers in vitreous humor over time.
PURPOSE: Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo. METHODS: Intravitreal injections of model contrast agents poly[N-(2-hydroxypropyl)methacrylamide]-GG-1,6-hexanediamine-(Gd-DO3A), biodegradable (Gd-DTPA)-cystine copolymers, and MultiHance were performed in rabbits; their distribution and elimination from the vitreous after injections were determined by MRI. RESULTS: Times for macromolecular contrast agents to decrease to half their initial concentrations in the vitreous ranged from 0.4-1.3 days post-injection. Non-biodegradable polymers demonstrated slower vitreal clearance than those of disulfide-biodegradable polymers. Biodegradable polymers had similar clearance as MultiHance. CONCLUSIONS: Usefulness of T(1) mapping and ms-DSEPI-T12 MRI to study ocular pharmacokinetics was demonstrated. Results suggest an enzymatic degradation mechanism for the disulfide linkage in polymers in the vitreous leading to breakup of polymers in vitreous humor over time.
Authors: Sophie J Bakri; Melissa R Snyder; Joel M Reid; Jose S Pulido; Mohamed K Ezzat; Ravinder J Singh Journal: Ophthalmology Date: 2007-12 Impact factor: 12.079