Quantitation of slow drug release from an implantable and degradable gentamicin conjugate by in vivo magnetic resonance imaging

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Abstract
A biodegradable model hydrogel containing a covalently bound aminoglycoside in which drug release can be monitored by magnetic resonance imaging (MRI) in vivo was developed. The hydrogel consists of the bishydroxysuccinimide ester of polyethylene glycol disuccinate cross-linked albumin, to which gentamicin and Gd-diethylenetriaminepentaacetic acid are covalently attached in stochiometric quantities. MRI allowed us to depict the three-dimensional structure of implanted gels, to accurately calculate their volumes, and thus to calculate the concentration of hydrogel-bound gentamicin. The correlation coefficient for the concentration of released gentamicin and the hydrogel volume was 0.965. Free and hydrogel-released gentamicin conjugates had similar antibiotic efficacies when tested in microbiological agar diffusion assays. In vivo, hydrogel-released gentamicin had a longer half-life in plasma than unaltered gentamicin (5.6 versus 0.7 h), presumably because of residual bound polyethylene glycol residues. Hydrogel implants into rats resulted in a prolonged (7 to 10 days) release of gentamicin and a decreased 24-h mortality in mice infected with a lethal dose of Pseudomonas aeruginosa. The results indicate the feasibility of imaging and quantitating therapeutic drug concentrations in vivo by MRI.