Intraocular Properties of a Repository Urokinase Receptor Antagonist Å36 Peptide in Rabbits

Abstract

Purpose: To evaluate the intraocular properties of Å36, a peptide that directly antagonizes the cell surface urokinase receptor and so prevents pericellular urokinase plasminogen activator activity.

Methods: A total of 41 rabbits were used. The toxicity study tested three doses of Å36: 1 mg/ eye, 0.3 mg/eye, and 0.1 mg/eye. At 2 and 12 weeks, eyes were evaluated by ERG and histology. Pharmacokinetics were studied in rabbit eyes with the dose of 1 mg/eye in two different formulations: a micronized preparation and a non-micronized formulation. Eyes were enucleated at months 1, 2, 3, 4, and 5. Vitreous, retina, and choroid were collected separately for active Å36 analysis.

Results: We did not find ocular toxicity with low and medium doses. At the highest dose, there was a transient toxicity at 2 weeks but was not notable at 3 months. The target choroid concentration of Å36 was chosen as ≥100 nM. The micronized formulation at months 1, 2, and 3 combined, showed variable levels in the choroid giving 5/10 (50%) of the therapeutic level; the non-micronized formulation at months 4 and 5 combined, gave 6/7 (86%) of the therapeutic level, although this difference was not statistically significant.

Conclusion: Å36 appears to be long lasting; the non-micronized formulation of Å36 gave concentrations above therapeutic level in the choroid at months 4 and 5. Optimization of the formulation of Å36, particularly the particle size, may result in a promising new compound for exudative age-related macular degeneration treatment.

KEYWORDS::

• Anti-angiogenesis
• Ocular drug delivery
• Ocular toxicity
• Rat CNV model
• Urokinase receptor antagonist

ACKNOWLEDGMENTS

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.