Episcleral implants for topotecan delivery to the posterior segment of the eye.

CARCABOSO A.M.; CHIAPPETTA D.A.; OPEZZO J.A.W.; HOCHT C.; FANDIÑO A.C.; CROXATTO J.O.; RUBIO M.C.; SOSNIK A.; ABRAMSON D.H.; BRAMUGLIA G.F.; CHANTADA G.L.

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

Association for Research in Vision and Ophthalmology

Año: 2010 vol. 51 p. 2126 - 2134

0146-0404

Purpose: Intravenous or periocular topotecan have been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may possibly cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective trans-scleral penetration. Methods: Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured. Adrenaline (500 Hg) was co-loaded to induce local vasoconstriction in vivo in selected animal groups. The implants were characterized in vitro and inserted in the episclera of rabbits and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results: In vitro, implants released 30-50% of the loaded drug within 48 hours and 45-70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 105 to 106 ng/g in sclera and choroid, and 102 to103 ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (~5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable, as a marker of tissue selectivity of the proposed strategy. Conclusions: These studies might contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and support the role of local vasculature and tissues promoting drug clearance and local accumulation during trans-scleral drug delivery.