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DL Vollmer, M Szlek, M Wood, S Vanech; Transscleral Iontophoretic Delivery of an Anti-Tumor Vascular Targeting Agent Combretastatin to Rabbit Eyes . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3873.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The study objective was to determine the amount of an anti-tumor vascular targeting agent, combretastatin A4 (CA4), that could be delivered to rabbit retina/choroid tissue via transscleral iontophoresis. Methods: The study was comprised of four groups (n=6) of New Zealand White rabbits treated with a 10-mg/mL aqueous combretastatin A4 phosphate (CA4P) solution at 0, 2, 3 or 4 mA of current for twenty minutes. An ocular rabbit applicator composed of an 170-µL silicone shell (backed with Ag/AgCl-coated Ag foil and containing a single layer of a hydrogel-impregnated polyvinyl acetal matrix) was used. The applicator was placed against the rabbit's eye in the upper cul-de-sac at the limbus with the front edge 1-2 mm distal from the corneoscleral junction. Following treatment, the rabbits were euthanized, the eyes enucleated and then frozen at -70 °C. The retina/choroid tissues were dissected from the treated and non-treated eyes and analyzed for CA4 and CA4P by a validated LC/MS/MS method. Results: The combretastatin amounts delivered to the retina/choroid tissues were much greater than originally anticipated and exceeded the upper limit of the standard curve, and therefore, had to be extrapolated after analysis. The average concentration of combretastatin found in the retina/choroid tissue in the 0-, 2-, 3-, and 4-mA treatment groups was 1.60, 27.1, 25.2, and 24.3 nmol/g, respectively. Over 90% of CA4P pro-drug was converted in vivo to the dephosphorylated CA4 active-drug. The concentrations found in the iontophoretic treatment groups were not statistically different and demonstrate a lack of transport dependence with respect to currents over 1 mA. The non-treated eye also showed an accumulation of combretastatin in the retina/choroid that was approximately 1% that of the treated eye. Conclusion: Delivery of this anti-tumor vascular targeting compound to the retina/choroid was enhanced approximately 15-fold with transscleral iontophoresis. Moreover, the levels found in this study represent a several thousand-fold excess over what is considered to be a therapeutically relevant concentration for inhibiting tubulin binding.
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