Clearance of Radiolabeled Somatostatin Analogs from the Vitreous: Implications for Targeted Intravitreal Therapy with Radiolabeled Somatostatin Analogs

Abstract

Abstract: : Purpose: Somatostatin analogs (SA) inhibit angiogenesis by targeting somatostatin receptor subtype 2 (sst–2). This receptor is uniquely expressed on endothelial cells of angiogenic, but not normal human blood vessels. ¹¹¹Indium pentetreotide, an Auger and conversion electron–emitting SA, has a radius of action of 10 microns. This agent produces receptor–dependent cytotoxicity only if internalized within sst–2 expressing cells. Thus, intravitreal delivery of this radiolabeled SA might selectively destroy angiogenic blood vessels within the retina while preserving normal retinal function. We hypothesized that ¹¹¹Indium pentetreotide would clear from the vitreous cavity with a half–life similar to that of octreotide acetate (T^1/2≈16 hours). Methods: Dutch rabbits were injected intravitreally or subcutaneously with ¹¹¹Indium pentetreotide, ¹¹¹In–DPTA, ¹¹¹In, or ¹²⁵I somatostatin–14 (SRIF–1), (10µCi/0.1cc/injection) in hyaluronic acid or in saline. The animals were treated in accordance with the ARVO resolution on the care and treatment of animals in research under a protocol approved by the IACUC. Results: All In–containing products had prolonged retention times in the vitreous or when delivered subcutaneously in hyaluronic acid (T^1/2≈2.7 days). These half–lives are the same as the physical half–life of ¹¹¹In, indicating that this heavy metal irreversibly binds to hyaluronic acid, thus significantly limiting the bioavailability of In–containing products to retinal neovascularization. In contrast, ¹²⁵I SRIF–14 was rapidly cleared from the vitreous and from the hyaluronic acid–containing subcutaneous site (T^/2≈2 hours). Conclusions: These results imply that intravitreal injections of SA labeled with heavy metals cannot be utilized to treat proliferative retinopathies while radioiodinated SA should maintain their effectiveness in this location.

Keywords: retinal neovascularization • drug toxicity/drug effects • vitreous