Preparation and preliminary evaluation of novel beta-cyclodextrin/IUDR prodrug formulations

Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:beta-cyclodextrin (beta-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR.

IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5'-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 1 and 5'-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2'-deoxy-uridine 4, respectively. beta-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of beta-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma.

IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3',5'-di-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5.

Inclusion complexes were formed between beta-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the beta-CyD inclusion complex approach for improved delivery of nucleoside derivatives.