β-Cyclodextrin Complexes of Hydrolyzable Adamantanoyl-IUdR Prodrugs - Radioiodination and Biodistribution in Mice Bearing Implanted KBALB Tumours

Xiao-Hong   (Jennifer)   Yang; Shradha      Singh; Piyush      Kumar; Jim      Diakur; Leonard   I.   Wiebe

Abstract

Purpose: Iododeoxyuridine (IUdR, 1), a thymidine mimic with antiviral and anti-cancer properties, has a very short in vivo half-life which limits its efficacy as a clinical therapeutic or diagnostic agent. This work reports the radioiodination of 1 and its adamantanoyl prodrugs 2 and 3, the β-cyclodextrin (β-CyD) complexation of the radiolabelled prodrugs (2* and 3* to β-CyD-2* and β-CyD-3*, respectively), and the biodistribution of 1*, β-CyD-2* and β-CyD-3* in tumor- bearing mice. Methods: The C-5-tributylstannyl-UdR synthons 1-TBS, 2-TBS and 3-TBS were prepared and then radioiodinated with Na[125I]I in acetic acid and hydrogen peroxide to afford 125I-labelled 1*, 2* and 3*. Biodistribution studies of 1*, β-CyD-2* and β-CyD-3* were undertaken in Balb/c mice bearing implanted KBALB tumours. Results: 1-TBS, 2-TBS and 3-TBS were synthesized in 70, 45 and 29 % yield, respectively. Radioiododestannylation afforded 1*, 2* and 3* in 25.5 %, 80 % and 45 % radiochemical yield, respectively. In vivo biodistribution patterns for 1*, β-CyD-2* and β- CyD-3* after i.v. injection into mice differed only marginally. Conclusions: Inclusion complexes are formed between β- CyD and adamantane-IUdR conjugates. Despite the strong complexation between β-CyD and 2* or 3*, the radiobiodistribution patterns of for 1*, β-CyD-2* and β-CyD-3* were not markedly different from each other in tumourbearing mice. Thus, despite creation of inclusion compounds with high dissociation constants, additional development is required to exploit the β-CyD inclusion complex approach for improved delivery of nucleoside derivatives.

Keywords: β-cyclodextrin, nucleosides, adamantanoyl-nucleoside prodrugs, inclusion complexes, radioiodination, KBALB tumours, biodistribution, iododeoxyuridine