Poly-L- and
poly-D-lysine were evaluated as carriers of
astatine and
biotin for prospective use as effector molecules in pretargeted
radioimmunotherapy of
micrometastases. The precursor
polylysine was derivatized in a three-step, single-pot procedure, including biotinylation with
biotin amidocaproic
N-hydroxysuccinimide, astatination via the intermediate
reagent N-succinimidyl 3-(trimethylstannyl)benzoate, and, finally, charge modification using
succinic anhydride. The chemistry was shown to be very facile, with a biotinylation efficiency of 75 +/- 5%, and overall radiochemical yields in the range of 50-70%. After charge modification, no
amines could be detected in the final product. The
biotin function was unaffected by the chemistry and the radiation, as confirmed by almost complete binding of the effector molecule to
avidin beads using a convenient filter tube assay. The effector molecules were evaluated in
tumor-free female nude mice with regard to whole-body retention and tissue distribution after i.p. administration. The distribution of the L-isomer effector molecule showed rapid whole-body clearance with low uptake in all tissues, whereas the D-
isoform showed whole-body clearance related to uptake in the kidneys. Both D-isomer and L-isomer showed faster blood clearance and generally lower tissue uptakes than labeled
antibodies. The normal tissue distribution after the peritoneal administration implies that pretargeting using L-structure
polylysine as the effector molecule may give a higher therapeutic index than that achieved in conventional
radioimmunotherapy.