New indium-111 labeled biotin derivatives for improved immunotargeting.
Investigations into the use of streptavidin-conjugated antibodies and labeled biotin to improve radioimmunotargeting have shown background levels drastically reduced over the conventional approach. Nevertheless, accumulation of 111In-biotin in normal tissue as well as streptavidin-independent accumulation in tumor, was observed. In this work, the effect of altering the biotin molecule to reduce this nonspecific uptake without decreasing specific localization has been investigated. Three EDTA and DTPA derivatives of biotin have been synthesized and investigated along with a commercial biotin derivative (DTPA-B2). The labeled biotin chelates were administered i.p. to normal mice implanted with avidin beads in one thigh. A wide variation in biodistribution was seen among the biotin derivatives. The most favorable results were obtained with biotinyl-hydrazino-EDTA (EDTA-B1), which showed the lowest accumulation in normal tissues but equivalent uptake in the target with respect to the other compounds. Averaged over 8 tissues sampled, the target-to-nontarget ratio was 140 vs 9 for EDTA-B1 vs DTPA-B2 (N = 6) at 24 h post administration. Similar observations have been made in culture with two tumor cell lines: positive accumulation of both DTPA-B2 and EDTA-B1 was measured in tumor cells independent of streptavidin-antibody conjugate, however in the case of the latter derivative, this accumulation was 3-5 fold lower. These studies show that modification of the biotin species can alter accumulation in normal tissues as well as the antibody-streptavidin independent accumulation in tumor tissue.
Virzi
F
F
Department of Nuclear Medicine, University of Massachusetts Medical Center, Worcester 01655.
Fritz
B
B
Rusckowski
M
M
Gionet
M
M
Misra
H
H
Hnatowich
D J
DJ
D000818:Animals; D001360:Avidin; D001667:Binding, Competitive; D001710:Biotin; D001798:Blood Proteins / Q000378:metabolism; D002614:Chelating Agents; D007205:Indium Radioisotopes; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives; D016719:Radioimmunodetection / Q000379:methods*; D013848:Thigh / Q000000981:diagnostic imaging
D001798:Blood Proteins; D002614:Chelating Agents; D007205:Indium Radioisotopes; D001360:Avidin; D001710:Biotin; D004369:Pentetic Acid