Preclinical studies of Bismuth-213 labeled plasminogen activator inhibitor type 2 (PAI2) in a prostate cancer nude mouse xenograft model

Objectives: The key objective of the study was to determine the single and multiple dose toxicity and efficacy of Bismuth-213 labeled PA12 based targeted alpha therapy by selectively targeting uPA and uPAR in regressing prostate cancer in a nude mouse model. Targeted alpha therapy (TAT) is an experimental therapeutic modality for cancer. Another objective was to compare the in vivo pharmacokinetics using two different chelators to form the radioisotope-protein construct. Methods: The single and multiple intra-peritoneal (IP) dose toxicity and efficacy of (213)BiPA12 was investigated in nude mice and its toxicity in rabbits. CD 31 staining for vasculature and uPA expression were measured at different stages of tumor growth. The pharmacokinetics of the chelators cDTPA and CHX-A" were measured. Results: All TAT regimes were well tolerated in mice and rabbits on biochemical and haematological examination. Capillaries became evident at six days post-cell inoculation. uPA expression was positive at all stages of turnout growth. No significant differences were observed between cDTPA and CHX-A." Inhibition of turnout growth was observed at 947 and 1,421 MBq/kg single dose injection at three days post-PC3 cell inoculation. The three day post-inoculation multiple dose regime gave complete turnout growth inhibition at a total dose of 947 MBq/kg given on five successive days. Mice treated at 6, 12 and 18 days post-inoculation showed significantly slower turnout growth compared to controls. Conclusions: The efficacy of single and multiple dose TAT in mice was demonstrated within tolerance limits, the multiple dose regime being no more toxic than the single dose. Either of the two chelators could be used for Bi-213 studies.