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

Abstract

Objectives. The key objective of the study was to determine the single and multiple dose toxicity and efficacy of Bismuth-213 labeled PAI2 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 BiPAI2 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 tumour growth. No significant differences were observed between cDTPA and CHX-A.I nhibition of tumour growth was observed at 947 and 1421 MBq/kg single dose injection at three days post-PC3 cell inoculation. The three day post-inoculation multiple dose regime gave complete tumour 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 tumour 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 213 Bi studies.

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

“…Mice. This study is an extension of the previously published study, 27 which showed the MTD to be more than 1420 MBq/kg up to 13 weeks using weight loss as the indicator for toxicity. Biochemistry, haematology and histopathology of the specimens were carried out at 13 weeks, in addition to the monitoring weight loss to investigate subclinical abnormalities.…”

“…Rabbits that received the lowest dose of 60 MBq/kg experienced weight gain similar to the controls, whereas weight gain was the slowest in the rabbits that received the highest dose of 350 MBq/kg. 27 Histopathology revealed that organs in all rabbits, except for the kidneys, were free of any radiation damage. The kidneys showed mild and patchy tubular necrosis at 60 and 120 MBq/kg, while at 350 MBq/kg, moderate to severe and widespread renal tubular necrosis with a compensatory expansion of interstitial tissue was observed.…”

“…Animals were monitored up to 13 weeks for any dramatic change in weight or distressed behaviour. 27 Rabbits were euthanized by ketamine and Iluim xylazil by intramuscular injection at a weight loss of 20% or more. Blood and organs were collected and sent for pathological examination.…”

Preparation and testing of bevacizumab radioimmunoconjugates with Bismuth-213 and Bismuth-205 / Bismuth-206

“…The Balb/c nude mice were inoculated with 2 x 10 6 PC3 cells subcutaneously as per procedures published elsewhere. 13,19,31,32 Two different doses of cold bevacizumab (1 and Clinical Gastroenterology and Hepatolog 3 mg/kg) were administered twice weekly for three weeks. The control mice received saline injection in equal volume at each bevacizumab administration in test mice.…”

“…3 We have successfully prepared and tested labeled monoclonal antibodies and proteins in vitro and have demonstrated their efficacy for targeted alpha therapy (TAT) in vivo with various cancer models. [11][12][13][14][15][16][17][18][19][20][21] One of the labeled TAT products (antimelanoma monoclonal antibody 9.2.27 labeled with alpha emitting radionuclide Bismuth-213) has been successfully tested in our ongoing Phase I melanoma trials. [22][23][24] We have found partial to complete response in some patients without any signs of associated toxicity.…”