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

Song, Emma; Rizvi, Syed Monem; Qu, Chang; Raja, Chand; Brechbiel, Martin W.; Morgenstern, Alfred; Apostolidis, Christos; Allen, Barry J.

doi:10.4161/cbt.6.6.4097

Cited by 25 publications

(25 citation statements)

References 27 publications

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“…In the present study, we have used cDTPA and CHX-A″ as chelators. [17][18][19] CHX-A″ has been used as a preferred chelator by a number of groups because of its better in vivo stability. [34][35][36][37][38] Our previous studies have shown similar in vitro stability for both chelators.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Research Papermentioning

confidence: 99%

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

Rizvi¹,

Song²,

Raja³

et al. 2008

Cancer Biology & Therapy

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Bevacizumab, a humanized anti-VEGF monoclonal antibody has shown promise in various clinical trials. We report the development and testing of Bi-213 (an a-emitting radionuclide) labeled bevacizumab for in vitro and in vivo studies using two different chelators viz cDTPA and CHX-A″.The developed labeling method showed high labeling yields of 93.6% and 89.7% for cDTPA and CHX-A″ respectively and the results were reproducible. The in vitro and in vivo stability tests were carried out using Bi-213 and long half-life Bismuth isotope (Bi-205/Bi-206) for pharmacokinetics. The in vitro results showed remarkable stability of the radiolabeled bevacizumab regardless of the chelator. The in vivo pharmacokinetics studies however, showed that the uptake and retention of cDTPA-bevacizumab was significantly higher in kidneys (p-value 0.02) and lower in liver and spleen (p-value <0.0001 and 0.0009 respectively). The values for the two conjugates compared well in blood but the longer term data for CHX-A″ conjugate showed slow clearance resulting in a significantly longer blood half-life of the product (211 hours compared to 4 hours for cDTPA-bevacizumab). Preliminary in vivo results showed increased efficacy of the combination therapy compared to bevacizumab only. The tumor area (mm 2 ) decreased from 24.8 ± 3.6 and 12.8 ± 1.7 for 1 and 3 mg/kg cold bevacizumab only to 6.5 ± 0.7 and 7.5 ± 4.8 when single dose of 333 MBq/kg of 213 Bibevacizumab was administered as combination therapy.In conclusion it can be said that stable radiolabeled bevacizumab conjugates can be prepared with Bi-213 with either chelators used. The shorter blood half-life with cDTPA-bevacizumab may not be a major concern with Bi-213 as its own half-life is 46 minutes only. The combination therapy proved superior to bevacizumab alone therapy, a phenomenon that can be particularly useful in cancers where bevacizumab alone has shown limited success like prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Research Papermentioning

confidence: 99%

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

Rizvi¹,

Song²,

Raja³

et al. 2008

Cancer Biology & Therapy

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“…In conclusion, ovarian cancer cells overexpressing uPAR were specifically targeted in vitro as well as in vivo by 213 Bi-P-P4D, and the kidney uptake was reduced by gelofusine. An additional study also using 213 Bi has been published by Song et al in which they investigated the pharmacokinetics, toxicity and in vivo stability of 213 Bi-PAI2, and also determined if a prior injection of the metal chelator Ca-DTPA or lysine would reduce the toxicity by decreasing the renal uptake (Song et al, 2007). Two different chelators (CHX-A"-DTPA and cDTPA) were used for the preparation of the 213 Bi-PAI2 conjugate; for i.p.…”

Section: 3mentioning

confidence: 99%

“…It has been used in one animal study (Knör et al, 2008). PAI2 is a targeting construct that is a plasminogen activator inhibitor type 2 and which is a member of the serine protease inhibitor (Serpin) superfamily and forms SDS-stable 1:1 complexes with urokinase plasminogen activator (uPA) (Song et al, 2007). It has been used in one animal study (Song et al, 2007).…”

Section: Targeting Constructsmentioning

confidence: 99%

Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations

Elgqvist¹,

Lindegren²,

Albertsson³

2012

Ovarian Cancer - Clinical and Therapeutic Perspectives

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Determination of the dose rate constant through Monte Carlo simulations with voxel phantoms

2018

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The results for the body dose rate constant calculated in this work, for 30 radionuclides and 57 radiopharmaceuticals, and their effective half-lives, may be used to estimate the dose emitted by a person who has incorporated a radionuclide in the Nuclear Medicine activity range. This dose will be optimized when the body dose rate constant and the effective half-life determined in this study are used together with dose reduction factors.

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

Cited by 25 publications

References 27 publications

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

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

Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations

Determination of the dose rate constant through Monte Carlo simulations with voxel phantoms

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