HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Palm, S. Articles by Sgouros, G. Search for Related Content PubMed PubMed Citation Articles by Palm, S. Articles by Sgouros, G.

Pharmacokinetics and Biodistribution of ⁸⁶Y-Trastuzumab for ⁹⁰Y Dosimetry in an Ovarian Carcinoma Model: Correlative MicroPET and MRI

¹ Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York
² Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
³ Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of ⁹⁰Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma. Methods: Female nude mice were inoculated intraperitoneally with 5·10⁶ ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12–18 MBq ⁸⁶Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with ⁸⁶Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or ⁸⁶Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by -counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). ⁸⁶Y-Trastuzumab pharmacokinetics were used to perform ⁹⁰Y-trastuzumab dosimetry. Results: Intraperitoneal injection of mAb led to rapid blood-pool uptake (5–9 h) followed by tumor localization (26–32 h), as confirmed by registered MR images. Tumor uptake was greatest for ⁸⁶Y-trastuzumab (7 ± 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 ± 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq ⁹⁰Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm. Conclusion: For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined ⁸⁶Y uptake. Coregistration with MR images confirmed the position of ⁸⁶Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.

Key Words: microPET • trastuzumab • ⁸⁶Y • ovarian carcinoma • pharmacokinetics

This article has been cited by other articles:

				S. Shanehsazzadeh, A. R. Jalilian, H. R. Sadeghi, and M. Allahverdi Determination of human absorbed dose of 67GA-DTPA-ACTH based on distribution data in rats Radiat Prot Dosimetry, June 1, 2009; 134(2): 79 - 86. [Abstract] [Full Text] [PDF]

				J. H.E. Baker, K. E. Lindquist, L. A. Huxham, A. H. Kyle, J. T. Sy, and A. I. Minchinton Direct Visualization of Heterogeneous Extravascular Distribution of Trastuzumab in Human Epidermal Growth Factor Receptor Type 2 Overexpressing Xenografts Clin. Cancer Res., April 1, 2008; 14(7): 2171 - 2179. [Abstract] [Full Text] [PDF]

				A. M. Ballangrud, W.-H. Yang, S. Palm, R. Enmon, P. E. Borchardt, V. A. Pellegrini, M. R. McDevitt, D. A. Scheinberg, and G. Sgouros Alpha-Particle Emitting Atomic Generator (Actinium-225)-Labeled Trastuzumab (Herceptin) Targeting of Breast Cancer Spheroids: Efficacy versus HER2/neu Expression Clin. Cancer Res., July 1, 2004; 10(13): 4489 - 4497. [Abstract] [Full Text] [PDF]