Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique

Abstract

Targeted a-therapy (TAT) appears to be an ideal therapeutic technique for eliminating malignant circulating, minimal residual, or micrometastatic cells. These types of malignancies are typically infraclinical, complicating the evaluation of potential treatments. This study presents a method of ex vivo activity quantification with an a-camera device, allowing measurement of the activity taken up by tumor cells in biologic structures a few tens of microns. Methods: We examined micrometastases from a murine model of ovarian carcinoma after injection of a radioimmunoconjugate labeled with 211 At for TAT. At different time points, biologic samples were excised and cryosectioned. The activity level and the number of tumor cells were determined by combined information from 2 adjacent sections: one exposed to the a-camera and the other stained with hematoxylin and eosin. The time-activity curves for tumor cell clusters, comprising fewer than 10 cells, were derived for 2 different injected activities (6 and 1 MBq). Results: High uptake and good retention of the radioimmunoconjugate were observed at the surface of tumor cells. Dosimetric calculations based on the measured time-integrated activity indicated that for an injected activity of 1 MBq, isolated tumor cells received at least 12 Gy. In larger micrometastases (#100 mm in diameter), the activity uptake per cell was lower, possibly because of hindered penetration of radiolabeled antibodies; however, the mean absorbed dose delivered to tumor cells was above 30 Gy, due to cross-fire irradiation. Conclusion: Using the a-camera, we developed a method of ex vivo activity quantification at the cellular scale, which was further applied to characterize the behavior of a radiolabeled antibody administered in vivo against ovarian carcinoma. This study demonstrated a reliable measurement of activity. This method of activity quantification, based on experimentally measured data, is expected to improve the relevance of small-scale dosimetry studies and thus to accelerate the optimization of TAT. On the basis of the characteristics of the a-particle, targeted a-therapy (TAT) has been acknowledged as a potentially efficient therapeutic technique (1) for decades. a-particles have a short range in tissue, making the irradiation specific, and a high linear energy transfer, making them highly cytotoxic (2). These properties make them suitable for the treatment of hematologic malignancies or minimal residual or micrometastatic diseases (3,4). The first clinical trials using TAT have been started for the treatment of leukemia (5,6), ovarian carcinoma (7), and residual tumor cells after surgery of malignant brain tumors (8).Micrometastatic diseases are infraclinical and hardy or not localized with in vivo imaging techniques. Thus, targeted radionuclide therapies of tumor cells or micrometastases require complex evaluations. Activity quantification of micrometric lesions by imaging is difficult in patients because of the limited spatial resolution. Only rough estimations of the activity of...

Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b

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Application of ²¹²Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

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Actinide bioimaging in tissues: Comparison of emulsion and solid track autoradiography techniques with the iQID camera

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