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Response of LNCaP Spheroids after Treatment with an -Particle Emitter (²¹³Bi)-labeled Anti-Prostate-specific Membrane Antigen Antibody (J591)¹

Departments of Medical Physics [Å. M. B., W-H. Y., K. A. H., G. S.], Medicine [M. R. M., D. M., D. A. S.], and Epidemiology and Biostatistics [K. S. P.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Weill Medical College of Cornell University, New York, New York 10021 [N. H. B.]; and Physics Department, Concordia University, Montreal, Quebec, Canada [D. E. C.]

A theoretical drawback to -particle therapy with ²¹³Bi is the short range of the particle track coupled with the short half-life of the radionuclide, thereby potentially limiting effective cytotoxicity to rapidly accessible, disseminated individual tumor cells (e.g., as in leukemia). In this work, a prostate carcinoma spheroid model was used to evaluate the feasibility of targeting micrometastatic clusters of tumor cells using ²¹³Bi-labeled anti-prostate-specific membrane antigen (PSMA) antibody, J591. In prostate cancer, vascular dissemination of tumor cells or tumor cell clusters to the marrow constitutes an important step in the progression of this disease to widespread skeletal involvement, an incurable state. Such prevascularized clusters are ideal targets for radiolabeled antibodies because the barriers to antibody penetration that are associated with the capillary basal lamina have not yet formed. ß- and -emitting radionuclides such as ¹³¹I, which are widely used in radioimmunotherapy, are not expected to be effective when targeting single cells or small cell clusters. This is because the range of the emissions is one to two orders of magnitude greater than the target size, and the energy deposited per traversal is insufficient to produce any significant radiobiological effect. Spheroids of the prostate cancer cell line, LNCaP-LN3, were used as a model of prevascularized micrometastases; their response to an anti-PSMA antibody, J591, radiolabeled with the -particle emitter ²¹³Bi (T_1/2, 45.6 min.) has been measured. The time course of spheroid volume reductions was found to be sensitive to the initial spheroid volume. J591 labeled with 0.9 MBq/ml ²¹³Bi resulted in a 3-log reduction in spheroid volume on day 33, relative to control, for spheroids with an initial diameter of 130 µm; 1.8 MBq/ml were required to achieve a similar response for spheroids with an initial diameter of 180 µm. Equivalent spheroid responses were observed after 12 Gy of acute external beam photon irradiation. Monte Carlo-based microdosimetric analyses of the ²¹³Bi decay distribution in individual spheroids of 130-µm diameter yielded an average -particle dose of 3.7 Gy to the spheroids, resulting in a relative biological effectiveness factor of 3.2 over photon irradiation. The activity concentrations used in the experiments were clinically relevant, and this work supports the possibility of using ²¹³Bi-labeled antibodies not only for disseminated single tumor cells, as found in patients with leukemia, but also for micrometastatic tumor deposits up to 180 µm in diameter (1200 cells).

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