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Radiolabeling of Avidin with Very High Specific Activity for Internal Radiation Therapy of Intraperitoneally Disseminated Tumors¹

Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan [M. M., T. S., H. K., T. I., T. H., N. S., J. K.], and National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. W. B.]

Purpose: For the effective internal radiation therapy of i.p. disseminated tumors, we developed avidin (Av)-dendrimer-chelate complex, which can be labeled with indium-111, emitting Auger and conversion electrons, with very high specific activity, and we studied its internalization, biodistribution, and therapeutic effect in nude mice with i.p. tumors.

Experimental Design: Generation 4 dendrimer (G4) was biotinylated and conjugated with 52 1B4M chelates. ¹¹¹In-G4-bt was mixed with Av to form ¹¹¹In-G4-Av complex. ¹¹¹In-G4-Av was incubated with ovarian cancer cells (SHIN-3), and the rate of internalization of the radiolabel into SHIN-3 cells was followed. ¹¹¹In-G4-Av was i.p. injected into nude mice that had i.p. disseminated SHIN-3 tumors, and the biodistribution was determined. Nude mice bearing i.p. disseminated tumors received i.p. injection of ¹¹¹In-G4-Av (9.25 or 18.5 MBq x 2, with a 1-week interval) and were followed for the formation of malignant ascites.

Results: Av could be labeled with ¹¹¹In with specific activity as high as 37 GBq/mg. More than 75% of the radioactivity was internalized 24 h after binding to cancer cells. ¹¹¹In-G4-Av accumulated rapidly and highly in the i.p. tumors (128.20% injected dose/gram of tissue at 2 h, 114.91% injected dose/gram of tissue at 24 h for unsaturated compound) with high tumor:background ratios. Treatment with a high dose of ¹¹¹In-G4-bt-Av was tolerable and showed dose-dependent therapeutic effect.

Conclusions: G4-Av complex, which could be labeled with ¹¹¹In with very high specific activity and showed efficient internalization into cancer cells and high accumulation to i.p. tumors, appears to be suitable for the internal radiation therapy of i.p. disseminated tumors using metallic radionuclides emitting Auger and conversion electrons.