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Specific and High-Level Targeting of Radiolabeled Octreotide Analogues to Human Medulloblastoma Xenografts¹

Departments of Radiology [G. V., D. J. A., M. R. Z.] and Pediatrics [H. S. F.], Duke University Medical Center, Durham, North Carolina 27710, and Department of Nuclear Medicine, Technical University of Münich, 81675 Münich, Germany [M. S., H-J. W.]

Purpose: The objective of this study was to determine the feasibility of exploiting the overexpression of somatostatin subtype-2 receptors (sstr₂) on human medulloblastoma cells to develop targeted radiodiagnostics and radiotherapeutics for this disease.

Experimental Design: The following radioiodinated peptides were prepared using chloramine-T and evaluated: [¹³¹I-Tyr³]octreotide ([¹³¹I]TOC), [¹³¹I-Tyr³]octreotate ([¹³¹I]TOCA), involving substitution of Thr(ol)⁸ in TOC with Thr⁸, and glucose-[¹³¹I-Tyr³]octreotide ([¹³¹I]Gluc-TOC) and glucose-[¹³¹I-Tyr³]octreotate ([¹³¹I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH₂ terminus. Specific internalization of the peptides by sstr₂-expressing AR42J rat pancreatic carcinoma cells in vitro was evaluated in paired-label assays. The tissue distribution of i.v. administered [¹³¹I]TOC, [¹³¹I]TOCA, [¹³¹I]Gluc-TOC, and [¹³¹I]Gluc-TOCA was evaluated in athymic mice bearing s.c. D341 Med human medulloblastoma xenografts.

Results: Compared with [¹²⁵I]TOC, internalized radioiodine levels were higher for the other three peptides. For example, internalized counts were 1.9 ± 0.2, 2.0 ± 0.3, and 5.7 ± 1.9 times higher for [¹³¹I]Gluc-TOC, [¹³¹I]TOCA, and [¹³¹I]Gluc-TOCA after a 3-h incubation, respectively, demonstrating that carbohydration and COOH-terminus modification significantly improved the retention of radioiodine activity in sstr₂-expressing tumor cells. COOH-terminus modification significantly increased ¹³¹I localization in D341 Med medulloblastoma xenografts {[¹³¹I]TOCA, 8.1 ± 2.2% of injected dose/g (% ID/g); [¹³¹I]TOC, 3.9 ± 0.5% ID/g at 1 h}, whereas carbohydration of the NH₂ terminus resulted in even higher gains in tumor accumulation ([¹³¹I]Gluc-TOC, 11.1 ± 1.8% ID/g; [¹³¹I]Gluc-TOCA, 21.4 ± 7.3% ID/g). In addition, the three modified peptides exhibited liver activity levels that were less than half those of [¹³¹I]TOC. Uptake of the two glucose-peptide conjugates in this human medulloblastoma xenograft was blocked by coinjection of 100 µg of octreotide, demonstrating that it was receptor-specific. Tumor:normal tissue uptake ratios for [¹³¹I]Gluc-TOCA generally were higher that those for [¹³¹I]Gluc-TOC. At 1 h, tumor:normal tissue ratios for [¹³¹I]Gluc-TOCA were 29:1, 15:1, 8:1, 8:1, 240:1, and 82:1 for blood, liver, kidney, spleen, brain, and muscle, respectively.

Conclusions: Our findings suggest that additional investigation of radiolabeled Gluc-TOCA analogues for the imaging and targeted radiotherapy of medulloblastoma is warranted.

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