TY - JOUR
T1 - Specific and high-level targeting of radiolabeled octreotide analogues to human medulloblastoma xenografts
AU - Vaidyanathan, Ganesan
AU - Friedman, Henry S.
AU - Affleck, Donna J.
AU - Schottelius, Margaret
AU - Wester, Hans Jürgen
AU - Zalutsky, Michael R.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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]GlucTOC) and glucose-[131I-Tyr3]octreotate ([131I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH2 terminus. Specific internalization of the peptides by sstr2expressing 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]GlucTOC, 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.
AB - 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]GlucTOC) and glucose-[131I-Tyr3]octreotate ([131I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH2 terminus. Specific internalization of the peptides by sstr2expressing 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]GlucTOC, 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.
UR - http://www.scopus.com/inward/record.url?scp=0037989830&partnerID=8YFLogxK
M3 - Article
C2 - 12738745
AN - SCOPUS:0037989830
SN - 1078-0432
VL - 9
SP - 1868
EP - 1876
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -
