A Synthetic Macromolecule for Sentinel Node Detection: 99mTc-DTPA-Mannosyl-Dextran

Journal of Nuclear Medicine

Robert F. Mattrey¹  David R. Vera¹  Anne M. Wallace¹  Carl K. Hoh¹ 

[1] Departments of Radiology and Surgery and UCSD Cancer Center, University of California, San Diego, La Jolla, California Departments of Radiology and Surgery and UCSD Cancer Center, University of California, San Diego, La Jolla, California Departments of Radiology and Surgery and UCSD Cancer Center, University of California, San Diego, La Jolla, California

关键词: sentinel node;    ^99mTc;    DTPA-mannosyl-dextran;    receptor-binding radiopharmaceutical;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

We report the synthesis and preliminary biologic testing of a synthetic macromolecule, 99mTc-diethylenetriaminepentaacetic acid (DTPA)–mannosyl-dextran, for sentinel node detection. Methods: Synthesis started with a 2-step process that attaches a high density of amino-terminated leashes to a dextran backbone. Allyl-bromide was reacted with pharmaceutical-grade dextran to yield allyl-dextran. After diafiltration with water, filtration, and lyophilization, the product was reacted with aminoethanethiol and ammonium persulfate. The resulting amino-conjugated dextran was dialyzed, filtered, and lyophilized. The mixed anhydride method was used to attach DTPA; after dialysis, filtration, and lyophilization, 2-imino-2-methoxyethyl-1-d-mannose was used to attach the receptor substrate. The molecular diameter was measured by dynamic light scattering. Amino, mannose, and DTPA densities were measured by trinitrobenzene sulfonate assay, sulfuric acid/phenol assay, and inductively coupled plasma spectroscopy of gadolinium-DTPA-mannosyl-dextran, respectively. Receptor affinity was measured by Scatchard assay of rabbit liver. Axillary, popliteal, and iliac lymph nodes and each injection site were assayed for radioactivity at 1 and 3 h after injection of approximately 3.7 MBq (0.050 mL) 99mTc-DTPA-mannosyl-dextran (0.22 nmol) or filtered 99mTc-sulfur colloid into the foot pads. Four animals were studied at each time point. Results: DTPA-mannosyl-dextran had a molecular weight of 35,800 g/mol and a molecular diameter of 7.1 nm. The final amine, mannose, and DTPA densities were 23, 55, and 8 mol per dextran. Labeling yields were in excess of 98% and stable for 6 h. Specific activities of 74 × 106 GBq/mol were achieved. The equilibrium dissociation constant for binding to the mannose-terminated glycoprotein receptor was 0.12 ± 0.07 nmol/L. The popliteal extraction at both 1 h and 3 h was significantly (P < 0.05) higher for 99mTc-DTPA-mannosyl-dextran (90.1% ± 10.7% and 97.7% ± 2.0%, respectively) than for filtered 99mTc-sulfur colloid (78.8 ± 6.5 and 67.4% ± 26.8%, respectively). 99mTc-DTPA-mannosyl-dextran exhibited significantly faster injection site clearance than did filtered 99mTc-sulfur colloid. The 99mTc-DTPA-mannosyl-dextran percentage injected dose (%ID) for the front and rear paws was 52.6 ± 10.5 and 52.3 ± 8.0 at 1 h and 45.7 ± 8.5 and 43.6 ± 8.2 at 3 h after administration. The filtered 99mTc-sulfur colloid %ID for the front and rear paws was 70.4 ± 11.0 and 66.3 ± 15.1 at 1 h and 55.5 ± 7.8 and 66.9 ± 8.5 at 3 h. Lymph node accumulation of each agent at either 1 or 3 h was not significantly different. Conclusion: 99mTc-DTPA-mannosyl-dextran is a receptor-based sentinel node radiotracer that exhibits the desired properties of rapid injection site clearance and low distal node accumulation. This molecule is the first member of a new class of diagnostic agents based on a macromolecular backbone with a high density of sites for the attachment of substrates and imaging reporters.

【 授权许可】

Unknown