Microfluidic labeling of biomolecules with radiometals for use in nuclear medicine

• Published in: Lab on a chip 2010-12, Vol.1 (24), p.3387-3396
• Main Authors: Wheeler, Tobias D, Zeng, Dexing, Desai, Amit V, Önal, Birce, Reichert, David E, Kenis, Paul J. A
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor; Chelating agents; Copper - chemistry; Equipment Design; Heterocyclic Compounds, 1-Ring - chemistry; Humans; Ligands; Materials Testing; Metals - chemistry; Microarray Analysis - methods; Microfluidic Analytical Techniques; Models, Chemical; Nuclear Medicine; Sodium - chemistry; Temperature
• ISSN: 1473-0197; 1473-0189
• DOI: 10.1039/c0lc00162g

Radiometal-based radiopharmaceuticals, used as imaging and therapeutic agents in nuclear medicine, consist of a radiometal that is bound to a targeting biomolecule (BM) using a bifunctional chelator (BFC). Conventional, macroscale radiolabeling methods use an excess of the BFC-BM conjugate (ligand) to achieve high radiolabeling yields. Subsequently, to achieve maximal specific activity (minimal amount of unlabeled ligand), extensive chromatographic purification is required to remove unlabeled ligand, often resulting in longer synthesis times and loss of imaging sensitivity due to radioactive decay. Here we describe a microreactor that overcomes the above issues through integration of efficient mixing and heating strategies while working with small volumes of concentrated reagents. As a model reaction, we radiolabel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated to the peptide cyclo (Arg-Gly-Asp-DPhe-Lys) with 64 Cu 2+ . We show that the microreactor (made from polydimethylsiloxane and glass) can withstand 260 mCi of activity over 720 hours and retains only minimal amounts of 64 Cu 2+ (50 µM), yields of over 90% can be achieved in the microreactor when using a 1 : 1 stoichiometry of radiometal to BFC-BM. These high yields eliminate the need for use of excess amounts of often precious BM and obviate the need for a chromatographic purification process to remove unlabeled ligand. The results reported here demonstrate the potential of microreactor technology to improve the production of patient-tailored doses of radiometal-based radiopharmaceuticals in the clinic. The high efficiency of the microreactor eliminates the need for purification and demonstrates the potential utility of microfluidics for the production of disease-specific, patient-tailored radiolabeled imaging probes in the clinic.