Development of anti-MUC1 DNA aptamers for the imaging and radiotherapy of breast cancer

Aptamers are novel oligonucleotide-based recognition molecules which can bind to almost any target, including extracellular proteins, antibodies, peptides and small molecules. Aptamers can be rapidly generated, and offer reduced immunogenicity, good tumour penetration, rapid uptake and clearance, and can thus be used as alternatives to monoclonal antibodies in molecular targeted radiotherapy and diagnostic imaging.

We have previously reported the isolation of high affinity and specificity DNA aptamers against the protein core of the MUC1 glycoprotein as a tumour marker on breast cancer cells. Once conjugated with a chelating agent and labelled with a radionuclide (^99mTc or ¹⁸⁸Re), such aptamers can be particularly useful in the diagnosis and targeted radiotherapy of breast cancer. The conjugation is achieved using standard peptide coupling reactions between an amino modification on the aptamer and the carboxylic group on the ligands.

We have coupled the aptamer with the highest affinity for the MUC1 glycoprotein to different ligands (MAG2 or meso-2,3-dimercaptosuccinic acid) and labelled it with ^99mTc and ¹⁸⁸Re to obtain stable complexes. An efficient and convenient labelling of the aptamer with short half-life radioisotopes was achieved as the last step of the synthesis (postconjugation labelling).

The selected ligands have strong ^99mTc and ¹⁸⁸Re binding properties and the resulting complexes are highly stable in vivo both in terms of nuclease degradation and leaching of the metal. The presence of more than one molecule of aptamer per complex or the conjugation of the aptamer to high molecular weight polyethylene glycol modifies the pharmacokinetic properties of the radiolabelled products, allowing the complex to remain longer in circulation and thus offering improved tumour imaging properties and further possibilities for development into a targeted radiopharmaceutical for breast cancer therapy.