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EGFR targeting of Lu-177 gold nanoparticles to colorectal and breast tumour cells: Affinity, duration of binding and growth inhibition of Cetuximab-resistant cellsShabbir, Rekaya; Mingarelli, M.; Cabello, G.; van Herk, Marcel; Choudhury, Ananya; Smith, Tim A D; University of Manchester, Division of Cancer Sciences, Manchester, Lancs (2021)Objective:Radioimmunotherapy (RIT) is a systemic therapy currently used in the treatment of patientswith lymphoma. RIT complexes consist of a targeting molecule, commonly an antibody, radionuclide che-lates and a linker which can be a nanoparticle platform. Nanoparticles facilitate the attachment of mul-tiple radionuclides and targeting groups to a single complex. Here the target affinity, duration of targetassociation and inhibition of colony formation of Cetuximab-resistant tumour cells with Cetuximab-targeted [177Lu]-AuNPs were investigated. Dose distribution in xenografts derived from EGFR-overexpressing cells was also determined.Methods:Cetuximab-targeted [177Lu]-AuNPs were generated by functionalising 15nm AuNPs with thechelator DOTA and Cetuximab and radiolabelling with177LuCl3.KDis, a measure of affinity, was deter-mined by competitive binding to EGFR expressing cells. Radio-sensitivity was determined in EGFRexpressing tumour cells including the Cetuximab resistant cell line HCT116 using a colony formationassay. Dose distribution was measured in sections from xenografts grown in nude mice using autoradio-graphy.Results:KDisfor the complex binding to EGFR on MDA-MB-468 cells was 20 nM. Loss of cell associated[177Lu] activity was biphasic with loss of about 50% of activity in about 4 h. Remaining activity dissociatedover a period of about 4 days. HCT8 and MDA-MB-468, but not HCT116 cells were sensitive to the growthinhibitory effect of Cetuximab. However, treatment with Cetuximab-targeted [177Lu]-AuNPs inhibitedcolony formation in all 3 cell lines. Dose distribution across sections from xenografts was found todemonstrate a co-efficient of variation of 15%.Conclusion:Cetuximab-targeted [177Lu]-AuNPs demonstrate high affinity for EGFR and could be an effec-tive treatment for Cetuximab-resistant colorectal cancer cells. A strategy involving pre-treatment withreceptor targeted[177Lu] to improve RIT therapeutic ratios has the potential to enhance clinical outcomes.