TY - JOUR

T1 - EGFR targeting of [177Lu] gold nanoparticles to colorectal and breast tumour cells: Affinity, duration of binding and growth inhibition of Cetuximab-resistant cells

AU - Shabbir, Rekaya

AU - Mingarelli, Marco

AU - Cabello, Gema

AU - Van Herk, Marcel

AU - Choudhury, Ananya

AU - Smith, Tim

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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 chelates and a linker which can be a nanoparticle platform. Nanoparticles facilitate the attachment of multiple 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 Cetuximabtargeted [177Lu]-AuNPs were investigated. Dose distribution in xenografts derived from EGFRoverexpressing cells was also determined.Methods: Cetuximab-targeted [177Lu]-AuNPs were generated by functionalising 15nm AuNPs with thechelator DOTA and Cetuximab and radiolabelling with 177LuCl3. KDis, a measure of affinity, was determined 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 autoradiography.Results: KDis for 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 effective 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.

AB - 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 chelates and a linker which can be a nanoparticle platform. Nanoparticles facilitate the attachment of multiple 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 Cetuximabtargeted [177Lu]-AuNPs were investigated. Dose distribution in xenografts derived from EGFRoverexpressing cells was also determined.Methods: Cetuximab-targeted [177Lu]-AuNPs were generated by functionalising 15nm AuNPs with thechelator DOTA and Cetuximab and radiolabelling with 177LuCl3. KDis, a measure of affinity, was determined 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 autoradiography.Results: KDis for 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 effective 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.

U2 - 10.1016/j.jksus.2021.101573

DO - 10.1016/j.jksus.2021.101573

M3 - Article

VL - 33

JO - Journal of King Saud University-Science

JF - Journal of King Saud University-Science

IS - 7

M1 - 101573

ER -