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Optimization of biodistribution and blood retention of affibody molecule radioligands
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Medicinal Chemistry)
2025 (English)Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
Abstract [en]

Affibodies are small, three-helix proteins with antibody-like binding properties but suffer from high kidney uptake, which make radioligand therapy applications challenging. In this study, a tumour stroma targeting affibody was modified with fatty acids of varying chain lengths, including a diacid-modified construct, to enhance albumin binding and reduce renal retention. Gallium-68 radiolabelled constructs were evaluated in healthy rats and tumour-bearing mice, and a Terbium-161 based proof-of-concept pilot study was also conducted. The unmodified affibody showed high kidney uptake (SUV 39.3 ± 14.5), while the diacid-modified construct significantly reduced this to SUV=13.4 ± 2.8. Although longer fatty acids improved blood retention, increased lipophilicity led to elevated liver uptake. The diacid modification reduced liver accumulation (liver SUV 2.3 ± 0.1) and supported improved systemic exposure. In tumour models, organ distribution patterns remained consistent with those in healthy rats, as well as high but variable binding in the tumour. Tumour accumulation peaked at 24 hours post-injection in the Terbium-161 study, but declined by 96 hours. In both Gallium-68 and Terbium-161 labelled studies, kidney uptake was found to be relatively high. These results highlight the need for further modifications to enhance albumin binding and tumour retention.

Place, publisher, year, edition, pages
2025.
National Category
Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-561118OAI: oai:DiVA.org:uu-561118DiVA, id: diva2:1973648
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Available from: 2025-06-26 Created: 2025-06-19 Last updated: 2025-06-26Bibliographically approved

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