Abstract
Integrin ανβ6 promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting ανβ6 with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for ανβ6. However, one concern of these ανβ6 integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either 68Ga for imaging or 177Lu for therapy. PET imaging with [68Ga]Ga-DOTA-(PEG28)2-A20FMDV2 revealed specific tumor uptake in ανβ6-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)2-A20FMDV2 and IBA-DOTA-(PEG28)2-A20FMDV2 were radiolabeled with 177Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both 177Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an ανβ6-positive tumor.
Highlights
Integrins are an important class of cell surface receptors that are responsible for cell-matrix adhesion and signaling across the membrane, controlling a variety of vital cell functions such as cellular growth, proliferation, migration, signaling, and cytokine activation that are critical to infection, inflammation, and cancer [1,2]
Our studies focused on the evaluation of two albuminbinding peptides Evans Blue (EB)-DOTA-(PEG28)2 -A20FMDV2 and IBA-DOTA-(PEG28)2 -A20FMDV2 radiolabeled with 177 Lu (T1/2 = 6.7 d, Eβ- avg = 134 keV) for their therapeutic potential with the main goal of using [68 Ga]Ga-DOTA-(PEG28)2 -A20FMDV2 and [177 Lu]Lu-EB/IBAPharmaceuticals 2022, 15, x FOR PEER REVIEW
[68 Ga]Ga-DOTA-(PEG28)2 -A20FMDV2 and [177 Lu]Lu-IBA-DOTA(PEG28)2 -A20FMDV2 could be used as a potential theranostic pair for imaging and therapy of αv β6 -expressing tumors
Summary
Integrins are an important class of cell surface receptors that are responsible for cell-matrix adhesion and signaling across the membrane, controlling a variety of vital cell functions such as cellular growth, proliferation, migration, signaling, and cytokine activation that are critical to infection, inflammation, and cancer [1,2]. We focus on a 20-amino-acid peptide sequence of NAVPNLRGDLQVLAQKVART (A20FMDV2) reported by Hausner et al that showed a high target affinity and selectivity for the integrin receptor [12]. This group translated a similar peptide in which the lysine at position 16 was replaced with an arginine (A20FMDV2K16R) for clinical imaging when radiolabeled with 18 F [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
