Abstract
Rationale: The integrin αvβ6, an epithelial-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas (PDAC). Here, we developed and tested a novel αvβ6-targeting peptide, DOTA-5G (1) radiolabeled with gallium-68 for positron emission tomography/computed tomography (PET/CT) imaging, and lutetium-177 for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-ABM-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase and their affinity for αvβ6 assessed by ELISA. The peptides were radiolabeled with gallium-68 and lutetium-177. In vitro cell binding, internalization, and efflux of 68Ga-1 and 177Lu-2 were evaluated in αvβ6 (+) BxPC-3 human pancreatic cancer cells. PET/CT imaging of 68Ga-1 and 68Ga-2 was performed in female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for 68Ga-1 (1 and 2 h p.i.), 68Ga-2 (2 and 4 h p.i.), and 177Lu-1 and 177Lu-2 (1, 24, 48, and 72 h p.i.). The 177Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of 177Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity for αvβ6 by ELISA. 68Ga-1, 68Ga-2, 177Lu-1 and 177Lu-2 were synthesized in high radiochemical purity (RCP). Rapid in vitro binding and internalization of 68Ga-1 and 177Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the ABM in 177Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data the dose-limiting organ for 177Lu-2 are the kidneys. Treatment with 177Lu-2 prolonged survival. Conclusion: 68Ga-1 and 177Lu-2 demonstrated high affinity for the integrin αvβ6 both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in pre-clinical studies with predominantly renal excretion and good tumor-to-normal tissue ratios. Favorable human dosimetry data suggest the potential of 177Lu-2 as a treatment for PDAC.
- Peptides
- PET
- Radionuclide Therapy
- Ga-68
- Lu-177
- albumin-binding moiety
- integrin αvβ6
- theranostics
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