1. Biodistribution and toxicity of innate defense regulator 1018 (IDR-1018).
- Author
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Esposito TVF, Rodríguez-Rodríguez C, Blackadar C, Haney EF, Pletzer D, Hancock REW, Saatchi K, and Häfeli UO
- Subjects
- Animals, Immunity, Innate, Mice, Microbial Sensitivity Tests, Tissue Distribution, Anti-Infective Agents, Antimicrobial Cationic Peptides toxicity
- Abstract
Innate defense regulators (IDRs) are synthetic host-defense peptides (HDPs) with broad-spectrum anti-infective properties, including immunomodulatory, anti-biofilm and direct antimicrobial activities. A lack of pharmacokinetic data about these peptides hinders their development and makes it challenging to fully understand how they work in vivo since their mechanism of action is dependent on tissue concentrations of the peptide. Here, we set out to define in detail the pharmacokinetics of a well-characterized IDR molecule, IDR-1018. To make the peptide traceable, it was radiolabeled with the long-lived gamma-emitting isotope gallium-67. After a series of bench-top characterizations, the radiotracer was administered to healthy mice intravenously (IV) or subcutaneously (SQ) at various dose levels (2.5-13 mg/kg). Nuclear imaging and ex-vivo biodistributions were used to quantify organ and tissue uptake of the radiotracer over time. When administered as an IV bolus, the distribution profile of the radiotracer changed as the dose was escalated. At 2.5 mg/kg, the peptide was well-tolerated, poorly circulated in the blood and was cleared predominantly by the reticuloendothelial system. Higher doses (7 and 13 mg/kg) as an IV bolus were almost immediately lethal due to respiratory arrest; significant lung uptake of the radiotracer was observed from nuclear scans of these animals, and histological examination found extensive damage to the pulmonary vasculature and alveoli. When administered SQ at a dose of 3 mg/kg, radiolabeled IDR-1018 was rapidly absorbed from the site of injection and predominately cleared renally. Apart from the SQ injection site, no other tissue had a concentration above the minimum inhibitory concentration that would enable this peptide to exert direct antimicrobial effects against most pathogenic bacteria. Tissue concentrations were sufficient, however, to disrupt microbial biofilms and alter the host immune response. Overall, this study demonstrated that the administration of synthetic IDR peptide in vivo is best suited to local administration which avoids some of the issues associated with peptide toxicity that are observed when administered systemically by IV injection, an issue that will have to be addressed through formulation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EFH and REWH have invented and filed for patent protection on IDR-1018 and related peptide sequences. This patent has been assigned to their employer, the University of British Columbia, and has been licensed to ABT Innovations Inc., in which both have an ownership position. ABT Innovations Inc. is a subsidiary of ASEP Medical Holdings Inc. EFH is employed by ASEP and receives salary while REWH holds an executive position and is on the Board of ASEP. TVFE, CB, DP, CRR, KS and UOH report no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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