Biodistribution and toxicity of innate defense regulator 1018 (IDR-1018)
Research output: Contribution to journal › Journal article › Research › peer-review
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.
| Original language | English |
|---|---|
| Journal | European Journal of Pharmaceutics and Biopharmaceutics |
| Volume | 179 |
| Pages (from-to) | 11-25 |
| ISSN | 0939-6411 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Funding Information:
This research was made possible by grants from the Lundbeck Foundation of Denmark (Lundbeck Foundation Professorship to UOH, No. 2014-4176), the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant to UOH, No. 2018-04958) and the Canadian Institutes of Health Research (CIHR, Foundation Grant to REWH, No. FDN-154287). Funding for the VECTor preclinical imaging platform at the UBC in vivo Imaging Centre was provided through a grant, in part to UOH, from the Canada Foundation for Innovation (CFI, No. 25413). KS acknowledges the support of Isologic Radiopharmaceutiques Novatuers for the supply of the radioisotope.
Funding Information:
This research was made possible by grants from the Lundbeck Foundation of Denmark (Lundbeck Foundation Professorship to UOH, No. 2014-4176), the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant to UOH, No. 2018-04958) and the Canadian Institutes of Health Research (CIHR, Foundation Grant to REWH, No. FDN-154287). Funding for the VECTor preclinical imaging platform at the UBC in vivo Imaging Centre was provided through a grant, in part to UOH, from the Canada Foundation for Innovation (CFI, No. 25413). KS acknowledges the support of Isologic Radiopharmaceutiques Novatuers for the supply of the radioisotope. REWH held a Canada Research Chair in Health and Genomics and a UBC Killam Professorship. TVFE received support from a Killam Doctoral Fellowship and a 4YF Fellowship from the University of British Columbia (UBC). CB received support from NSERC via an Undergraduate Student Research Award (USRA). DP received a Cystic Fibrosis Canada Postdoctoral Fellowship and a Michael Smith Foundation for Health Research - Research Trainee Award. We would like to thank Maryam Osooly for helping to administer the radiotracers intravenously. We are grateful to the veterinary staff, particularly Dr. Laura Mowbray, at the UBC Center for Comparative Medicine (CCM) for all their support during animal studies. And finally, we would like to thank Jana Hodasova from UBC CCM for all the help and expertise she provided with the histology studies.
Funding Information:
REWH held a Canada Research Chair in Health and Genomics and a UBC Killam Professorship. TVFE received support from a Killam Doctoral Fellowship and a 4YF Fellowship from the University of British Columbia (UBC). CB received support from NSERC via an Undergraduate Student Research Award (USRA). DP received a Cystic Fibrosis Canada Postdoctoral Fellowship and a Michael Smith Foundation for Health Research - Research Trainee Award.
- Host defence peptide, Isotope, Nuclear imaging, Pharmacokinetics, Radiotracer, SPECT/CT
Research areas
ID: 318707089