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Biodistribution of Native and Nanoformulated Innate Defense Regulator Peptide 1002.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2024 Jun 03; Vol. 21 (6), pp. 2751-2766. Date of Electronic Publication: 2024 May 01. - Publication Year :
- 2024
-
Abstract
- Innate defense regulator-1002 (IDR-1002) is a synthetic peptide with promising immunomodulatory and antibiofilm properties. An appreciable body of work exists around its mechanism of action at the cellular and molecular level, along with its efficacy across several infection and inflammation models. However, little is known about its absorption, distribution, and excretion in live organisms. Here, we performed a comprehensive biodistribution assessment with a gallium-67 radiolabeled derivative of IDR-1002 using nuclear tracing techniques. Various dose levels of the radiotracer (2-40 mg/kg) were administered into the blood, peritoneal cavity, and subcutaneous tissue, or instilled into the lungs. The peptide was well tolerated at all subcutaneous and intraperitoneal doses, although higher levels were associated with delayed absorption kinetics and precipitation of the peptide within the tissues. Low intratracheal doses were rapidly absorbed systemically, and small increases in the dose level were lethal. Intravenous doses were rapidly cleared from the blood at lower levels, and upon escalation, were toxic with a high proportion of the dose accumulating within the lung tissue. To improve biocompatibility and prolong its circulation within the blood, IDR-1002 was further formulated onto high molecular weight hyperbranched polyglycerol (HPG) polymers. Constructs prepared at 5:1 and 10:1 peptide-to-polymer ratios were colloidally stable, maintained the biological profile of the peptide payload and helped reduce red blood cell lysis. The 5:1 construct circulated well in the blood, but higher peptide loading was associated with rapid clearance by the reticuloendothelial system. Many peptides face pharmacokinetic and biocompatibility challenges, but formulations such as those with HPG have the potential to overcome these limitations.
- Subjects :
- Animals
Female
Male
Mice
Gallium Radioisotopes pharmacokinetics
Gallium Radioisotopes chemistry
Gallium Radioisotopes administration & dosage
Immunity, Innate drug effects
Lung metabolism
Lung drug effects
Mice, Inbred C57BL
Tissue Distribution
Antimicrobial Cationic Peptides pharmacokinetics
Antimicrobial Cationic Peptides chemistry
Nanoparticles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 21
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 38693707
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.3c01169