Biodistribution of Native and Nanoformulated Innate Defense Regulator Peptide 1002

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.