Biodistribution and toxicity of innate defense regulator 1018 (IDR-1018)

Esposito, Tullio; Rodríguez‐Rodríguez, Cristina; Blackadar, Colin; Haney, Evan F.; Pletzer, Daniel; Hancock, Robert E. W.; Saatchi, Katayoun; Häfeli, Urs O.

doi:10.1016/j.ejpb.2022.08.004

Cited by 2 publications

(10 citation statements)

References 81 publications

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“…Following an IV bolus, 67 Ga-NOTA-IDR-1002 was rapidly cleared at the 2.2 mg/kg dose level, which is in line with our previous work with radiolabeled IDR-1018 as well as the broader HDP literature. − Acute respiratory toxicity and enhanced lung uptake were observed upon IV dose escalation of 67 Ga-NOTA-IDR-1002 in a similar manner as with IDR-1018 . Although the exact reasons for IDR-1002 toxicity was not explored further here, it may be due to lytic disruption of the blood/air exchange surfaces or embolic effects due to the peptide precipitating in the blood. ,− Both IDR-1002 and IDR-1018 displayed toxicity at relatively lower doses compared to other IDR peptides given intravenously, such as HH-2 (8 mg/kg in mice), IDR-1 (100 mg/kg in mice) and IMX942 (8 mg/kg in man) . The reason for these differences is poorly understood and warrants further investigation.…”

Section: Discussionsupporting

confidence: 83%

“…Extravascularly administered 67 Ga-NOTA-IDR-1002 at a low dosing level (2–3 mg/kg) was rapidly absorbed, in line with SQ IDR-1018 and IP Bac7 derivatives, , and then rapidly cleared renally. The delayed absorption rate and degree of peptide spread at the SQ injection site upon dose escalation of 67 Ga-NOTA-IDR-1002 was unexpected and may be attributed to local precipitation or lysis of the tissue as seen with SQ aurein2.2 and IDR-1018. , These local effects may further explain the delayed kinetics observed with the 39 mg/kg IP dose trial and the poor tolerability of IDR-1002 when instilled directly into the lungs above 2.5 mg/kg.…”

Section: Discussionmentioning

confidence: 80%

“…Radiolabeling was carried out by combining a 300-μL aliquot of NOTA-IDR-1002 (0.7–0.8 mg) with HEPES buffer (0.1 mL, 0.1 M, pH 7) and 30–100 MBq of 67 GaCl 3 in 0.1 M HCl (∼2 GBq/mL). Concentrated 67 GaCl 3 was prepared from clinical-grade 67 Ga-citrate as previously described . The radiolabeling reaction was allowed to proceed at 25 °C with 500 rpm mixing for 3–5 h. Due to the high RCC achieved (>95%), the obtained 67 Ga-NOTA-IDR-1002 was used without any additional purification steps.…”

Section: Methodsmentioning

confidence: 99%

“…60 A 5-molar excess of p-SCN-Bn-NOTA was then added in DMSO, and the reaction was allowed to proceed at 25 °C and 500 rpm mixing overnight. NOTA-IDR-1002 was isolated using a process previously described 31 where the modified peptide was trapped onto a silica gel cartridge and water was used to rinse away any unincorporated chelator. NOTA-IDR-1002 was then eluted using 0.25 mL fractions of 0.01 M HCl, which was monitored using a Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific) measuring absorbance at 280 nm.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…SPECT/CT imaging was conducted and analyzed as previously described 31,65 using a MILabs VECTor platform outfitted with an extra-ultrahigh sensitivity mouse pinhole collimator (MILabs; Houten, The Netherlands). 66,67 Acquisition times and details are provided in Supplemental Table 2.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Biodistribution of Native and Nanoformulated Innate Defense Regulator Peptide 1002

Esposito,

Blackadar,

et al. 2024

Mol. Pharmaceutics

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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 peptideto-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.

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