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.

中文翻译：

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天然和纳米制剂先天防御调节肽 1002 的生物分布

先天防御调节剂-1002 (IDR-1002) 是一种合成肽，具有良好的免疫调节和抗生物膜特性。围绕其在细胞和分子水平上的作用机制及其在多种感染和炎症模型中的功效，存在着大量的工作。然而，人们对它在活生物体中的吸收、分布和排泄知之甚少。在这里，我们使用核示踪技术对 IDR-1002 的镓 67 放射性标记衍生物进行了全面的生物分布评估。将不同剂量水平的放射性示踪剂（2-40 mg/kg）注入血液、腹膜腔和皮下组织，或滴入肺部。该肽在所有皮下和腹膜内剂量下均具有良好的耐受性，尽管较高的水平与组织内肽的吸收动力学延迟和沉淀有关。气管内低剂量会迅速被全身吸收，剂量水平的小幅增加是致命的。静脉注射的剂量在较低水平时会迅速从血液中清除，随着剂量的增加，会产生毒性，大部分剂量会积聚在肺组织内。为了提高生物相容性并延长其在血液中的循环，IDR-1002 被进一步配制到高分子量超支化聚甘油 (HPG) 聚合物上。以 5:1 和 10:1 肽与聚合物比例制备的构建体具有胶体稳定性，保持了肽有效负载的生物学特征，并有助于减少红细胞裂解。 5:1 构建体在血液中循环良好，但较高的肽负载量与网状内皮系统的快速清除有关。许多肽面临药代动力学和生物相容性挑战，但含有 HPG 的制剂有可能克服这些限制。