Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada; Department of Physics and Astronomy, Faculty of Science, University of British Columbia, Vancouver, Canada.
Eur J Pharm Biopharm. 2022 Oct;179:11-25. doi: 10.1016/j.ejpb.2022.08.004. Epub 2022 Aug 24.
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.
先天防御调节剂（IDR）是具有广谱抗感染特性的合成宿主防御肽（HDP），包括免疫调节、抗生物膜和直接抗菌活性。由于缺乏这些肽的药代动力学数据，阻碍了它们的发展，并且由于其作用机制依赖于肽在组织中的浓度，因此难以全面了解它们在体内的作用方式。在这里，我们着手详细定义一种特征明确的 IDR 分子 IDR-1018 的药代动力学。为了使该肽可追踪，我们用长寿命的伽马发射同位素镓-67 对其进行放射性标记。经过一系列的台架特性分析，放射性示踪剂以不同剂量水平（2.5-13 mg/kg）静脉内（IV）或皮下（SQ）给予健康小鼠。核成像和离体生物分布用于随时间量化放射性示踪剂在器官和组织中的摄取。当作为静脉内推注给药时，随着剂量的增加，放射性示踪剂的分布模式发生变化。在 2.5 mg/kg 时，肽的耐受性良好，在血液中循环不良，主要通过网状内皮系统清除。更高剂量（7 和 13 mg/kg）作为静脉内推注几乎立即因呼吸停止而致命；从这些动物的核扫描中观察到放射性示踪剂明显在肺部摄取，组织学检查发现肺部血管和肺泡广泛受损。当以 3 mg/kg 的剂量皮下给药时，放射性标记的 IDR-1018 从注射部位迅速吸收，并主要通过肾脏清除。除了 SQ 注射部位外，没有其他组织的浓度高于能够使该肽对大多数致病菌发挥直接抗菌作用的最小抑菌浓度。然而，组织浓度足以破坏微生物生物膜并改变宿主免疫反应。总体而言，这项研究表明，体内给予合成 IDR 肽最适合局部给药，这可以避免通过静脉内注射全身给药时观察到的与肽毒性相关的一些问题，这是通过制剂必须解决的问题。
