Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
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. 2024 Sep;202:114398. doi: 10.1016/j.ejpb.2024.114398. Epub 2024 Jul 5.
Human cathelicidin LL-37, a cationic host defense peptide (CHDP), has several important physiological roles, including antimicrobial activity, immune modulation, and wound healing, and is a being investigated as a therapeutic candidate for several indications. While the effects of endogenously produced LL-37 are well studied, the biodistribution of exogenously administered LL-37 are less known. Here we assess the biodistribution of a gallium-67 labeled variant of LL-37 using nuclear imaging techniques over a 48 h period in healthy mice. When administered as an intravenous bolus just over 20 µg, the LL-37-based radiotracer was rapidly cleared from the blood, largely by the liver, while an appreciable fraction of the dose temporarily distributed to the lungs. When administered subcutaneously at the same dose level, the radiotracer was absorbed systemically following a two-phase kinetic model and was predominately cleared renally. Uptake into sites rich in immune cells, such as the lymph nodes and the spleen, was observed for both routes of administration. Scans of free gallium-67 were also performed as controls. Important preclinical insights into the biodistribution of exogenously administered LL-37 were gained from this study, which can aid in the understanding of this and related cationic host-defense peptides.
人源杀菌肽 LL-37 是一种阳离子宿主防御肽 (CHDP)，具有多种重要的生理作用，包括抗菌活性、免疫调节和伤口愈合，目前正在作为多种适应症的治疗候选药物进行研究。虽然内源性产生的 LL-37 的作用已经得到了很好的研究，但外源性给予的 LL-37 的生物分布知之甚少。在这里，我们使用核成像技术在健康小鼠中评估了一种放射性标记的 LL-37 变体在 48 小时内的生物分布。当作为静脉内推注给予略高于 20μg 的剂量时，基于 LL-37 的放射性示踪剂很快从血液中清除，主要通过肝脏，而相当一部分剂量暂时分布到肺部。当以相同的剂量水平皮下给予时，放射性示踪剂在体内通过两阶段动力学模型被吸收，并主要通过肾脏清除。两种给药途径都观察到放射性示踪剂在富含免疫细胞的部位（如淋巴结和脾脏）的摄取。还进行了游离镓 67 的扫描作为对照。本研究获得了对外源性给予的 LL-37 的生物分布的重要临床前见解，这有助于理解这种和相关的阳离子宿主防御肽。
