Abstract:
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.
摘要:
人cathelicidinLL-37,一种阳离子宿主防御肽(CHDP),有几个重要的生理作用,包括抗菌活性,免疫调节,伤口愈合,并且正在作为几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的作用得到了很好的研究,外源施用的LL-37的生物分布是鲜为人知的。在这里,我们使用核成像技术在48小时内在健康小鼠中评估LL-37的镓-67标记变体的生物分布。当作为静脉推注给药时,刚刚超过20微克,LL-37型放射性示踪剂被迅速从血液中清除,主要是肝脏,而剂量的相当一部分暂时分配到肺部。当以相同的剂量水平皮下给药时,放射性示踪剂在两相动力学模型下被系统吸收,并且主要在肾脏被清除。摄取富含免疫细胞的部位,比如淋巴结和脾脏,观察到两种给药途径。游离镓-67的扫描也作为对照进行。从这项研究中获得了有关外源施用LL-37的生物分布的重要临床前见解,这可以帮助理解这种和相关的阳离子宿主防御肽。