Di Martino Maria Teresa, Arbitrio Mariamena, Fonsi Massimiliano, Erratico Claudio Alberto, Scionti Francesca, Caracciolo Daniele, Tagliaferri Pierosandro, Tassone Pierfrancesco
Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy.
Consiglio Nazionale delle Ricerche (CNR) - Istituto per la Ricerca e l'Innovazione Biomedica (IRIB)- Section of Catanzaro, 88100 Catanzaro, Italy.
Cancers (Basel). 2019 Dec 19;12(1):27. doi: 10.3390/cancers12010027.
LNA-i-miR-221 is a novel phosphorothioate backbone 13-mer locked nucleic acid oligonucleotide-targeting microRNA-221 designed for the treatment of human malignancies. To understand the pharmacokinetic properties of this new agent, including unbound/total clearance, we investigated the LNA-i-miR-221 protein binding in three different species, including rat (Sprague-Dawley), monkey (Cynomolgus), and human. To this end, we generated a suitable ultrafiltration method to study the binding of LNA-i-miR-221 to plasma proteins. We identified that the fraction of LNA-i-miR-221 (at concentration of 1 and 10 µM) bound to rat, monkey, and human plasma proteins was high and ranged from 98.2 to 99.05%. This high protein binding of LNA-i-miR-221 to plasma proteins in all the species tested translates into a pharmacokinetic advantage by preventing rapid renal clearance. The integration of these results into multiple allometric interspecies scaling methods was then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, thereby providing a framework for definition of safe starting and escalation doses and moving towards a first human clinical trial of LNA-i-miR-221.
LNA-i-miR-221是一种新型的硫代磷酸酯骨架13聚体锁定核酸寡核苷酸，靶向微小RNA-221，用于治疗人类恶性肿瘤。为了解这种新药的药代动力学特性，包括非结合/总清除率，我们研究了LNA-i-miR-221在三种不同物种（大鼠（Sprague-Dawley）、猴子（食蟹猴）和人类）中的蛋白结合情况。为此，我们开发了一种合适的超滤方法来研究LNA-i-miR-221与血浆蛋白的结合。我们发现，LNA-i-miR-221（浓度为1和10 μM）与大鼠、猴子和人类血浆蛋白的结合比例很高，范围在98.2%至99.05%之间。在所有测试物种中，LNA-i-miR-221与血浆蛋白的这种高蛋白结合通过防止快速肾清除转化为药代动力学优势。然后，将这些结果整合到多种异速生长种间缩放方法中，以推断LNA-i-miR-221在人体内的药代动力学，从而为确定安全的起始剂量和递增剂量提供框架，并朝着LNA-i-miR-221的首次人体临床试验迈进。
