miR-221 is overexpressed in several malignancies where it promotes tumor growth and survival by interfering with gene transcripts, including p27Kip1, PUMA, PTEN, and p57Kip2. We previously demonstrated that a novel 13-mer miR-221 inhibitor (locked nucleic acid [LNA]-i-miR-221) exerts antitumor activity against human cancer with a pilot-favorable pharmacokinetics and safety profile in mice and non-naive monkeys. In this study, we report a non-good laboratory practice (GLP)/GLP dose-finding investigation of LNA-i-miR-221 in Sprague-Dawley rats. The safety of the intravenous dose (125 mg/kg/day) for 4 consecutive days, two treatment cycles, was investigated by a first non-GLP study. The toxicokinetics profile of LNA-i-miR-221 was next explored in a GLP study at three different doses (5, 12.5, and 125 mg/kg/day). Slight changes in blood parameters and histological findings in kidney were observed at the highest dose. These effects were reversible and consistent with an in vivo antisense oligonucleotide (ASO) class effect. The no-observed-adverse-effect level (NOAEL) was established at 5 mg/kg/day. The plasma exposure of LNA-i-miR-221, based on C₀ (estimated concentration at time 0 after bolus intravenous administration) and area under the curve (AUC), suggested no differential sex effect. Slight accumulation occurred between cycles 1 and 2 but was not observed after four consecutive administrations. Taken together, our findings demonstrate a safety profile of LNA-i-miR-221 in Sprague-Dawley rats and provide a reference translational framework and path for the development of other LNA miR inhibitors in phase I clinical study.

miR-221在几种恶性肿瘤中过表达，通过干扰p27Kip1，PUMA，PTEN和p57Kip2等基因转录本来促进肿瘤的生长和存活。我们先前证明了一种新型的13-mer miR-221抑制剂（锁核酸[LNA] -i-miR-221）在小鼠和非初生猴中具有抗癌活性，并具有先导性的药代动力学和安全性。在这项研究中，我们报告了Sprague-Dawley大鼠中LNA-i-miR-221的非良好实验室规范（GLP）/ GLP剂量寻找研究。首次非GLP研究研究了连续两个治疗周期连续4天静脉注射剂量（125 mg / kg /天）的安全性。接下来，在GLP研究中以三种不同剂量（5、12.5和125 mg / kg / day）研究了LNA-i-miR-221的毒代动力学。在最高剂量下观察到血液参数的轻微变化和肾脏的组织学发现。这些影响是可逆的，并且与体内反义寡核苷酸（ASO）类作用。未观察到的不良反应水平（NOAEL）确定为5 mg / kg /天。LNA-i-miR-221的血浆暴露（基于C ₀（推注静脉给药后时间0的估计浓度））和曲线下面积（AUC）表明，没有性别差异。在第1和第2周期之间发生了轻微的积累，但连续四次给药后未观察到。综上所述，我们的发现证明了LNA-i-miR-221在Sprague-Dawley大鼠中的安全性，并为I期临床研究中其他LNA miR抑制剂的开发提供了参考翻译框架和途径。