Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB's effectiveness.

中文翻译：

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一种长达一年的缓释纳米配方卡博特拉韦前药。

长效卡博特拉韦 (CAB) 将抗逆转录病毒药物的给药从每天延长到每月。然而，给药量、注射部位反应和医疗保健监督是广泛使用的障碍。具有可控水解和组织外显率的泊洛沙姆包被的疏水性和亲脂性 CAB 前药的产生可以克服这些障碍。为此，将添加了 14、18 和 22 个碳链的脂肪酸酯 CAB 纳米晶体前药包裹在名为 NMCAB、NM2CAB 和 NM3CAB 的生物相容性表面活性剂中，并测试药物释放、活化、细胞毒性、抗逆转录病毒活性、药代动力学和生物分布。在小鼠和恒河猴中进行的具有 18 碳酯链 NM2CAB 的药代动力学研究显示血浆 CAB 水平高于蛋白质调整的 90% 抑制浓度长达一年。与 NMCAB 和 NM3CAB 相比，NM2CAB 在单次 45 mg/kg 体重肌肉注射后表现出延长的药物释放、血浆循环时间和组织药物浓度。这些前药修饰可以大大提高 CAB 的有效性。