制备具有改良抗逆转录病毒特征的纳米结构卡博特韦前药。
Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles.
机构信息
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
出版信息
Biomaterials. 2018 Jan;151:53-65. doi: 10.1016/j.biomaterials.2017.10.023. Epub 2017 Oct 15.
Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB). MCAB formed crystals that were formulated into nanoparticles (NMCAB) of stable size and shape facilitating avid monocyte-macrophage entry, retention and reticuloendothelial system depot formulation. Drug release kinetics paralleled sustained protection against HIV-1 challenge. After a single 45 mg/kg intramuscular injection to BALB/cJ mice, the NMCAB pharmacokinetic profiles was 4-times greater than that recorded for CAB LAP. These observations paralleled replicate measurements in rhesus macaques. The results coupled with improved viral restriction in human adult lymphocyte reconstituted NOD/SCID/IL2Rγc mice led us to conclude that NMCAB can improve biodistribution and viral clearance profiles upon current CAB LAP formulations.
长效注射（LAP）抗逆转录病毒药物在治疗和预防 HIV-1 感染方面引起了相当大的兴趣。一种新的 LAP 是卡博特韦（CAB），一种高效的整合酶抑制剂，半衰期长达 54 天，允许每两个月进行一次注射。尽管具有出色的特性，但大剂量给药、注射部位反应和低体液药物浓度会影响病毒感染和易感人群的广泛使用。为了改善药物输送特性，我们创建了一个豆蔻酰化的 CAB 前药（MCAB）。MCAB 形成了晶体，这些晶体被制成具有稳定大小和形状的纳米颗粒（NMCAB），促进单核细胞-巨噬细胞的摄取、保留和网状内皮系统的储存制剂。药物释放动力学与对 HIV-1 攻击的持续保护相平行。在 BALB/cJ 小鼠中单次肌肉注射 45mg/kg 的 NMCAB 后，其药代动力学特征比 CAB LAP 记录的高出 4 倍。这些观察结果与恒河猴的重复测量结果一致。这些结果加上在人类成人淋巴细胞重建的 NOD/SCID/IL2Rγc 小鼠中改善的病毒限制，使我们得出结论，NMCAB 可以改善当前 CAB LAP 制剂的生物分布和病毒清除特征。
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