Kinman Loren, Bui Tot, Larsen Kay, Tsai Che-Chung, Anderson David, Morton William R, Hu Shiu-Lok, Ho Rodney J Y
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
J Acquir Immune Defic Syndr. 2006 Jun;42(2):155-61. doi: 10.1097/01.qai.0000214822.33905.87.
In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.
在接受高效抗逆转录病毒治疗的HIV感染者中，淋巴组织中可发现残留病毒。接受高效抗逆转录病毒治疗患者的淋巴结单核细胞中的茚地那韦浓度约为血液单核细胞中茚地那韦浓度的25%至35%，这表明药物不足导致了淋巴组织中的残留病毒。因此，我们研发了靶向淋巴组织的新型脂质 - 茚地那韦纳米颗粒。皮下注射这些纳米颗粒后，在外周和内脏淋巴结中，其提供的茚地那韦浓度比血浆茚地那韦浓度高250%至2270%。茚地那韦递送的改善体现在病毒RNA减少和CD4(+) T细胞反弹降低。本研究针对感染HIV的猕猴的淋巴组织中的茚地那韦优化了脂质纳米颗粒制剂。无论测试的脂质特性（电荷、流动性和空间修饰）如何，茚地那韦在pH 7.4时与脂质完全结合，但在pH 5.5或更低时会逆转。与先前的制剂相比，由二硬脂酰磷脂酰胆碱和甲基聚乙二醇 - 二硬脂酰磷脂酰乙醇胺（DSPC:mPEG - DSPE）组成的纳米颗粒在淋巴结中的茚地那韦水平高6倍，并增强了血液中的药物暴露。增强的抗HIV活性与改善的细胞内药物积累平行。总体而言，这些数据表明由DSPC:mPEG - DSPE组成的茚地那韦纳米颗粒提供了最有效的淋巴递送，并能最大程度地抑制淋巴组织中的病毒。
