Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.

中文翻译：

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Darunavir 纳米制剂抑制巨噬细胞中的 HIV 发病机制并改善小鼠大脑的药物输送

尽管抗逆转录病毒疗法（ART）可以抑制外周HIV，但由于大脑中ART药物水平不足，患者仍然患有神经HIV。因此，本研究重点开发一种基于聚乳酸-乙醇酸（PLGA）纳米粒子的ART药物递送系统，用于采用鼻内途径的达芦那韦（DRV），该系统可以克服药物代谢稳定性和血脑屏障（BBB）的限制) 渗透性。对 PLGA-DRV 的理化性质进行了表征。结果表明，PLGA-DRV 制剂直接抑制 U1 巨噬细胞中的 HIV 复制，并且在 BBB 存在的情况下，不会诱导细胞毒性。然而，PLGA-DRV 并没有比单独的 DRV 更能抑制 HIV 复制。值得注意的是，在 U1 细胞中用 DRV 或 PLGA-DRV 处理后，总抗氧化能力保持不变。与单独的 DRV 相比，PLGA-DRV 进一步减少了活性氧，表明该制剂减少了氧化应激。 HIV 感染通常会增加氧化应激，导致炎症加剧。尽管PLGA-DRV制剂没有进一步减少炎症反应，但该制剂没有在HIV感染的U1巨噬细胞中引起炎症反应。正如预期的那样，体外实验显示 PLGA-DRV 对 U1 巨噬细胞的 DRV 渗透性比单独的 DRV 更高。重要的是，体内实验，特别是在野生型小鼠中鼻内施用 PLGA-DRV，证明与游离 DRV 相比，DRV 的脑与血浆比率显着增加。总体而言，这项研究的结果证明了 PLGA-DRV 纳米制剂在减少巨噬细胞中 HIV 发病机制和增强药物向大脑输送方面的潜力，为治疗 HIV 相关神经系统疾病提供了一条有希望的途径。