Bazargani Arya, Hejazi Mohammad, Fernandez Matthew, Cordeiro Arthur, Tsala Ebode Johanna, Lewinski Nastassja, da Rocha Sandro, Golshahi Laleh
College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA; School of Pharmacy, Virginia Commonwealth University, 410 N 12th St, Richmond, VA 23298, USA.
College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA.
Int J Pharm. 2025 Feb 10;670:125166. doi: 10.1016/j.ijpharm.2025.125166. Epub 2025 Jan 4.
Intranasal drug administration offers a promising strategy for delivering combination antiretroviral therapy (cART) directly to the central nervous system to treat NeuroAIDS, leveraging the nose-to-brain route to bypass the blood-brain barrier. However, challenges such as enzymatic degradation in the nasal mucosa, low permeability, and mucociliary clearance within the nasal cavity must first be addressed to make this route feasible. To overcome these barriers, this study developed solid lipid nanoparticles (SLNs) with varying PEGylation levels (0 %, 5 %, 10 %, and 15 % w/w of PEGylated lipid), co-encapsulated with Elvitegravir (EVG) and Atazanavir (ATZ) as an integrase and protease inhibitor, respectively. Pre-formulation studies confirmed the compatibility of the drugs with the excipients. Characterization showed that PEGylation reduces SLN size by approximately up to 12 % while maintaining monodispersity and a high encapsulation efficiency of over 99 % for both EVG and ATZ in their amorphous forms. Incubation of the formulations in artificial nasal mucus revealed that increased PEGylation consistently reduces nanoparticle aggregation and mean aggregate size, suggesting improved SLN stability in the mucus. Importantly, higher PEGylation levels significantly enhanced model drug permeability across the nasal mucus barrier by up to 10-fold. Lastly, cellular uptake studies using the RPMI 2650 nasal epithelial cell line indicated that PEGylation does not reduce nanoparticle uptake rates. These findings highlight the potential of PEGylated SLNs as an effective vehicle for enhancing the intranasal delivery of cART to treat NeuroAIDS. However, further in vivo studies are needed to confirm the brain targeting potential of this formulation.
鼻内给药提供了一种很有前景的策略，可将联合抗逆转录病毒疗法（cART）直接递送至中枢神经系统以治疗神经艾滋病，利用鼻脑途径绕过血脑屏障。然而，要使该途径可行，必须首先解决诸如鼻腔黏膜中的酶降解、低渗透性以及鼻腔内的黏液纤毛清除等挑战。为克服这些障碍，本研究开发了具有不同聚乙二醇化水平（聚乙二醇化脂质的重量比分别为0%、5%、10%和15%）的固体脂质纳米粒（SLN），并分别共包封了作为整合酶抑制剂的埃替格韦（EVG）和作为蛋白酶抑制剂的阿扎那韦（ATZ）。处方前研究证实了药物与辅料的相容性。表征显示，聚乙二醇化可使SLN尺寸减小约12%，同时保持单分散性，且对于无定形形式的EVG和ATZ，二者的包封效率均超过99%。将制剂在人工鼻黏液中孵育后发现，聚乙二醇化程度增加会持续降低纳米颗粒的聚集和平均聚集体尺寸，表明SLN在黏液中的稳定性提高。重要的是，较高的聚乙二醇化水平可使模型药物透过鼻黏液屏障的渗透性显著提高多达10倍。最后，使用RPMI 2650鼻上皮细胞系进行的细胞摄取研究表明，聚乙二醇化不会降低纳米颗粒的摄取率。这些发现突出了聚乙二醇化SLN作为增强鼻内递送cART以治疗神经艾滋病的有效载体的潜力。然而，需要进一步的体内研究来证实该制剂的脑靶向潜力。
