PEGylated solid lipid nanoparticles for the intranasal delivery of combination antiretroviral therapy composed of Atazanavir and Elvitegravir to treat NeuroAIDS

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.