DOI
https://doi.org/10.25772/WC9M-R036
Author ORCID Identifier
0000-0002-6296-3916
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Engineering
First Advisor
Laleh Golshahi
Abstract
Intranasal drug delivery offers a promising alternative to systemic administration for treating central nervous system (CNS) disorders such as NeuroAIDS by bypassing the blood-brain barrier and directly targeting the brain via the nose-to-brain route. However, challenges including enzymatic degradation in the nasal mucosa, low permeability, mucociliary clearance, and complex nasal anatomy must be overcome. This dissertation combines two complementary studies to address these barriers and enhance the intranasal delivery of combination antiretroviral therapy (cART).
To overcome the first three challenges, the first 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 12% while maintaining monodispersity and 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.
The second study addressed the challenge of effectively targeting the olfactory region of the nasal cavity, which is the primary deposition site for nose-to-brain drug delivery. To enhance delivery to this region, we developed a nasal device that combines a vibrating mesh nebulizer with a gas-propelled aerosol mixer. Using the optimized PEGylated cART-loaded SLNs (cART-SLNs) from the first study, we first evaluated the impact of nebulization on the nanoparticle size distribution and observed minimal changes, confirming the device’s suitability for delivering cART-SLNs. We then conducted deposition studies using fluorescein sodium salt as a model fluorescent drug in place of cART-SLNs. These studies explored the effects of auxiliary airflow (10–40 LPM), insertion tip geometry (wide vs. narrow), and head angle across three anatomically accurate nasal models. The results showed that greater airflow rates, narrower insertion tips, and higher sagittal angles significantly enhanced deposition in the olfactory region, with up to 10 percent of the recovered dose reaching the target site. This approach also reduced deposition in the less absorptive anterior nasal region, potentially improving overall targeting efficiency. This study provides the first in vitro demonstration of a gas-propelled vibrating mesh nebulizer specifically designed for the olfactory delivery of cART-SLNs. The findings underscore the importance of auxiliary airflow and insertion geometry in optimizing nose-to-brain (N-t-B) delivery.
Together, these two studies offer critical insights into overcoming barriers to nose-to-brain delivery of HIV therapies. PEGylated SLNs enhance drug stability, permeability, and uptake, while the optimized nasal delivery device improves the targeting of the olfactory region. By integrating advanced nanocarriers with innovative aerosol delivery techniques, this work lays a foundation for future in vivo studies and eventual clinical applications. The research advances the feasibility of treating NeuroAIDS via the intranasal route and opens the door to broader therapeutic opportunities for CNS disorders.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-7-2025
Included in
Other Materials Science and Engineering Commons, Other Mechanical Engineering Commons, Pharmaceutics and Drug Design Commons