Date of Award
8-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Pharmaceutical Sciences
Track
Pharmaceutics
Research Advisor
Santosh Kumar, Ph.D.
Committee
Alina Cernasev, PhD, PharMD; Hao Chen, PhD; Harry Kochat, PhD; Santosh Kumar, PhD; Bernd Meibohm, PhD
Keywords
HIV-associated Neurocognitive Disorder; Intranasal; Antiretroviral Therapy; drug delivery; nanoparticles; Extracellular Vesicles; Hybrid nanoparticles
Abstract
Despite the significant reduction in HIV prevalence and improvement in life expectancy achieved through the availability of widespread antiretroviral therapy (ART), there remains no definitive cure for HIV. Further, HIV infects the brain as early as eight days after initial peripheral infection leading to neuroHIV and subsequently neuronal damage and cognitive impairment. HIV can enter the brain through several mechanisms, including the migration of infected immune cells (Trojan Horse Mechanism), direct infection of endothelial cells, and cytokine-mediated disruption of the blood-brain barrier (BBB). Consequently, HIV-associated neurocognitive disorder (HAND) remains a significant challenge in the ART era, with an estimated prevalence of 42.6% among people living with HIV. The persistence of HAND is primarily due to inadequate ART penetration into the central nervous system, allowing ongoing viral replication and chronic inflammation, which contribute to cognitive decline and neuronal damage in the brain. Addressing HAND requires strategies that improve ART delivery across the blood-brain barrier and effectively target both viral replication and the resulting inflammatory responses. One of the objectives of this study was to develop a drug delivery system that enhances the penetration of ART drugs through the BBB while safely suppressing viral replication and inflammatory responses in the brain, ensuring appropriate biocompatibility. Additionally, we aimed to establish an evaluation platform for ART therapy to assess the safety and efficacy of treating HAND from in vitro to in vivo studies. Our hypothesis posits that the selected ART drug, Darunavir (DRV), will exhibit improved BBB penetration when encapsulated in nanoformulations, combined with an optimized dosing strategy, thereby enhancing DRV distribution in the EcoHIV mouse brain and alleviating HAND symptoms. In Aim 1, we investigated the distribution of DRV to the brain via intranasal (IN) and intravenous (IV) routes in mice. IN significantly enhanced brain concentrations while reducing plasma and liver levels compared to IV. These findings suggest IN delivery as a promising approach for treating HIV in brain reservoirs. In Aim 2, we developed a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART delivery system for DRV via IN to enhance metabolic stability and BBB permeability. PLGA-DRV suppressed HIV replication and inflammatory response, which was similar to that of DRV alone, in U1 macrophages without causing cytotoxicity. However, PLGA-DRV reduced oxidative stress more than DRV alone. In vitro, PLGA-DRV showed higher cellular uptake to U1 macrophages than DRV alone. Furthermore, in vivo, PLGA-DRV via the IN route increased the brain-to-plasma ratio of DRV, highlighting its potential for treating HIV-related neurological disorders. In Aim 3, to further improve nanoparticle biocompatibility, we developed an Extracellular Vesicle-Liposome Darunavir (EV-Lip-DRV) formulation through thin film hydration and extrusion. This formulation exhibited good encapsulation efficiency, appropriate particle size, and surface charge for brain drug delivery. EV-Lip-DRV demonstrated hemocompatibility, sustained 24-hour drug release, significant HIV suppression in U1 macrophages, and modulation of oxidative and neuroinflammatory responses. Furthermore, EV-Lip-DRV formulation enhanced brain delivery and improved cognitive and motor functions in EcoHIV mice compared to DRV and/or EV-Lip control alone. These findings highlight EV-Lip-DRV as a promising vehicle for brain-targeted antiretroviral therapy. In conclusion, this study demonstrates that intranasal administration of nanoparticles, especially EV-Lip-DRV, is a promising therapeutic strategy to enhance ART drug distribution to the brain, mitigate HAND, and improve overall outcomes of HIV treatment.
DOI
10.21007/aetd.cghs.2024.0009
Recommended Citation
Zhou, Lina , "Development of a Novel Drug Delivery Platform to Treat HIV-Associated Neurocognitive Disorder" (2024). Alternative Theses and Dissertations (AETDs). Paper 9. http://dx.doi.org/10.21007/aetd.cghs.2024.0009.
https://dc.uthsc.edu/aetd/9