Acquired immune deficiency syndrome (AIDS) was first discovered in the 1980s, since then, human immunodeficiency virus (HIV) infection and AIDS have become global health, social, and economic concerns. HIV was identified as the cause of AIDS in 1985, and this launched a wide-reaching effort to understand its biology. The knowledge acquired from these vast research efforts contributed to the development of modern therapeutic and preventative treatment strategies. According to recent data from the United Nations Program on HIV/AIDS (UNAIDS), the ratio of infected people to AIDS- related deaths has decreased because of the expanding access to antiretroviral drugs (ARVs). The application of ARVs to HIV+ patients increases patients’ lifespans and improves the quality of life. Remaining as an incurable disease, expanding access to antiretroviral drugs and using prevention strategies are the best options to control the HIV pandemic for now. Treatment strategies with ARVs, however, are not sufficient to adequately address the HIV pandemic. Traditional combinational antiretroviral therapies (cART) for HIV treatment are limited by multiple drawbacks such as possible toxicity, limited drug concentrations, drug resistance, and viral rebound. Additionally, inadequate physicochemical properties of ARVs, such as poor solubility, permeability, and bioavailability, lead to limited absorption and biodistribution, resulting in poor clinical outcomes. Patient compliance and suboptimal efficacy lead to the development of resistant viruses and viral reservoirs. The presence of HIV reservoirs would cause viral rebound two to four weeks after terminating treatments. The complexity of reservoir structure, prolonged cell half-life, and the latent HIV viruses complicate HIV treatments iii targeting viral reservoirs. cART exhibits insufficient efficacy towards reservoir sites because of biological barriers and poor physicochemical properties. These problems highlight an urgent need for novel treatment strategies that are safe and effective to address HIV reservoirs. Innovative and improved delivery systems have been proposed over the years, especially lipid-formulations. Lipid formulations have emerged as promising vehicles owing to their ability to encapsulate molecules with poor solubility and bioavailability, improve active targeting, prolong circulation time, and sustain drug release. Cell-mediated delivery strategy have posed the obstacles of insufficient drug transport and safety. Macrophages, the very same cells that carry the HIV virus, could reach tissues that would otherwise have little or no drug penetration. Macrophages can protect drugs from metabolic degradation with large quantities of drugs for delivery. Activated macrophages express the folate receptor, a potential targeting moiety. In this study, I intended to develop a novel folate-decorated nanoemulsion (FA- NE) for the delivery of ARVs to HIV infected macrophages. To reach the goal, I focused on two goals: (1) construction of a nanocarrier capable of encapsulating ARV drugs with physiological properties suitable for use in drug delivery and (2) enhancement of delivery to HIV infected macrophages. In Chapter 2, I discuss the rationale for nanoART for HIV treatments. I introduce current HIV treatments and their drawbacks, notably the viral rebound due to limited drug concentration in viral reservoirs. Then I explain why nanotechnology would be a promising strategy for HIV treatment and provide examples of nanomedicine. In all iv cases, however, cell uptake and drug release were limited or complicated by toxicity, which is a significant issue for a validated delivery system that are safe and effective. In chapter 3, I introduce the design and development of the FA-NE. This system includes (1) an oil core to encapsulate antiretroviral drugs that are highly hydrophobic, (2) a lipid monolayer to protect the oil core and to form nanoemulsion (3) folate for target. The system was prepared using the emulsification solvent evaporation method, developed and optimized based on physical properties, including size, PDI, zeta potential, and other in vitro characterizations, such as encapsulation efficacy, drug loading, stability, and drug release. Chapter 4 is a continuation of the work done in Chapter 3 and focuses on the enhancement of cellular uptake with folate overexpression cell models. A lipopolysaccharide (LPS) activated macrophages was built and utilized for intracellular drug release and retention evaluations. In Chapter 5, cytotoxicity and antiretroviral efficacy studies are described. With the conclusion drawn in Chapter 4, I was curious if the enhanced cellular uptake can be translated into improved efficacy. As a result, collaborated with Dr. Kamel Khalili, School of Medicine, Temple University, we evaluated antiretroviral efficacy with an HIV indicator cell and monocyte-derived-macrophages from human donors. Furthermore, I performed cytotoxicity assay to evaluate this nanoemulsion system safety profile. Chapter 6 summarizes the highlights and conclusions of this project and provides suggestions for the future. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/565 |
| Date | January 2020 |
| Creators | Wu, Di |
| Contributors | Wong, Ho-Lun, Blass, Benjamin E., Fassihi, Reza, Liang, Bo |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 150 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/547, Theses and Dissertations |
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