| dc.description.abstract |
<p>There were 2.5 million people newly infected with HIV in 2007, clearly motivating
the need for additional novel prevention methods. In response, topical vaginal antimicrobials,
or microbicides, are being developed. These products aim to stop HIV transmission
through local, vaginal delivery of antiviral compounds. To succeed, microbicides require
a potent active compound within a well-engineered delivery vehicle.</p><p>A well-engineered
delivery vehicle provides an antiviral compound with the greatest opportunity to interact
with HIV and/or infected cells, thereby increasing overall microbicide effectiveness.
The theoretical and experimental investigations within this dissertation are concerned
with the study of HIV and active compound transport within microbicide delivery vehicles
and with the mechanisms by which these transport processes can be affected to maximize
viral neutralization. To initially investigate the factors contributing to microbicide
effectiveness, a combined pharmacokinetic and pharmacodynamic model of HIV transport
and neutralization within a microbicide product was created. Model results suggested
that thin (~100µm) layers of microbicide product may protect against HIV infection.
Model results also indicated that a specific and engineerable property of delivery
vehicles - the ability to restrict viral transport - may increase the overall effectiveness
of a microbicide. Two new experimental assays were developed to test the hypothesis
that delivery vehicles can slow viral transport. First, a novel methodology was created
to measure particle diffusion over length scales relevant to microbicide delivery
(50-500µm). Results showed that current vehicles significantly restrict the transport
of small molecules and proteins. The second assay was designed to test HIV transport
in a biologically relevant, layered (fluid-microbicide-tissue) configuration of a
microbicide product in vivo; infectious HIV was placed above a thin layer of a microbicide
delivery vehicle. Assay results showed that HIV transport is significantly slowed
by two different placebo gels. This experimental confirmation of viral restriction
in hydrogels, combined with the theoretical finding that viral restriction increased
microbicide effectiveness, strongly motivates the future development of new delivery
vehicles that intentionally slow viral transport. These new experimental methodologies
can also be used to screen and compare future delivery vehicles to produce optimal
microbicide products.</p><p>Finally, a two-dimensional, computational finite-element
vaginal model was created to evaluate the transport of drugs from an intravaginal
ring. This model determined that while IVRs may be effective in the delivery of antiviral
compound, their performance is influenced by the flow of vaginal fluid. The analysis
also warns about the potential for local toxicity. </p><p>Well-engineered delivery
vehicles are an essential component to microbicide performance because they maximize
the opportunities for active compounds to interact with and neutralize HIV. The studies
in this dissertation demonstrate that delivery vehicles have a significant effect
on active compound and HIV transport. To create an effective microbicide, vehicle
effects on transport processes must be well understood, purposefully engineered, and
carefully optimized to ensure maximal interactions between antiviral compounds and
virus. Directed engineering of delivery vehicles contribute to the foundation for
microbicide success.</p>
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