Drug delivery to the female reproductive tract to prevent sexually transmitted infection and unwanted pregnancy

Thesis (Ph.D.)--University of Washington, 2023Strategies to prevent HIV infection in the female reproductive tract that offer local drug delivery, long-term efficacy, and high user acceptability are critical in pursuit of alleviating the global burden of HIV among people with female reproductive anatomy. Current pre-exposure prophylaxis (PrEP) regimens demand daily oral administration and fall short in terms of their adherence, discretion, and accessibility. Long-acting reversible contraception (LARC) modalities demonstrate sustained delivery of active pharmaceutical agents that partition to the female reproductive tract and therefore provide a technological premise for sustained, adherence independent antiretroviral (ARV) drug delivery. Here, we develop a novel multipurpose prevention technology (MPT) that incorporates ARV delivery onto a copper intrauterine device (IUD) frame. In the first aim of this dissertation, we evaluate global access and utilization of family planning and STI/HIV prevention services in order to motivate the demand for a long-acting MPT device. This work informs the design criteria of an integrated ARV-releasing copper IUD that can deliver drug at relevant clinical doses to the vaginal mucosa to protect against HIV for at least one year. In the second aim, we describe the fabrication and characterization of matrix and reservoir-type drug delivery systems (DDS) for sustained release of multiclass ARVs. We demonstrate an in-vitro-in-silico workflow to rationally design long-acting DDS for tunable release of physicochemically distinct agents. Lastly, we assess the safety and pharmacokinetics of novel MPT upon intrauterine installation in a non-human primate model and provide evidence for local drug transport from the upper to lower female reproductive tract (FRT). This work motivates the further development of long-acting MPT for prevention of unwanted pregnancy, HIV, and other prophylactic and therapeutic targets within the FRT