Modeling of nanoparticle transport through the female reproductive tract for the treatment of infectious diseases.

The secreted mucus layer in the vaginal epithelium presents a formidable barrier to the transport of active agents for the prevention and treatment of female reproductive tract (FRT) infections. Nanoparticle-mediated drug delivery has been proposed to help facilitate the transport and release of active agents through the cervicovaginal mucus (CVM) and underlying mucosa. However, both nanoparticles (NPs) and free active agents face a variety of challenges, often requiring the administration of high localized doses to circumvent leakage and poor penetration to targeted intravaginal tissue compartments. To address these challenges, "stealth" NP modifications have been investigated, due to their favorable mucus-penetrating properties, resulting in improved intravaginal active agent retention and transport. A number of other NP characteristics including size, surface modification type, ligand density, and co-modification, as well as the complexity of the FRT tissue are involved in obtaining adequate tissue penetration and, if needed, cell internalization. Studies that systematically investigate variations of these characteristics have yet to be conducted, with the goal to obtain a better understanding of what properties most impact prophylactic and therapeutic benefit. To complement the progress made with experimental evaluation of active agent transport in in vitro and in vivo, mathematical modeling has recently been applied to analyze the transport performance of agents and delivery vehicles in the FRT. Here, we build upon this work to simulate NP transport through mucus gel, epithelial, and stromal compartments, with the goal to provide a platform that can systematically evaluate transport based on NP and tissue characteristics. Model parameters such as PEG density and NP release (decay) rate from mucus gel into the epithelium, are set from previous in vitro and in vivo experimental work that assessed the transport of poly(lactic-co-glycolic acid (PLGA) NPs. The modeling results show that while unmodified and 2% PEG-modified NPs were retained in mucus for ∼1-4 h, dependent upon decay constant values, and traverse to the epithelium, no NP penetration was observed in the stroma. In contrast, NPs modified with 3% PEG, exhibited prolonged retention in each compartment, remaining for ∼4-6 h. Moreover, a significant concentration of NPs is observed in the stroma, indicating a transition in transport behavior. For NPs modified with 5, 8, or 25% PEG, steady retention profiles were noted, which gradually decline over 24 h. To supplement this modeling study and to develop a more representative experimental system that may be useful in future work, we report on the feasibility of constructing single and multicellular layered (MCL) culture systems to represent the epithelial and stromal tissue of the FRT. We anticipate that a combined mathematical/experimental approach may longer term enable prediction and customization of patient tissue-specific approaches to attain effective NP-mediated drug delivery and release for the treatment of infectious disease.