Our overall goal is to optimize hypotonic rectal enema formulations for delivering tenofovir (TFV) and TFV analogs to the entire colorectal surface with as high a dose as can be delivered safely. We have investigated the role of enema vehicle tonicity in drug delivery in the mouse rectum, including hypotonic formulations that cause rapid water uptake from the lumen, and hypertonic formulations that cause rapid secretion of water into the lumen. Our results are consistent with the studies done by Hendrix and coworkers in the human colorectum: (i) tap water, a maximally hypotonic formulation, drives drug delivery and absorption locally, and not as far up the colon as is likely necessary, and (ii) Fleet enema, a markedly hypertonic vehicle, causes fluid secretion that prevents uniform drug distribution. In contrast, moderately hypotonic formulations provide the best surface distribution, and they do so rapidly. Hypotonic formulations deliver drugs and drug-loaded nanocrystals by advection caused by sodium (Na+)-driven, osmotically-induced flow of water from the lumen into the tissues, similar to the natural process by which the colorectum dehydrates the feces. Importantly, relatively high Na+ in semen makes it hypotonic in the colorectum, which is likely to deliver HIV rapidly to the epithelium by advection, thus suggesting that our moderately-hypotonic enema drug delivery method may be critical to ensure that drug is delivered to all surfaces where HIV can reach.
In Aim 1, we will optimize a mildly hypotonic formulation for delivering TFV and TFV analogs to the colorectum of mice, and then in non-human primates (NHP), to select the enhanced bioavailability product to be used in clinical studies in Projects 1 and 4.
In Aim 2, we will be designing an enhanced enema product for increased bioavailability, and sustained drug release.
In Aim 2 A, we will determine whether mucus-penetrating drug nanocrystals can prolong the duration of prophylactic drug concentrations of TFV and TFV analogs in mice, and then in NHP.
In Aim 2 B, we will test the hypothesis that a gelling agent will prolong retention on the colorectal surface, and possibly form a barrier to HIV.
In Aim 2 C, we will test the product with the optimized combination of bioavailability enhancements and sustained release properties for protection against SHIV challenge in NHP.
A safe, effective HIV pre-exposure prophylaxis strategy with high levels of adherence is urgently needed to protect men and women at highest risk of HIV infection from anal sex. We propose development of a TFV enema to take advantage of common enema use associated with anal sex and the proven efficacy of TFV. This project optimizes the TFV enema formulation in animal models to inform clinical development.
|Carballo-Diéguez, Alex; Lentz, Cody; Giguere, Rebecca et al. (2017) Rectal Douching Associated with Receptive Anal Intercourse: A Literature Review. AIDS Behav :|
|Chuchuen, Oranat; Maher, Jason R; Henderson, Marcus H et al. (2017) Label-free analysis of tenofovir delivery to vaginal tissue using co-registered confocal Raman spectroscopy and optical coherence tomography. PLoS One 12:e0185633|
|Date, Abhijit A; Hanes, Justin; Ensign, Laura M (2016) Nanoparticles for oral delivery: Design, evaluation and state-of-the-art. J Control Release 240:504-526|
|Maisel, Katharina; Reddy, Mihika; Xu, Qingguo et al. (2016) Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo. Nanomedicine (Lond) 11:1337-43|
|Suk, Jung Soo; Xu, Qingguo; Kim, Namho et al. (2016) PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev 99:28-51|
|Maisel, Katharina; Ensign, Laura; Reddy, Mihika et al. (2015) Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse. J Control Release 197:48-57|
|Maisel, Katharina; Chattopadhyay, Sumon; Moench, Thomas et al. (2015) Enema ion compositions for enhancing colorectal drug delivery. J Control Release 209:280-7|