HYPOTONIC DELIVERY OF DRUGS AND DRUG-LOADED NANOPARTICLES TO THE GASTROINTESTINAL TRACT

mucus penetrating particle;microbicide;Biomedical Engineering

Maisel, KatharinaCone, Richard A. ;

Johns Hopkins University

关键词: mucus penetrating particle;    microbicide;    Biomedical Engineering;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40663/MAISEL-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Innovative gastrointestinal (GI) drug delivery vehicles such as mucus penetrating nanoparticles (MPP) and fluid-absorption inducing (hypotonic) delivery vehicles have potential to improve therapeutic outcomes over conventional methods such as mucoadhesive particles (MAP) for GI diseases, including ulcerative colitis (UC) and HIV pre-exposure prophylaxis (PrEP). More than 80% of all drugs are absorbed via the GI tract for either systemic or local treatment. MAP delivered to the GI tract are thought to improve oral absorption or local targeting of difficult-to-deliver drug classes. Mucus is a continuously secreted barrier that effectively traps foreign particulates to protect the underlying epithelium. Rapid clearance of the most superficial luminal mucus layers in the GI tract may limit the effectiveness of MAP. Here, I test the current dogma of mucoadhesion by comparing MAP and MPP GI drug delivery via the oral and rectal routes. In addition I investigate the development of several vehicles including rectal enemas and gels for more effective delivery of nanocarriers or free drugs. First, I illustrate that MPP uniformly coat all surfaces of the GI epithelium, while MAP aggregated in mucus in the center of the lumen, far away from the absorptive epithelium, both in healthy mice and mice with UC. In the mouse colorectum, MPP penetrated into mucus in the deeply in-folded surfaces to evenly coat the entire epithelial surface. Moreover, in UC mice, MPP were transported preferentially into the disrupted, ulcerated tissue. Next, I sought to design an effective enema vehicle for delivering MPP and non-mucoadhesive drugs locally to the colorectum. I found that MPP and free drug are only rapidly transported to the epithelial surface in sodium-based enemas, while potassium-based or isotonic and hypertonic (secretion-inducing) enemas cause heterogeneous surface coverage. Strongly hypertonic and hypotonic enemas cause rapid systemic drug absorption, while moderately hypotonic enemas improve local drug retention in tissue. Finally, I designed a microbicide-loaded MPP for PrEP, to be delivered in a novel osmotic thermogel. The MPP formulation evenly coated both the vaginal and colorectal epithelium and the hypotonically delivered thermogel effectively traps HIV, and significantly enhances drug and nanoparticle retention in the cervicovaginal tract.