Abstract
Uptake of nanoparticles through Peyer's Patches following oral administration could enable translocation through lymph to lymphatic organs like the lungs. An important consideration, however, is nanosize and particle hydrophobicity. Furthermore, as delivering the nanoparticles to the intestine where the Peyer's Patches are localized is important, their intact and rapid transit through the stomach into the intestine is highly desirable. We report hydrophobization of mucoadhesive Rifampicin-GantrezAN-119 nanoparticles (GzNP) using a hydrophobic polymer, ethyl cellulose (EC), with the objectives of augmenting Peyer's Patch uptake due to enhanced hydrophobicity and increased intestinal localization as a result of decreased mucoadhesion. RIF-Gantrez-EC nanoparticles (ECGzNP2) exhibited >13% RIF loading and an average particle size of 400-450 nm, which is appropriate for translation through lymph following Peyer's Patch uptake. Higher contact angle (67.3 ± 3.5° vs 30.3 ± 2.1°) and lower mucoadhesion (30.7 ± 4.8 g vs 87.0 ± 3.0 g) of ECGzNP2 over GzNP confirmed hydrophobization and lower mucoadhesion. Fluorescence photomicrographs of intraduodenally administered coumarin-labeled RIF-NP in rats demonstrated higher Peyer's Patch uptake with ECGzNP2, while the increased lung/plasma RIF ratio signified lymph mediated lung targeting. The gastrointestinal transit study in rats, which revealed a significantly higher intestine-to-stomach accumulation ratio with ECGzNP2 (3.4) compared to GzNP (1.0) [ p < 0.05], confirmed availability of the NP in the intestine for Peyer's Patch uptake. Such uptake enabled 182.4 ± 22.6% increase in relative bioavailability, a ∼2-fold higher plasma AUC/MIC ratio and significantly higher lung concentration with ECGzNP2, thereby proposing better efficacy. A significantly higher lung/liver ratio with ECGzNP2 also suggested lower hepatic exposure. The repeated dose 28-day oral toxicity study demonstrated the safety of the nanocarrier and reduced hepatotoxicity with ECGzNP2 compared to RIF. We hereby demonstrate uptake of orally administered NP through Peyer's Patches as a feasible strategy for lung targeting.
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