Department of Pharmaceutical Sciences and Technology , Institute of Chemical Technology , N. P. Marg, Matunga (E) , Mumbai - 400019 , Maharashtra , India.
National Center for Preclinical Reproductive and Genetic Toxicology , National Institute for Research in Reproductive Health (NIRRH) , ICMR, J. M. Street, Parel , Mumbai - 400 012 , India.
Mol Pharm. 2018 Oct 1;15(10):4434-4445. doi: 10.1021/acs.molpharmaceut.8b00382. Epub 2018 Aug 28.
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.
口服后，纳米颗粒通过派伊尔斑被吸收，可能通过淋巴转移到肺部等淋巴器官。然而，一个重要的考虑因素是纳米尺寸和颗粒疏水性。此外，由于将纳米颗粒递送到派伊尔斑所在的肠道很重要，因此希望它们完整且快速地通过胃进入肠道。我们报告了使用疏水性聚合物乙基纤维素（EC）对具有粘膜粘附性的利福平-GantrezAN-119 纳米颗粒（GzNP）进行疏水处理，目的是由于疏水性增加而增加派伊尔斑摄取，并且由于粘膜粘附性降低而增加肠道定位。RIF-Gantrez-EC 纳米颗粒（ECGzNP2）表现出> 13％的 RIF 负载和 400-450nm 的平均粒径，这适合通过派伊尔斑摄取后通过淋巴转移。与 GzNP 相比，ECGzNP2 的接触角更高（67.3 ± 3.5°对 30.3 ± 2.1°），粘膜粘附性更低（30.7 ± 4.8g 对 87.0 ± 3.0g），这证实了疏水性和较低的粘膜粘附性。在大鼠中，用荧光显微镜观察到口服给予香豆素标记的 RIF-NP 后，派伊尔斑摄取更高，而肺/血浆中 RIF 比值的增加表明了淋巴介导的肺部靶向。在大鼠中的胃肠道转运研究表明，与 GzNP（1.0）相比，ECGzNP2 的肠-胃累积比显著更高（3.4）[p <0.05]，这证实了 NP 在肠道中用于派伊尔斑摄取的存在。这种摄取使相对生物利用度增加了 182.4 ± 22.6％，血浆 AUC/MIC 比值增加了约 2 倍，并且 ECGzNP2 的肺部浓度明显更高，从而提出了更好的疗效。与 ECGzNP2 相比，ECGzNP2 还具有更高的肺/肝比，这表明肝暴露较低。重复剂量 28 天口服毒性研究表明，与 RIF 相比，纳米载体的安全性和 ECGzNP2 的肝毒性降低。我们在此证明，通过派伊尔斑吸收口服给予的 NP 是肺部靶向的一种可行策略。
