Liquid CO2 Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem,ACS Biomaterials Science & Engineering

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Liquid CO2 Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2021-01-07 , DOI: 10.1021/acsbiomaterials.0c01284
Aun Raza _{1,

2} , Fekade Bruck Sime _{1,

2} , Peter J. Cabot ₁ , Jason A. Roberts _{1,

2,

3,

4} , James R. Falconer ₁ , Tushar Kumeria _{1,

5} , Amirali Popat _{1,

6}

Affiliation

Meropenem (MER) is an effective broad-spectrum antibiotic currently only available in the parenteral form requiring frequent drug preparation and administration due to its extremely poor stability. The unavailability of oral Meropenem is primarily due to its ultrapoor handling and processing stability, hydrophilic nature that inhibits the passive diffusion across the gastrointestinal (GI) epithelium, degradation in the harsh gastric environment, and GI expulsion through enterocyte efflux glycoproteins. In this regard, we have developed an oral drug delivery system that confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41 ∼141 nm) using a novel liquid carbon dioxide (CO₂) method. MER was efficiently encapsulated within pristine, phosphonate (negatively charged MSN), and amine (positively charged MSN) modified MSNs with loading capacity ranging between 25 wt % and 31 wt %. Next, the MER-MCM-NH₂ particles were electrostatically coated with Eudragit S100 enteric polymer that protected MER against gastric pH (pH 1.9) and enabled site-specific delivery in the small intestine (pH 6.8). Cellular uptake results in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient cellular uptake of nanoparticles in all three cell lines. More importantly, the bidirectional transport (absorptive and secretory) of MER across Caco-2 monolayer was significantly improved for both MSN-based formulations, particularly MSNs coated with a polymer (Eud-MER-MCM-NH₂) where permeability was significantly enhanced (∼2.4-fold) for absorptive transport and significantly reduced (∼1.8-fold) for secretory transport. Finally, in vitro antibacterial activity [minimum inhibitory concentration (MIC)] and time-kill assay against S. aureus and P. aeruginosa showed that drug-loaded nanoparticles were able to retain antibacterial activity comparable to that of free MER in a solution at equivalent dose. Thus, Eudragit-coated silica nanoparticles could offer a promising and novel solution for oral delivery of Meropenem and other such drugs.

中文翻译：

pH响应口服美罗培南的液态CO ₂配制的介孔二氧化硅纳米颗粒

美洛培南（MER）是一种有效的广谱抗生素，由于其极差的稳定性，目前仅以肠胃外形式需要进行频繁的药物制备和给药。口服美罗培南的缺乏主要是由于其超差的处理和加工稳定性，亲水性抑制了胃肠道（GI）上皮的被动扩散，在恶劣的胃环境中降解以及通过肠细胞外排糖蛋白排出的GI。在这方面，我们开发了一种口服药物递送系统，可使用新型液态二氧化碳（CO ₂）将MER限制在介孔二氧化硅纳米颗粒（MSN，即MCM-41〜141 nm）中）方法。MER有效地封装在原始，膦酸酯（带负电的MSN）和胺（带正电的MSN）修饰的MSN中，负载量范围为25 wt％至31 wt％。接下来，MER-MCM-NH ₂用Eudragit S100肠溶性聚合物静电包裹颗粒，该聚合物可保护MER不受胃pH值（pH 1.9）的侵害，并能够在小肠中进行定点递送（pH 6.8）。RAW 264.7巨噬细胞，Caco-2和LS174T细胞的细胞摄取结果证实了所有三种细胞系中纳米颗粒的有效细胞摄取。更重要的是，对于两种基于MSN的制剂，尤其是涂有渗透率显着提高的聚合物（Eud-MER-MCM-NH ₂）的MSN，MER跨Caco-2单层的MER双向运输（吸收性和分泌性）均得到了显着改善。吸收性转运约为2.4倍，吸收性转运则约为1.8倍。最后，体外对金黄色葡萄球菌和铜绿假单胞菌的抗菌活性[最小抑菌浓度（MIC）]和时间杀灭试验表明，在相同剂量的溶液中，载有药物的纳米颗粒能够保持与游离MER相当的抗菌活性。因此，Eudragit包被的二氧化硅纳米粒子可以为美洛培南和其他此类药物的口服给药提供有希望的新颖解决方案。

更新日期：2021-01-07

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