Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal; i3S, Group Genetics of Cognitive Dysfunction, Institute for Molecular and Cell Biology, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
Mater Sci Eng C Mater Biol Appl. 2019 Dec;105:110022. doi: 10.1016/j.msec.2019.110022. Epub 2019 Jul 29.
This paper advances the development of a novel drug nanodelivery solution to the oral administration of resveratrol (RSV), a low soluble drug whose recognized therapeutic applications are circumscribed when administered in the free compound form. Layer-by-Layer (LbL) self-assembly is an emergent nanotechnology proposed to address this concern with means to afford control over key formulation parameters, which are able to ultimately promote an improved pharmacokinetics. LbL self-assembly consists in the sequential adsorption of oppositely charged polyelectrolytes upon a low soluble drug nanoparticle (NP) template, giving rise to onion-like multilayered nanoarchitectures. In this work, RSV nanoprecipitation followed by LbL self-assembly of polyelectrolytes, led by a washless approach, was carried out by using the cationic poly(allylamine hydrochloride) (PAH) and the anionic dextran sulfate (DS) as polyelectrolytes towards the nanoencapsulation of RSV. Each saturated polyelectrolyte layer deposition involved the rigorous polyelectrolyte concentration assessment which was accomplished by tracing titration curves. This way, aqueous RSV nanocores and RSV LbL nanoformulations with a distinct number of PAH/DS bilayers were developed, including 2.5 (RSV-(PAH/DS) NPs), 5.5 (RSV-(PAH/DS) NPs) and 7.5 (RSV-(PAH/DS) NPs) bilayered nanoformulations. Homogenous particle size distributions at the desired nanoscale interval (ca. 116-220 nm; polydispersity index below 0.15), good colloidal (zeta potential magnitudes ca. ± 20-30 mV) and chemical stabilizations, high encapsulation efficiency (above 90%) together with an excellent cytocompatibility with Caco-2 cells (cell viability above 90%) were observed for all the nanoformulations. Eventfully, LbL NPs promoted a controlled release of RSV pursuant to the number of polyelectrolyte bilayers under simulated gastrointestinal conditions, particularly in the intestine medium, emphasizing their biopharmaceutical advantage. Our findings manifestly pinpoint that LbL PAH/DS NPs constitute a promising nanodelivery system for the oral delivery of RSV, providing a rational strategy to enlarge the implementation range of this interesting polyphenol, which is possibly the most actively investigated phytochemical worldwide.
本文提出了一种新型药物纳米递药系统，用于口服白藜芦醇（RSV），RSV 是一种低溶解度的药物，当其以游离化合物的形式给药时，其公认的治疗应用受到限制。层层自组装（LbL）是一种新兴的纳米技术，旨在通过控制关键制剂参数来解决这一问题，这些参数最终能够促进改善药代动力学。LbL 自组装由带相反电荷的聚电解质在低溶解度药物纳米颗粒（NP）模板上的顺序吸附组成，形成洋葱状多层纳米结构。在这项工作中，通过无洗涤方法进行 RSV 纳米沉淀，然后进行聚电解质的 LbL 自组装，使用阳离子聚（烯丙基胺盐酸盐）（PAH）和阴离子葡聚糖硫酸盐（DS）作为聚电解质，实现 RSV 的纳米封装。每个饱和聚电解质层的沉积都涉及到严格的聚电解质浓度评估，这是通过跟踪滴定曲线来完成的。通过这种方式，开发了具有不同数量的 PAH/DS 双层的 RSV 纳米核和 RSV LbL 纳米制剂，包括 2.5（RSV-(PAH/DS) NPs）、5.5（RSV-(PAH/DS) NPs）和 7.5（RSV-(PAH/DS) NPs）双层纳米制剂。在所需的纳米间隔（约 116-220nm；多分散指数低于 0.15）内具有均匀的颗粒尺寸分布、良好的胶体稳定性（zeta 电位幅度约 ± 20-30mV）和化学稳定性、高包封效率（高于 90%）以及与 Caco-2 细胞的优异细胞相容性（细胞活力高于 90%），所有纳米制剂均观察到。重要的是，在模拟胃肠道条件下，根据聚电解质双层的数量，LbL NPs 促进了 RSV 的控制释放，特别是在肠介质中，强调了它们的生物制药优势。我们的研究结果清楚地表明，LbL PAH/DS NPs 构成了口服递送 RSV 的有前途的纳米递药系统，为这种有趣的多酚的应用范围提供了一种合理的策略，它可能是全球研究最活跃的植物化学物质。
