Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore 119085, Singapore.
Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
Int J Mol Sci. 2019 Jan 28;20(3):541. doi: 10.3390/ijms20030541.
Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic--glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.
口干或口腔干燥症是多药治疗的老年人群中常见的医学病症。全身性毛果芸香碱被纳入口腔干燥症的一线药物治疗方案中。然而，由于其不良反应和每日多次给药，现有的毛果芸香碱制剂的疗效有限。为了克服这些缺点，本研究开发了一种针对唾液腺 (SG) 的毛果芸香碱局部制剂。所提出的制剂由通过电纺技术装载毛果芸香碱的聚 (乳酸-乙醇酸) (PLGA)/聚乙二醇 (PEG) 纳米纤维垫组成。对纳米纤维垫的大小、网眼孔隙率、药物包封效率和体外药物释放进行了全面表征。在 SG 器官离体评估了垫的生物相容性和功效，并在细胞水平上测定了增殖和促凋亡标志物的表达。进行了短期体内研究，以评估急性 SG 治疗后毛果芸香碱负载纳米纤维垫以及系统性毛果芸香碱后的唾液分泌情况，以便进行比较。结果表明，毛果芸香碱负载垫均匀分布（直径：384 ± 124nm）在高度多孔的网中，并且具有高包封效率（81%）。药物释放研究表明，毛果芸香碱初始释放 26%（4.5 小时），随后在 15 天内逐渐增加（46%）。毛果芸香碱负载纳米纤维垫支持 SG 生长，细胞毒性可忽略不计，且细胞增殖和稳态正常。体内 SG 皮内治疗后 4.5 小时，负载药物的纳米纤维显著增加了唾液分泌。总体而言，这项研究强调了 PLGA/PEG 纳米纤维垫用于局部每日递送达泊酚的优势，并揭示了其在口干症患者未来临床转化中的潜力。
