Subbiah Naren, Campagna Jesus, Spilman Patricia, Alam Mohammad Parvez, Sharma Shivani, Hokugo Akishige, Nishimura Ichiro, John Varghese
Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA.
Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, Los Angeles, CA, USA.
J Drug Deliv. 2017;2017:4759839. doi: 10.1155/2017/4759839. Epub 2017 Apr 5.
Phospholipid-based deformable nanovesicles (DNVs) that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol). AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue-cranial bone-by DNVs as compared to nondeformable nanovesicles (NVs) or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery.
基于磷脂的可变形纳米囊泡（DNV）具有形状灵活性，为封装各类治疗剂提供了一种适应性强且简便的方法，有助于局部透皮给药，同时将全身暴露降至最低。在此，我们报告了使用微流控反应器合成DNV，并表明改变诸如流速以及摩尔比和流速比等输入参数可提高药物包封效率，并能对DNV的大小、弹性和表面电荷进行微调。为了确定包裹药物的DNV经皮递送至局部部位的能力，我们合成、表征并测试了携带荧光标记亲水性双膦酸盐药物AF - 647唑来膦酸（AF647 - Zol）的DNV。AF647 - Zol DNV经冻干、重悬后，作为糊剂局部应用于小鼠颅骨皮肤。高分辨率荧光成像和共聚焦显微镜显示，与不可变形纳米囊泡（NV）或水性药物溶液相比，DNV将包裹的有效载荷递送至靶组织——颅骨的能力显著增强。有趣的是，NV递送并不优于水性药物溶液。我们的研究表明，通过微流控反应器合成的DNV产量高、包封效率高、可重复性好，储存后稳定性良好，是局部透皮给药的有用载体。
