Huang Yuhang, Jazani Arman Moini, Howell Elliot P, Reynolds Lisa A, Oh Jung Kwon, Moffitt Matthew G
Department of Chemistry, University of Victoria, PO Box 1700 Stn CSC, Victoria, BC V8W 2Y2, Canada.
Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec H4B 1R6, Canada.
ACS Biomater Sci Eng. 2020 Sep 14;6(9):5069-5083. doi: 10.1021/acsbiomaterials.0c00896. Epub 2020 Aug 18.
We demonstrate microfluidic manufacturing of glutathione (GSH)-responsive polymer nanoparticles (PNPs) with controlled pharmacological properties for selective drug delivery. This work leverages previous fundamental work on microfluidic control of the physicochemical properties of GSH-responsive PNPs containing cleavable disulfide groups in two different locations (core and interface, DualM PNPs). In this paper, we employ a two-phase gas-liquid microfluidic reactor for the flow-directed manufacturing of paclitaxel-loaded or DiI-loaded DualM PNPs (PAX-PNPs or DiI-PNPs, where DiI is a fluorescent drug surrogate dye). We find that both PAX-PNPs and DiI-PNPs exhibit similar flow-tunable sizes, morphologies, and internal structures to those previously described for empty DualM PNPs. Fluorescent imaging of DiI-PNP formulations shows that microfluidic manufacturing greatly improves the homogeneity of drug dispersion within the PNP population compared to standard bulk microprecipitation. Encapsulation of PAX in DualM PNPs significantly increases its selectivity to cancerous cells, with various PAX-PNP formulations showing higher cytotoxicity against cancerous MCF-7 cells than against non-cancerous HaCaT cells, in contrast to free PAX, which showed similar cytotoxicity in the two cell lines. In addition, the characterization of DualM PNP formulations formed at various microfluidic flow rates reveals that critical figures of merit for drug delivery function-including encapsulation efficiencies, GSH-triggered release rates, rates of cell uptake, cytotoxicities, and selectivity to cancerous cells-exhibit microfluidic flow tunability that mirrors trends in PNP size. These results highlight the potential of two-phase microfluidic manufacturing for controlling both structure and drug delivery function of biological stimuli-responsive nanomedicines toward improved therapeutic outcomes.
我们展示了具有可控药理特性的谷胱甘肽（GSH）响应性聚合物纳米颗粒（PNP）的微流体制备方法，用于选择性药物递送。这项工作利用了先前关于微流控控制GSH响应性PNP物理化学性质的基础研究，该PNP在两个不同位置（核心和界面，双位点修饰PNP）含有可裂解的二硫键。在本文中，我们采用两相气液微流控反应器，通过流动导向制备负载紫杉醇或DiI的双位点修饰PNP（PAX-PNP或DiI-PNP，其中DiI是一种荧光药物替代染料）。我们发现，PAX-PNP和DiI-PNP均表现出与先前描述的空双位点修饰PNP相似的流动可调尺寸、形态和内部结构。DiI-PNP制剂的荧光成像表明，与标准的批量微沉淀法相比，微流体制备极大地提高了药物在PNP群体中的分散均匀性。将PAX封装在双位点修饰PNP中可显著提高其对癌细胞的选择性，与游离PAX相比，各种PAX-PNP制剂对癌细胞MCF-7的细胞毒性高于对非癌细胞HaCaT的细胞毒性，而游离PAX在两种细胞系中表现出相似的细胞毒性。此外，对在不同微流控流速下形成的双位点修饰PNP制剂的表征表明，药物递送功能的关键指标——包括包封效率、GSH触发的释放速率、细胞摄取速率、细胞毒性以及对癌细胞的选择性——表现出微流控流动可调性，这反映了PNP尺寸的变化趋势。这些结果突出了两相微流体制备在控制生物刺激响应性纳米药物的结构和药物递送功能以改善治疗效果方面的潜力。
