Journal of Drug Delivery Science and Technology ( IF 4.5 ) Pub Date : 2020-07-09 , DOI: 10.1016/j.jddst.2020.101866
The-Thien Tran , Nur Amalina , Wean Sin Cheow , Kunn Hadinoto
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Dry powder inhaler (DPI) formulations of small nucleic acids (e.g. pDNA, siRNA) have been established as the preferred delivery mode for pulmonary gene therapy. While numerous studies have demonstrated the in vivo gene activity and in vitro aerosolization efficiency of the DPI formulations, few studies have examined their storage stability. Herein we investigated the effects of storage at 4 °C and 25 °C for 1 and 3 months on the in vitro stability and aerosolization efficiency of DPI of pDNA-chitosan nanoparticles prepared by spray-freeze-drying. The DPI of pDNA-chitosan nanoparticles exhibited sustained pDNA release profile and minimal cytotoxicity towards human lung epithelium cells. It lost approximately 10% and 20% of its activity after 3-month storage at 4 °C and 25 °C, respectively. As expected, the DPI formulation exhibited higher storage stability than the nanoparticle suspension form (40–50% loss). While the effect of raising the storage temperature to 25 °C on the pDNA activity was not very significant, it greatly affected the aerosolization efficiency, where the particle fraction suitable for deposition in the deep lungs decreased from 17% to 7%. The present results reaffirmed the previous studies performed on naked pDNA and pDNA polyplex that storage at 4 °C was generally adequate for DPI of pDNA.
中文翻译:
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贮存对质粒DNA-壳聚糖纳米粒干粉吸入器制剂稳定性和雾化效率的影响
小核酸(例如pDNA,siRNA)的干粉吸入器(DPI)制剂已被确定为肺部基因治疗的首选递送方式。尽管大量研究表明DPI制剂具有体内基因活性和体外雾化效率,但很少有研究检查它们的储存稳定性。在这里,我们研究了在4°C和25°C下储存1个月和3个月对体外的影响喷雾冷冻干燥制得的pDNA-壳聚糖纳米颗粒的DPI稳定性和气雾化效率 pDNA-壳聚糖纳米粒子的DPI表现出持续的pDNA释放曲线,对人肺上皮细胞的细胞毒性最小。在4°C和25°C下存放3个月后,其活性分别损失了大约10%和20%。不出所料,DPI制剂比纳米颗粒悬浮液具有更高的储存稳定性(损失40-50%)。虽然将储存温度提高到25°C对pDNA活性的影响不是很明显,但它极大地影响了雾化效率,适合深部肺部沉积的颗粒分数从17%降低到7%。