Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
Pharm Res. 2020 Apr 14;37(4):82. doi: 10.1007/s11095-020-02794-z.
PURPOSE: Myricetin (MYR) flavonoid is well-recognized for its antioxidant, anti-inflammatory and anti-tumor potential. Introducing nanomedicine was the ultimate resort to solve the imperfections of this nutraceutical, namely solubility, stability and delivery issues. The study, thus, aims at developing inhalable microparticles comprising MYR solid lipid nanoparticles (SLNs) for lung cancer therapy. METHODS: A two-step preparation procedure starting with complexation of MYR with the phospholipid Lipoid-S100, followed by nanoencapsulation in Gelucire-based, surfactant-free SLNs was developed. SLNs were characterized in terms of physicochemical properties, MYR loading, release behavior as well as anti-tumor potential and cellular uptake. Respirable microparticles were then obtained by spray drying SLNs with carbohydrate carriers. Their size, flowability and pulmonary deposition pattern were assessed. RESULTS: Optimized SLNs were 75.98 nm in diameter with a zeta-potential of -22.5 mV, and an encapsulation efficiency of 84.5%. Attempts to ameliorate drug loading implicate MYR-phospholipid complexation (MYR-PH-CPX) prior to its entrapment in SLNs, which ensured 5-fold increase in drug loading. Viability assays were modified to guarantee MYR chemical stability. Superior antitumor activity of MYR-phospholipid-complex and 3-fold reduction in IC were accomplished with MYR-SLNs. This could be related to enhanced cellular uptake revealed by confocal imaging and doubled fluorescence intensity. SLNs entrapping MYR-PH-CPX were spray-dried with carbohydrate carriers to produce respirable microparticles. The latter ensured MMAD of 2.39 μm and span index of 1.84, in addition to good flowability and > 80% release over 8 h. Deposition experiments revealed MMAD of 2.77 μm, FPF of 81.23 and EF of 93% indicating particle deposition in the targeted bronchial region. CONCLUSIONS: The study highlights the ability of phospholipid-complex on the nanoencapsulation, cellular uptake and antitumor activity of MYR. Formulation of respirable microparticles gives promises of efficacious therapy of lung carcinoma.
目的：杨梅素（MYR）类黄酮因其抗氧化、抗炎和抗肿瘤潜力而广为人知。引入纳米医学是解决这种营养保健品的不完美之处的最终手段，即溶解度、稳定性和输送问题。因此，本研究旨在开发包含 MYR 固体脂质纳米粒（SLN）的可吸入微球用于肺癌治疗。
方法：采用两步法制备，首先将 MYR 与磷脂 Lipoid-S100 络合，然后在基于 Gelucire 的无表面活性剂 SLN 中进行纳米包封。SLN 的理化性质、MYR 载药量、释放行为以及抗肿瘤活性和细胞摄取均进行了表征。然后通过将 SLN 与碳水化合物载体喷雾干燥来获得可吸入的微球。评估了它们的粒径、流动性和肺部沉积模式。
结果：优化后的 SLN 粒径为 75.98nm，Zeta 电位为-22.5mV，包封效率为 84.5%。尝试改善药物载药量需要在将 MYR 包埋在 SLN 之前进行 MYR-磷脂复合物（MYR-PH-CPX）的复合，这确保了药物载药量增加了 5 倍。对活力测定进行了修改以保证 MYR 的化学稳定性。用 MYR-SLNs 实现了 MYR-磷脂复合物的优异抗肿瘤活性和 IC 降低 3 倍。这可能与共聚焦成像揭示的增强的细胞摄取以及荧光强度增加一倍有关。将包封 MYR-PH-CPX 的 SLN 与碳水化合物载体喷雾干燥制成可吸入的微球。后者确保了 MMAD 为 2.39μm，跨度指数为 1.84，此外还具有良好的流动性和 8 小时以上超过 80%的释放。沉积实验表明 MMAD 为 2.77μm，FPF 为 81.23%，EF 为 93%，表明颗粒沉积在目标支气管区域。
结论：本研究强调了磷脂复合物在 MYR 的纳米包封、细胞摄取和抗肿瘤活性方面的能力。可吸入微球的制剂为有效的肺癌治疗提供了前景。
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