Manta Konstantina, Papakyriakopoulou Paraskevi, Chountoulesi Maria, Diamantis Dimitrios A, Spaneas Dimitrios, Vakali Vasiliki, Naziris Nikolaos, Chatziathanasiadou Maria V, Andreadelis Ioannis, Moschovou Kalliopi, Athanasiadou Ioanna, Dallas Paraskevas, Rekkas Dimitrios M, Demetzos Costas, Colombo Gaia, Banella Sabrina, Javornik Uroš, Plavec Janez, Mavromoustakos Thomas, Tzakos Andreas G, Valsami Georgia
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou 15771, Greece.
Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, Ioannina 45110, Greece.
Mol Pharm. 2020 Nov 2;17(11):4241-4255. doi: 10.1021/acs.molpharmaceut.0c00672. Epub 2020 Oct 19.
Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further and evaluation toward nasal administration and nose-to-brain delivery of Que.
槲皮素（Que）是一种具有高氧自由基清除活性以及对阿尔茨海默病具有潜在神经保护活性的黄酮类化合物。Que的口服生物利用度因其低水溶性和广泛的外周代谢而受到限制；因此，鼻腔给药可能是在大脑中实现有效Que浓度的一种有前景的替代方法。先前发现Que - 2 - 羟丙基化 - β - 环糊精（Que/HP - β - CD）复合物可增加该分子在水性介质中的溶解度和稳定性。制备了Que - 甲基 - β - 环糊精（Que/Me - β - CD）包合物，采用生物物理和计算方法（相溶解度、荧光和核磁共振光谱、差示扫描量热法（DSC）以及分子动力学模拟（MDS））对其进行表征，并与Que/HP - β - CD复合物进行比较，作为制备Que鼻脑递送系统的候选物。DSC热谱图、核磁共振、荧光光谱和MDS证实了Que与两种环糊精均形成了包合物。观察到两种制剂在热力学稳定性和控制分子相互作用细节的包合模式方面存在差异。Que在pH 1.2和4.5的水性介质中的溶解度相似，且随两种环糊精浓度呈线性增加。在pH 6.8时，Que的溶解度更高，并且在存在HP - β - CD时比存在Me - β - CD时更偏离线性正相关，这可能表明复合物中涉及不止一个HP - β - CD分子。总体而言，冻干的Que/Me - β - CD和Que/HP - β - CD产品在pH 1.2 - 6.8时的水溶性分别约为纯Que的7 - 40倍和14 - 50倍。此外，关于兔鼻黏膜渗透的概念验证实验表明，两种环糊精的Que渗透曲线均可测量且相似，而纯Que的渗透可忽略不计。这些结果对于进一步研究和评估Que的鼻腔给药及鼻脑递送相当令人鼓舞。
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