Abstract：
In the present work, we study different physicochemical properties related to LADME processes of volasertib, a Polo-like kinase 1 inhibitor in advanced clinical trials. Firstly, the protonation equilibria, the extent of ionization at the physiological pH and pKa values of this drug are studied combining spectroscopic techniques and computational calculations. Secondly, the binding process of volasertib to the human serum albumin (HSA) protein is analyzed by fluorescence spectroscopy. We report a high binding constant to HSA (Ka = 4.10 × 106 M-1) and their pharmacokinetic implications are discussed accordingly. The negative enthalpy and entropy (ΔH0 = -54.49 kJ/mol; ΔS0 = -58.90 J K-1 mol-1) determined for the binding process suggests the implication of hydrogen bonds and van der Waals interactions in the formation of the HSA-volasertib complex. Additionally, volasertib is encapsulated in an alginate/montmorillonite bionanocomposite as a proof of concept for an oral delivery nanocarrier. The physical properties of that nanocomposite as well as volasertib delivery kinetics are analyzed.
摘要：
在目前的工作中,我们研究了与volasertib的LADME过程相关的不同物理化学性质，高级临床试验中的Polo样激酶1抑制剂。首先,质子化平衡，结合光谱技术和计算计算研究了该药物在生理pH和pKa值下的电离程度。其次,通过荧光光谱法分析了volasertib与人血清白蛋白（HSA）蛋白的结合过程。我们报告了与HSA的高结合常数（Ka=4.10×106M-1），并相应地讨论了它们的药代动力学含义。为结合过程确定的负焓和熵（ΔH0=-54.49kJ/mol；ΔS0=-58.90JK-1mol-1）表明氢键和范德华相互作用在HSA-volasertib络合物的形成中的含义。此外,volasertib封装在藻酸盐/蒙脱石生物纳米复合材料中，作为口服递送纳米载体的概念证明。分析了该纳米复合材料的物理性质以及volasertib递送动力学。
