School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, 201418, China.
Center for Drug Delivery Systems Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Pharm Res. 2019 Jun 3;36(8):117. doi: 10.1007/s11095-019-2650-3.
To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF).
VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) C solid-state nuclear magnetic resonance spectroscopy ( C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles.
As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD), and nanoclusters in the confined spherical cages of (γ-CD) confirmed by SAXS and C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD) are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion.
The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.
研究通过环糊精金属有机骨架（CD-MOF）超装载提高水不溶性药物缬沙坦（VAL）溶解度和生物利用度的机制。
通过 VAL 在乙醇溶液中的磁搅拌，成功地将 VAL 超装载到 CD-MOF 中。采用粉末 X 射线衍射（PXRD）、差示扫描量热法（DSC）、基于同步辐射的傅里叶变换红外光谱（SR-FTIR）C 固态核磁共振光谱（ C SS-NMR）、氮气吸附和小角 X 射线散射（SAXS）等方法对 VAL 在 CD-MOF 中的机制和包合行为进行了表征。还使用球磨过程结合分子建模来确认机制。通过在比格犬体内的药代动力学实验证实了生物利用度的提高。
作为一种载体制备的负载量比常规 CD 络合高 150%的载药系统，CD-MOF 包含作为络合物的 VAL 分子在（γ-CD）的腔室中，以及在（γ-CD）的受限球形笼中的纳米簇通过 SAXS 和 C SS-NMR 得到证实。球磨结合分子建模推断，具有超高载药量的研磨 CD-MOF 的释放速率降低主要是由于 VAL 纳米簇的部分聚集。与γ-CD 包合相比，VAL 纳米簇作为（γ-CD）笼中的分子对于显著提高 VAL 的表观溶解度（39.5 倍）和口服生物利用度（1.9 倍）至关重要。
对 CD-MOF 中药物纳米簇的新认识将有助于设计使用具有纳米腔的 CD-MOF 载体的更有效的药物传递系统。
