Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol-Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood-Brain Barrier Level
Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol-Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood-Brain Barrier Level
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DOI：
10.1021/acs.jcim.6b00215
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发表时间：
2016-10-01
影响因子：
5.6
通讯作者：
Broscheit, Jens-Albert
中科院分区：
文献类型：
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作者：
Shityakov, Sergey;Salmas, Ramin Ekhteiari;Broscheit, Jens-Albert
在这项研究中，我们研究了全身麻醉药丙泊酚（PR）与改性β-环糊精（包括磺丁基醚-β-环糊精（SBE β CD）和羟丙基-β-环糊精（HP β CD））形成包合物的能力。制备并表征了PR/SBE β CD和PR/HP β CD复合物，并在体内检查了所配制的PR的血脑屏障（BBB）渗透潜力以用于受控药物递送的目的。发现PR/SBE β CD复合物在溶液中更稳定，最小降解常数为0.25 h（-1），t（1/2）为2.82 h，K-c为5.19 X 10（3）M-1，考虑到计算的脑-血浓度比（logBB）值，与参比物质（PR-LIPURO）相比，显示BBB渗透率更高。此外，在分子动力学模拟中，通过最大结合吉布斯自由能（Δ G（结合）= -18.44 kcal.mol（-1））证实了PR与SBE β CD的结合亲和力降低，表明PR/SBE β CD解离更快。总体而言，结果表明，SBE β CD有可能用作药物递送载体开发的潜在候选物，以改善全身麻醉剂在BBB水平的药代动力学和药效学特性。
In this study, we investigated the ability of the general anesthetic propofol (PR) to form inclusion complexes with modified beta-cyclodextrins, including sulfobutylether-beta-cyclodextrin (SBE beta CD) and hydroxypropyl-beta-cyclodextrin (HP beta CD). The PR/SBE beta CD and PR/HP beta CD complexes were prepared and characterized, and the blood brain barrier (BBB) permeation potential of the formulated PR was examined in vivo for the purpose of controlled drug delivery. The PR/SBE beta CD complex was found to be more stable in solution with a minimal degradation constant of 0.25 h(-1), a t(1/2) of 2.82 h, and a K-c of 5.19 X 10(3) M-1 and revealed higher BBB permeability rates compared with the reference substance (PR-LIPURO) considering the calculated brain-to-blood concentration ratio (logBB) values. Additionally, the diminished PR binding affinity to SBE beta CD was confirmed in molecular dynamics simulations by a maximal Gibbs free energy of binding (Delta G(bind) = -18.44 kcal.mol(-1)), indicating the more rapid PR/SBE beta CD dissociation. Overall, the results demonstrated that SBE beta CD has the potential to be used as a prospective candidate for drug delivery vector development to improve the pharmacokinetic and pharmacodynamic properties of general anesthetic agents at the BBB level.