磷脂酰纳米螺旋载体HSBH2D介导γ-GSH高效镇静苏醒及脑靶向二级递送机制研究

Gamma sodium hydroxybutyrate (GSH) is the sedative with physiological sleep. However, because of its strong hydrophilicity, it has poor permeability in the blood brain barrier (BBB) and brain tissue (BT), and shows slow onset and recovery, and large dosage. The current formulations without brain targeting have not completely solved the disadvantages of GSH. In this study, the new strategy has been used, including the double targets of cephalin in BBB and phospholipase D in BT, combined with the hydrophobic penetration of phosphatidyl prodrug. The hydrophilic small molecular drug brain targeting nano-helix two stages drug delivery system (HSBH2D) is designed, which is the phosphatidyl hydrophilic small molecule central nervous system prodrug (PHSCP) loaded in the hydrophobic cavity of esterified amylose nano-helix. The preliminary study found HSBH2D mediated GSH to effectively sedate and recover, cephalin triggered HSBH2D to release PHSCP, and phospholipase D enzymolysis PHSCP to release GSH. Therefore, HSBH2D shows the potential to be the new formulation achieved rapid onset, fast recovery, and little dosage. The hypothesis of brain targeting two stages drug delivery in HSBH2D has been proposed: After intravenous injection, the first stage of delivery is that the cephalin in BBB deliveries PHSCP across BBB for triggering the amylose helix; the second stage of delivery is that phospholipase D deliveries GSH to brain parenchyma for enzymolyzing PHSCP. The molecular simulation, fluorescence labeling and other visualized technologies have been applied to testify the hypothesis, which provides the new strategy for hydrophilic small molecule drugs to efficiently act on brain parenchyma.

γ-羟丁酸钠（GSH）具有生理睡眠镇静作用，但亲水性强，导致血脑屏障（BBB）和脑组织（BT）渗透性差，起效与苏醒慢、用量大。现改良制剂无脑靶向，未根本解决GSH缺点。本研究采用BBB脑磷脂和BT磷脂酶D二级靶向，联合磷脂酰前药疏水渗透策略，设计了亲水小分子药物脑靶向纳米螺旋二级递送载药体系(HSBH2D)，其结构为磷脂酰前药 (PHSCP)负载于酯化直链淀粉纳米螺旋疏水腔内。前期研究发现：HSBH2D可实现GSH高效镇静苏醒，脑磷脂触发HSBH2D释放PHSCP，磷脂酶D水解PHSCP释放GSH。因此，HSBH2D有望成为起效与苏醒快、用量少的GSH新剂型；并提出脑靶向二级递送假说：静注后，BBB脑磷脂触发,淀粉螺旋载体一级递送PHSCP通过BBB；磷脂酶D水解，PHSCP二级递送GSH作用脑实质。采用分子模拟、荧光标记等可视化技术验证假说，为亲水小分子药物高效作用脑实质提供新策略。

γ-羟丁酸钠（GSH）具有生理睡眠镇静作用，但亲水性强，导致血脑屏障（BBB）和脑组织渗透性差，起效与苏醒慢、用量大。现改良制剂无脑靶向，未根本解决GSH缺点。本研究采用BBB脑磷脂和脑组织磷脂酶D二级靶向，联合磷脂酰前药疏水渗透策略，设计了亲水小分子药物脑靶向纳米螺旋二级递送载药体系(HSBH2D)，其结构为磷脂酰前药(PHSCP)负载于酯化直链淀粉纳米螺旋疏水腔内。研究发现HSBH2D可实现GSH高效镇静苏醒，脑磷脂触发HSBH2D释放PHSCP，磷脂酶D水解PHSCP释放GSH。因此，HSBH2D有望成为起效与苏醒快、用量少的GSH新剂型；并提出脑靶向二级递送假说：静注后，BBB脑磷脂触发，淀粉螺旋载体一级递送PHSCP通过BBB；磷脂酶D水解，PHSCP二级递送GSH作用脑实质。采用分子模拟、荧光标记等可视化技术验证假说，为亲水小分子药物高效作用脑实质提供新策略。在此研究基础上，并基于中枢神经系统亲疏药物，联合用药可发挥协同效应，然而鲜有相关研究报道，课题组继续研究亲疏水双药制剂。采用分子模拟、电荷测量预测等技术，制备阳离子淀粉球，采用静电吸附实现淀粉球空隙负载GHB，淀粉螺旋内部疏水区负载丙泊酚，制备成Lf-HA-（SNPs -Pro/GHB），并采用小动物成像、有创脑电等技术，验证释放机制假说，即通过Lf-HA与BBB表面Lf受体结合，将载体停泊于BBB表面，通过BBB脑磷脂则解螺旋释放外层丙泊酚，进而使载体纳米球松散缓释内部GHB、丙泊酚，二者再依靠BBB通透性和局部浓度梯度透过BBB，作用于脑实质，从而实现脑靶向、减毒、增效的协同疗效，为亲疏水双药中枢神经系统协同递送提供新思路。