Iron complexation to histone deacetylase inhibitors SAHA and LAQ824 in PEGylated liposomes can considerably improve pharmacokinetics in rats.
Iron complexation to histone deacetylase inhibitors SAHA and LAQ824 in PEGylated liposomes can considerably improve pharmacokinetics in rats.
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DOI：
10.18433/j3ts4v
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Xiong M
中科院分区：
文献类型：
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作者：
Wang Y;Tu S;Steffen D;Xiong M
组蛋白去乙酰化酶抑制剂（HDACi）的制剂由于水溶性差和药物在体内的快速消除而具有挑战性。本研究考察了络合铁（Fe 3+）对HDACi辛二酰苯胺异羟肟酸（SAHA）和LAQ 824（LAQ）在其包封到聚乙二醇化脂质体中之前的影响，并考察了这种技术是否可以改善药物溶解度、体外释放和体内药代动力学（PK）性质。测定了SAHA和LAQ铁配合物的反应化学计量、结合常数和溶解度。复合物被动封装到聚乙二醇化脂质体，其特征在于尺寸分布，zeta电位，包封效率（EE），并在体外药物释放研究。PC-3细胞用于验证制剂的体外抗癌活性。评价了脂质体LAQ-Fe（L-LAQ-Fe）在大鼠体内的药代动力学特性。SAHA和LAQ以1：1的化学计量比与Fe形成络合物，结合常数约为104 M−1。Fe络合改善了SAHA和LAQ的水溶性和脂质体包封效率（29- 35%EE，最终药物浓度> ImM）。脂质体包封的复合物（L-HDACi-Fe）表现出持续的体外释放性能相比，L-HDACi，但对PC-3细胞的细胞毒性是相当的游离药物。与游离LAQ（0.79 h，0.5 μg·h/ml）相比，L-LAQ-Fe的PK显示血浆t1/2（12.11 h）改善15倍，AUC∞（105.7 μ g·h/ml）改善211倍。同样，在使用放射性Fe-59的另一项实验中，Fe的血浆t1/2测定为11.83小时。大部分的Fe-59活性被发现在肝脏和脾脏的大鼠和相关的脂质体的单核吞噬细胞系统的摄取。我们已经证明，将HDACi的Fe络合物包封到PEG化脂质体中可以改善总体药物水溶性、体外释放和体内药代动力学性质。
The formulation of histone deacetylase inhibitors (HDACi) is challenging due to poor water solubility and rapid elimination of drugs in vivo. This study investigated the effects of complexing iron (Fe3+) to the HDACi suberoylanilide hydroxamic acid (SAHA) and LAQ824 (LAQ) prior to their encapsulation into PEGylated liposomes, and investigated whether this technique could improve drug solubility, in vitro release and in vivo pharmacokinetic (PK) properties. The reaction stoichiometry, binding constants and solubility were measured for Fe complexes of SAHA and LAQ. The complexes were passively encapsulated into PEGylated liposomes and characterized by size distribution, zeta-potential, encapsulation efficiency (EE), and in vitro drug release studies. PC-3 cells were used to verify the in vitro anticancer activity of the formulations. In vivo pharmacokinetic properties of liposomal LAQ-Fe (L-LAQ-Fe) was evaluated in rats. SAHA and LAQ form complexes with Fe at 1:1 stoichiometric ratio, with a binding constant on the order of 104 M−1. Fe complexation improved the aqueous solubility and the liposomal encapsulation efficiency of SAHA and LAQ (29–35% EE, final drug concentration > 1 mM). Liposomal encapsulated complexes (L-HDACi-Fe) exhibited sustained in vitro release properties compared to L-HDACi but cytotoxicity on PC-3 cells was comparable to free drugs. The PK of L-LAQ-Fe revealed 15-fold improvement in the plasma t1/2 (12.11 h) and 211-fold improvement in the AUC∞ (105.7 μg·h/ml) compared to free LAQ (0.79 h, 0.5 μg·h/ml). Similarly, the plasma t1/2 of Fe was determined to be 11.83 h in a separate experiment using radioactive Fe-59. The majority of Fe-59 activity was found in liver and spleen of rats and correlates with liposomal uptake by the mononuclear phagocyte system. We have demonstrated that encapsulation of Fe complexes of HDACi into PEGylated liposomes can improve overall drug aqueous solubility, in vitro release and in vivo pharmacokinetic properties.