目的 基于顶端钠依赖性胆盐转运体（ASBT）对胆酸（BA）的特异性识别，为提高阿苯达唑（ABZ）的跨膜转运效率，制备阿苯达唑-胆酸衍生物（ABZ-C6O2-BA），并对其固态性质、跨膜转运行为和降解机制进行评价。方法 以6-氨基-1-羟基-二己脂作为Linker连接ABZ与BA，合成ABZ-C6O2-BA；使用核磁共振氢谱（¹H-NMR）和傅里叶红外技术（FTIR）对ABZ-C6O2-BA进行验证；通过粉末X射线衍射（PXRD）法、差示扫描量热（DSC）法和扫描电子显微镜（SEM）法进行固态性质的表征；建立Caco-2单层细胞模型在体外对ABZ-C6O2-BA进行跨膜转运研究；进行ABZ-C6O2-BA体外羧酸酯酶（CES）水解反应，通过超高效液相色谱-质谱联用（UPLC-MS）定性分析ABZ-C6O2-BA水解产物。结果 ¹H-NMR和FT-IR结果显示特征峰的偏移，证实ABZ-C6O2-BA制备成功；PXRD、DSC和SEM结果显示ABZ-C6O2-BA为无定型形态，且微观结构较ABZ有明显不同；体外跨膜转运实验结果显示高质量浓度的ABZ-C6O2-BA跨膜转运表观渗透系数（P_app）显著高于高浓度的ABZ（P＜0.05），中、低质量浓度的ABZ-C6O2-BA P_app相近于ABZ；ABZ-C6O2-BA在72 h时降解率＞92.8%，代谢良好；通过UPLC-MS定性分析ABZ-C6O2-BA水解产物为ABZ-Linker，即CES水解了酯键，使得BA与ABZ分开。结论 所制备的ABZ-C6O2-BA以无定型态存在，跨膜转运效率在一定浓度下较ABZ显著增加，且与浓度不相关，推测跨膜方式为主动转运，连接的BA可被体内的酶水解。

Objective To improve the transcellular transport efficiency of albendazole (ABZ) by preparing a novel compound, ABZC6O2-BA, based on the specific recognition of the apical sodium-dependent bile acid transporter (ASBT) for bile acid (BA). The solid state properties, transcellular transport behavior, and degradation mechanism of ABZ-C6O2-BA were evaluated. Method ABZC6O2-BA was synthesized by linking ABZ with BA using 6-aminodihydroxy-dipentyl glycerol as the linker. The synthesized ABZC6O2-BA was verified by ¹H-NMR and FT-IR. The solid state properties were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The transcellular transport behavior of ABZC6O2-BA was studied in vitro using a Caco-2 monolayer cell model. The degradation mechanism of ABZ-C6O2-BA was evaluated by in vitro carboxylesterase (CES) hydrolysis, and the hydrolysis products were quantitatively analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS). Results The ¹H-NMR and FT-IR results showed a shift in characteristic peaks, confirming the successful synthesis of ABZ-C6O2-BA. The PXRD, DSC, and SEM results showed that ABZ-C6O2-BA was amorphous in form, and its microstructure was significantly different from that of ABZ. The in vitro transcellular transport experiment results showed that the apparent permeability coefficient (P_app) of high-quality ABZ-C6O2-BA across the membrane was significantly higher than that of high-concentration ABZ (P < 0.05), and the P_app of medium-and low-quality ABZ-C6O2-BA was similar to that of ABZ. The degradation rate of ABZ-C6O2-BA was > 92.8% at 72 h. By UPLC-MS qualitative analysis, the hydrolysis product of ABZ-C6O2-BA was identified as ABZ-Linker, indicating that the CES hydrolyzed the ester bond, separating BA from ABZ. Conclusion The ABZ-C6O2-BA prepared in this study exists in an amorphous state, and its transmembrane transport efficiency is significantly increased at certain concentrations, which is independent of the concentration, suggesting that the transmembrane mode is active transport. The connected BA can be hydrolyzed by enzymes in the body.

R943

2022年青海省科技厅科技援青合作专项（2022-QY-201）