转运体介导的肾靶向雷公藤内酯醇前体药物TPS-L-Carnitine的合成及体外细胞摄取研究

李里; 朱迪; 孙逊

转运体介导的肾靶向雷公藤内酯醇前体药物TPS-L-Carnitine的合成及体外细胞摄取研究

Cellular Uptake of TPS-L-Carnitine Synthesised as Transporter-based Renal Targeting Prodrug

摘要

摘要: 【摘要】目的研究有机阳离子转运体(OCN2)介导的肾靶向雷公藤内酯醇(P)前体药物P丁二酸酯(P)-L-肉毒碱(P-L-Carnitine)的合成方法和体外靶向细胞摄取。方法将P与丁二酸酐在碱性条件下生成P,再与L-肉毒碱成酯得前体药物P-L-Carnitine, 利用OCN2对L-肉毒碱的特异性识别和结合，使前药主动靶向到肾近端小管上皮细胞。初步研究不同温度、浓度以及竞争抑制剂存在时人近端小管上皮细胞株K-2细胞对前药和母体药物的摄取。结果 K-2细胞对前药的吸收可饱和，具有温度和浓度依赖性，可被竞争抑制剂抑制，37 ℃相同给药浓度时, 细胞对P-L-Carnitine的摄取明显多于P，证实细胞对P-L-Carnitine的摄取机制是通过转运体介导的内吞作用。结论 P-L-Carnitine具有良好的肾靶向性，为进一步体内肾靶向研究奠定了基础。

Abstract: 【Abstract】 Objective To synthesize transporter-based renal targeting prodrug TPS-L-Carnitine and to determine its cellular uptake in vitro． Methods Triptolide (TP) was conjugated with L-carnitine using succinate as the linker to form TPS-L-Carnitine, which could be specifically recognized by OCTN2, a cationic transporter with high affinity to L-Carnitine and is highly expressed on the apical membrane of renal proximal tubule cells. Cellular uptake assays of the prodrug and its parent drug were performed on HK-2 cells, a human proximal tubule cell line, in different temperature, concentration and in the presence of competitive inhibitors. Results TPS-L-Carnitine was taken up into HK-2 cells in a saturable and temperature- and concentration-dependent manner. The uptake process could be inhibited by the competitive inhibitors. The uptake of TPS-L-Carnitine was significantly higher than that of TP at 37 ℃ in the same drug concentration. TPS-L-Carnitine was taken through endocytosis mediated by transporter. Conclusion 　TPS-L-Carnitine provides a good renal targeting property and lays the foundation for further studies in vivo.

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