Park Yohan, Park Ju-Hwan, Park Suryeon, Lee Song Yi, Cho Kwan Hyung, Kim Dae-Duk, Shim Won-Sik, Yoon In-Soo, Cho Hyun-Jong, Maeng Han-Joo
College of Pharmacy, Inje University, Gyeongnam 50834, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
Molecules. 2016 Sep 22;21(10):1272. doi: 10.3390/molecules21101272.
In this study, we synthesized the valine (Val)-conjugated amide prodrug of doxorubicin (DOX) by the formation of amide bonds between DOX and Val. The synthesis of the DOX-Val prodrug was identified by a proton nuclear magnetic resonance (¹H-NMR) assay. In the MCF-7 cells (human breast adenocarcinoma cell; amino acid transporter-positive cell), the cellular accumulation efficiency of DOX-Val was higher than that of DOX according to the flow cytometry analysis data. Using confocal laser scanning microscopy (CLSM) imaging, it was confirmed that DOX-Val as well as DOX was mainly distributed in the nucleus of cancer cells. DOX-Val was intravenously administered to rats at a dose of 4 mg/kg, and the plasma concentrations of DOX-Val (prodrug) and DOX (formed metabolite) were quantitatively determined. Based on the systemic exposure (represented as area under the curve (AUC) values) of DOX-Val (prodrug) and DOX (formed metabolite), approximately half of DOX-Val seemed to be metabolized into DOX. However, it is expected that the remaining DOX-Val may exert improved cellular uptake efficiency in cancer cells after its delivery to the cancer region.
在本研究中，我们通过在阿霉素（DOX）和缬氨酸（Val）之间形成酰胺键，合成了缬氨酸共轭的阿霉素酰胺前药。阿霉素-缬氨酸前药的合成通过质子核磁共振（¹H-NMR）分析进行鉴定。根据流式细胞术分析数据，在MCF-7细胞（人乳腺腺癌细胞；氨基酸转运体阳性细胞）中，阿霉素-缬氨酸的细胞摄取效率高于阿霉素。使用共聚焦激光扫描显微镜（CLSM）成像证实，阿霉素-缬氨酸以及阿霉素主要分布在癌细胞的细胞核中。以4 mg/kg的剂量将阿霉素-缬氨酸静脉注射给大鼠，并定量测定阿霉素-缬氨酸（前药）和阿霉素（形成的代谢物）的血浆浓度。基于阿霉素-缬氨酸（前药）和阿霉素（形成的代谢物）的全身暴露（以曲线下面积（AUC）值表示），大约一半的阿霉素-缬氨酸似乎代谢为阿霉素。然而，预计剩余的阿霉素-缬氨酸在输送到癌症区域后，可能会提高癌细胞对其的摄取效率。
