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Molecules 2016, 21(10), 1272;

Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug

College of Pharmacy, Inje University, Gyeongnam 50834, Korea
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
College of Pharmacy, Kangwon National University, Gangwon 24341, Korea
College of Pharmacy, Gachon University, Incheon 21936, Korea
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 1 August 2016 / Revised: 9 September 2016 / Accepted: 17 September 2016 / Published: 22 September 2016
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [1933 KB, uploaded 22 September 2016]   |  


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. View Full-Text
Keywords: amino acid transporters; cancer cell; cellular uptake; doxorubicin; valine prodrug; amide bond amino acid transporters; cancer cell; cellular uptake; doxorubicin; valine prodrug; amide bond

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Park, Y.; Park, J.-H.; Park, S.; Lee, S.Y.; Cho, K.H.; Kim, D.-D.; Shim, W.-S.; Yoon, I.-S.; Cho, H.-J.; Maeng, H.-J. Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug. Molecules 2016, 21, 1272.

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