Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug.
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.
College of Pharmacy, Inje University, Gyeongnam 50834, Korea. yohanpark@inje.ac.kr.
Yohan
Y
Park
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea. cyclone5pjh@naver.com.
Ju-Hwan
JH
Park
College of Pharmacy, Inje University, Gyeongnam 50834, Korea. mbong16@gmail.com.
Suryeon
S
Park
College of Pharmacy, Kangwon National University, Gangwon 24341, Korea. heymush@kangwon.ac.kr.
Song Yi
SY
Lee
College of Pharmacy, Inje University, Gyeongnam 50834, Korea. chokh@inje.ac.kr.
Kwan Hyung
KH
Cho
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea. ddkim@snu.ac.kr.
Dae-Duk
DD
Kim
College of Pharmacy, Gachon University, Incheon 21936, Korea. wsshim@gachon.ac.kr.
Won-Sik
WS
Shim
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea. yooninsu99@naver.com.
In-Soo
IS
Yoon
College of Pharmacy, Kangwon National University, Gangwon 24341, Korea. hjcho@kangwon.ac.kr.
Hyun-Jong
HJ
Cho
College of Pharmacy, Gachon University, Incheon 21936, Korea. hjmaeng@gachon.ac.kr.
Han-Joo
HJ
Maeng
D061605:Administration, Intravenous; D000577:Amides / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D011355:Prodrugs; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D014633:Valine / Q000737:chemistry*
D000577:Amides; D011355:Prodrugs; D004317:Doxorubicin; D014633:Valine
amide bond; amino acid transporters; cancer cell; cellular uptake; doxorubicin; valine prodrug
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