Targeted Cancer Therapy with a 2-Deoxyglucose–Based Adriamycin Complex

Jie Cao,Jie Cao,Jie Cao,Changli Du,Zhiyu Qian,Zhiyu Qian,Zhiyu Qian,Yueqing Gu,Yueqing Gu,Yueqing Gu,Siwen Li,Siwen Li,Siwen Li,Sisi Cui,Sisi Cui,Sisi Cui,Wei R Chen,Wei R Chen,Wei R Chen,Shunan Wan,Guangji Wang,Guangji Wang,Guangji Wang,Junmei Tian

doi:10.1158/0008-5472.can-12-2072

Abstract

Adriamycin (ADM) has been effective against many types of solid tumors in clinical applications. However, its use is limited because of systemic toxicities, primarily cardiotoxicity, and multidrug resistance. In this study, a new active receptor-mediated complex, ADM conjugated with 2-amino-2-deoxy-d-glucose and succinic acid (2DG-SUC-ADM), was designed to target tumor cells through glucose transporter 1 (GLUT1). MTT assay and confocal images showed that the complex had better inhibition rate to tumor cells and low toxicity to normal cells. Most importantly, the complex displayed a potential to reverse overcome multidrug resistance in cancer cells, with more complex transported into the nucleus of tumor cells. Our in vivo experiments also showed that this new complex could significantly decrease organ toxicity and enhance the antitumor efficacy compared with free ADM, indicating a promising drug of 2DG-SUC-ADM for targeted cancer therapy.

Highlights

Anticancer drugs have been used extensively in cancer therapy over the past 6 decades [1]
We developed a new active receptor-mediated complex, by conjugating adriamycin with 2-amino-2-deoxy-Dglucose and succinic acid (2DG–SUC–ADM), which modified the primary amine group with 2DG using succinic anhydride as reaction linkage
The successful conjugation of 2DG and ADM was further evidenced by mass spectrum and nuclear magnetic resonance (NMR)

Summary

Introduction

Anticancer drugs have been used extensively in cancer therapy over the past 6 decades [1]. Most anticancer drugs are small molecules that penetrate into cells by diffusion [2, 3]. One of their main drawbacks is that these therapeutic agents cannot target tumor cells within the pathologic sites, which both weakens their anticancer effects and results in serious toxic and side effects [4,5,6,7]. Multidrug resistance of ADM limits its clinical applications To overcome these limitations, loading ADM into macromolecular carriers, such as iron oxide, carboxymethylpullulan, poly (L-lysine citramide), and polyethylene glycol has attracted much attention [8,9,10,11]. Such delivery systems can Authors' Affiliations: 1Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University; 2Department of Biomedical Engineering, School of Automation, Nanjing University of Aeronautics and Astronautics, Nanjing, China; and 3Department of Engineering and Physics, University of Central Oklahoma, Edmond, Oklahoma; 4State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China

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Conclusion