Doxorubicin-loaded dextran-based nano-carriers for highly efficient inhibition of lymphoma cell growth and synchronous reduction of cardiac toxicity

Ying Fang,1,* Hao Wang,2,* Hong-Jing Dou,2,* Xing Fan,1,* Xiao-Chun Fei,3 Lei Wang,2 Shu Cheng,1 Anne Janin,4,5 Li Wang,1,4 Wei-Li Zhao1,4 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, China; 3Department of Pathology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 4Sino-French Research Center of Life Science and Genomics, Laboratory of Molecular Pathology, Shanghai, China; 5Joint Research Unit 1165, Inserm, University Paris VII, Saint-Louis Hospital, Paris, France *These authors contributed equally to this work Purpose: Cardiac side effects of doxorubicin (Dox) have limited its clinical application. The aim of this study was to explore new Dox-loaded dextran-based nano-carriers (NCs) in efficiently targeting tumor growth with less cardiac toxicity. Methods: Inspired by recent reports that polymeric NCs could function as sustained, controlled and targeted drug delivery systems, we developed Dox-loaded NCs which displayed a 2-fold release ratio of Dox in the mimic tumor site condition (pH 5.0 with 10 mM glutathione, GSH)as much as that in systemic circulation condition (pH 7.4). Results: Lymphoma cells treated with Dox-NCs had significantly higher intracellular Dox concentrations and more apoptotic induction, with lower P-gp expression, when compared with those treated with Dox alone. The identified mechanism of action, apoptosis, was triggered through survivin reduction and caspase-3 activation. Even in the Dox-resistant cells, Dox-NCs could significantly inhibit cell growth and induce apoptosis. In murine lymphoma xenograft models, Dox-NCs also remarkably significantly retarded tumor growth, assessed by murine weight, and demonstrated less cytotoxicity. Noticeably, apoptotic myocardial cells were decreased in the Dox-NCs-treated group, when compared with the control group, which was consistent with low intracellular Dox concentration in the cardiac cell line H9C2. Conclusion: Dox-NCs showed an anti-lymphoma effect with reduced cardiac toxicity in both in vivo and in vitro models and, therefore, could be a potential therapeutic agent in the treatment of lymphoma. Keywords: anti-lymphoma activity, targeted therapy, doxorubicin-loaded, dextran, nano-carrier, cardiac toxicit