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

Authors Fang Y, Wang H, Dou HJ, Fan X, Fei XC, Wang L, Cheng S, Janin A, Wang L, Zhao WL

Received 31 December 2017

Accepted for publication 16 July 2018

Published 24 September 2018 Volume 2018:13 Pages 5673—5683

DOI https://doi.org/10.2147/IJN.S161203

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 3

Editor who approved publication: Dr Lei Yang


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 toxicity

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