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Current approaches for the treatment of chronic lymphocytic leukemia (CLL) have greatly improved the prognosis for survival, but some patients remain refractive to these therapeutic regimens. Hence, in addition to reducing the long-term sideeffects of therapeutics for all leukemia patients, there is an urgent need for novel therapeutic strategies for difficult-to-treat leukemia cases. Due to the cytotoxicity of drugs, the major challenge currently is to deliver the therapeutic agents to neoplastic cells while preserving the viability of non-malignant cells. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanoparticles coated with an anti-CD20 antibody.We first demonstrated the ability of the nanoparticles to target and internalize in tumor B-cells. Moreover, these nanoparticles could kill not only p53-mutated/deleted leukemia cells expressing a low amount of CD20, but also circulating primary cells isolated from chronic lymphocytic leukemia patients. The safety of these nanoparticles was also demonstrated in healthy mice, and their therapeutic effects were shown in a new model of aggressive leukemia. These results showed that anti-CD20 nanoparticles containing hydroxychloroquine and chlorambucil can be effective in controlling aggressive leukemia and provided a rationale for adopting this approach for the treatment of other B-cell disorders.

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Publication history

Received: 16 July 2015
Revised: 27 October 2015
Accepted: 30 October 2015
Published: 10 December 2015
Issue date: February 2016

Copyright

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2015

Acknowledgements

Acknowledgements

This study has been made possible by research grants from Italian Association for Cancer Research (AIRC Project No. 12965/2012), Italian Ministry of Health (Nos. GR-2011-02346826 and GR-2011-02347441), Fondazione Casali-Trieste, Italy and Stiftung Foundation-Liechtenstein. Nanoparticles fabrication at LNK Chemsolutions, USA, was possible in part by Grant 2R44CA135906-02 (SBIR Phase Ⅱ) from the National Institutes of Health (USA) to Ruben Spretz, Gustavo Larsen, Sandra Noriega and Luis Núñez.

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Reprints and Permission requests may be sought directly from editorial office.
Email: nanores@tup.tsinghua.edu.cn

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