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Nano Research

Article Title

A new approach for the treatment of CLL using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles

Authors

Sara Capolla, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Nelly Mezzaroba, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Sonia Zorzet, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Claudio Tripodo, Department of Human Pathology, University of Palermo, 90133 Sicilia Italy
Ramiro Mendoza-Maldonado, Molecular Oncology Unit, National Laboratory Consorzio Interuniversitatio per le Biotecnologie (CIB), 34012 Trieste, Italy
Marilena Granzotto, Dipartimento Universitario Clinico di Scienze mediche, Chirurgiche e della Salute, University of Trieste, 34149 Trieste, Italy
Francesca Vita, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Ruben Spretz, LNK Chemsolutions LLC, Lincoln, NE 68521, USA
Gustavo Larsen, LNK Chemsolutions LLC, Lincoln, NE 68521, USA Bio-Target Inc., Chicago, IL 60637, USA;
Sandra Noriega, LNK Chemsolutions LLC, Lincoln, NE 68521, USA
Eduardo Mansilla, Centro nico Coordinador de Ablacion e Implante Provincia de Buenos Aires (C.U.C.A.I.B.A.), Ministry of Health, La Plata, Buenos Aires,Argentina
Michele Dal Bo, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico(I.R.C.C.S.), 33081 Aviano, Italy
Valter Gattei, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico(I.R.C.C.S.), 33081 Aviano, Italy
Gabriele Pozzato, Dipartimento Universitario Clinico di Scienze mediche, Chirurgiche e della Salute, University of Trieste, 34149 Trieste, Italy
Luis Núez, LNK Chemsolutions LLC, Lincoln, NE 68521, USA Bio-Target Inc., Chicago, IL 60637, USA;
Paolo Macor, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy Callerio Foundation Onlus, Institutes of Biological Researches, 34127 Trieste, Italy

Keywords

chronic lymphocytic leukemia, immune targeted nanoparticles, treatment, xenograft model

Abstract

ABSTRACT 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.

Graphical Abstract

Publisher

Tsinghua University Press

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