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

作　　者：Sara Capolla Nelly Mezzaroba Sonia Zorzet Claudio Tripodo Ramiro Mendoza-Maldonado Marilena Granzotto Francesca Vita Ruben Spretz Gustavo Larsen Sandra Noriega Eduardo Mansilla Michele Dal Bo Valter Gattei Gabriele Pozzato Luis Nunez Paolo Macor 

机构地区：[1]Department of Life Sciences, University of Trieste, 34127 Trieste, Italy [2]Department of Human Pathology, University of Palermo, 90133 Sicilia, Italy [3]Molecular Oncology Unit, National Laboratory Consorzio Interuniversitatio per le Biotecnologie (CIB), 34012 Trieste, Italy [4]Dipartimento Universitario Clinico di Scienze mediche, Chirurgiche e della Salute, University of Trieste, 34149 Trieste, Italy [5]LNK Chemsolutions LLC, Lincoln, NE 68521, USA [6]Bio-Target Inc., Chicago, IL 60637, USA [7]Centro Unico Coordinador de Ablacion e Implante Provincia de Buenos Aires (C.U.CA.I.B.A.), Ministry of Health, La Plata, Buenos Aires,Argentina [8]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 [9]Callerio Foundation Onlus, Institutes of Biological Researches, 34127 Trieste, Italy

出　　处：《Nano Research》2016年第2期537-548,共12页纳米研究（英文版）

摘　　要：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 side- effects 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 ceils. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanopartides 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 ceils 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.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 side- effects 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 ceils. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanopartides 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 ceils 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.

关 键 词：chronic lymphocytic leukemia immune targeted nanoparticles TREATMENT xenograft model 

分 类 号：O531.5[理学—等离子体物理] S858.315.3[理学—物理]