TY - JOUR
T1 - A new approach for the treatment of CLL using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles
AU - Capolla, Sara
AU - Mezzaroba, Nelly
AU - Zorzet, Sonia
AU - Tripodo, Claudio
AU - Mendoza-Maldonado, Ramiro
AU - Granzotto, Marilena
AU - Vita, Francesca
AU - Spretz, Ruben
AU - Larsen, Gustavo
AU - Noriega, Sandra
AU - Mansilla, Eduardo
AU - Dal Bo, Michele
AU - Gattei, Valter
AU - Pozzato, Gabriele
AU - Núñez, Luis
AU - Macor, Paolo
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
KW - chronic lymphocytic leukemia
KW - immune targeted nanoparticles
KW - treatment
KW - xenograft model
UR - http://www.scopus.com/inward/record.url?scp=84958102109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958102109&partnerID=8YFLogxK
U2 - 10.1007/s12274-015-0935-3
DO - 10.1007/s12274-015-0935-3
M3 - Article
AN - SCOPUS:84958102109
VL - 9
SP - 537
EP - 548
JO - Nano Research
JF - Nano Research
SN - 1998-0124
IS - 2
ER -