New potential therapeutic approach for the treatment of B-Cell malignancies using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles

• Published in: PloS one 2013-09, Vol.8 (9), p.e74216
• Main Authors: Mezzaroba, Nelly, Zorzet, Sonia, Secco, Erika, Biffi, Stefania, Tripodo, Claudio, Calvaruso, Marco, Mendoza-Maldonado, Ramiro, Capolla, Sara, Granzotto, Marilena, Spretz, Ruben, Larsen, Gustavo, Noriega, Sandra, Lucafò, Marianna, Mansilla, Eduardo, Garrovo, Chiara, Marín, Gustavo H, Baj, Gabriele, Gattei, Valter, Pozzato, Gabriele, Núñez, Luis, Macor, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antigens, CD20 - immunology; Antigens, CD20 - therapeutic use; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Biodegradability; Biodegradation; Blood & organ donations; Burkitt's lymphoma; Cancer; Cancer therapies; CD20 antigen; Cell Survival - drug effects; Chemical compounds; Chemotherapy; Childrens health; Chlorambucil; Chlorambucil - pharmacology; Chlorambucil - therapeutic use; Cloning; Coating effects; Cyclin-dependent kinases; Cytotoxic agents; Cytotoxicity; Disease Models, Animal; Drug Combinations; Drug Delivery Systems - methods; Drug dosages; Female; Flow Cytometry; Health aspects; Hydroxychloroquine; Hydroxychloroquine - pharmacology; Hydroxychloroquine - therapeutic use; Immunoglobulins; Immunohistochemistry; Immunotherapy; Killing; Kinases; Laboratories; Leukemia; Life sciences; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - drug therapy; Lymphomas; Maternal & child health; Mice; Mice, SCID; Microscopy, Electron, Transmission; Monoclonal antibodies; Nanoparticles; Nanoparticles - therapeutic use; Non-Hodgkin's lymphomas; p53 Protein; Patients; Pharmacology; Polyethylene glycol; Rituximab; Targeted cancer therapy; Tumor cell lines; Tumor proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0074216

Current B-cell disorder treatments take advantage of dose-intensive chemotherapy regimens and immunotherapy via use of monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents, and often cause adverse effects on patients. In this contribution, we propose a novel therapeutic approach in which relatively high doses of Hydroxychloroquine and Chlorambucil were loaded into biodegradable nanoparticles coated with an anti-CD20 antibody. We demonstrate their ability to effectively target and internalize in tumor B-cells. Moreover, these nanoparticles were able to kill not only p53 mutated/deleted lymphoma cell lines expressing a low amount of CD20, but also circulating primary cells purified from chronic lymphocitic leukemia patients. Their safety was demonstrated in healthy mice, and their therapeutic effects in a new model of Burkitt's lymphoma. The latter serves as a prototype of an aggressive lympho-proliferative disease. In vitro and in vivo data showed the ability of anti-CD20 nanoparticles loaded with Hydroxychloroquine and Chlorambucil to increase tumor cell killing in comparison to free cytotoxic agents or Rituximab. These results shed light on the potential of anti-CD20 nanoparticles carrying Hydroxychloroquine and Chlorambucil for controlling a disseminated model of aggressive lymphoma, and lend credence to the idea of adopting this therapeutic approach for the treatment of B-cell disorders.