Abstract
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.
Highlights
B-cell malignancies are a heterogeneous group of clinical conditions with highly variable clinical courses that span between indolent diseases like the chronic lymphocytic leukemia (CLL) and highly aggressive lymphoproliferative disorders, like Burkitt lymphoma (BL) [1,2,3,4]
We demonstrate the ability of a certain class of nanoparticles to kill p53 mutated/deleted leukemia/lymphoma cells expressing a low amount of CD20, and their safety and therapeutic effects in a BL model, as an aggressive lymphoprolipherative disease prototype
The use of Ab-coated nanoparticles represents a new strategy to target only tumor cells with high-dose chemotherapy, even in the context of an adverse genetic profile. We characterized both in vitro and in vivo the effects of a new kind of biodegradable nanoparticles coated with the anti-CD20 chimeric antibody Rituximab, and loaded with CLB and HCQ
Summary
B-cell malignancies are a heterogeneous group of clinical conditions with highly variable clinical courses that span between indolent diseases like the chronic lymphocytic leukemia (CLL) and highly aggressive lymphoproliferative disorders, like Burkitt lymphoma (BL) [1,2,3,4]. B-cell tumor treatments include doseintensive chemotherapy regimens and immunotherapy via monoclonal antibodies (mAbs) [5]. Despite the promising survival rates, these intensive multi-agent treatments display a high degree of toxicity, and a significant percentage of patients are unresponsive [6,7,8]. Several limitations have been described to explain refractory/relapse patients. Genetic modification in specific onco- or oncosuppressor genes, such as p53 [9], is associated with unsuccessful chemotherapeutic regimens. Antibody-based immunotherapy has little side effects but its efficacy is mainly driven by the expression of sufficient amounts of tumorassociated antigen on the neoplastic cell surface [10]
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