Therapeutic targeting of chronic lymphocytic leukemia by silver nanoparticles

Abstract

Abstract Background Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances obtained in CLL therapy with the new target agents, in some cases relapses and resistances could occur making necessary the finding of new alternatives to manage CLL refractoriness. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored.Methods We studied the action mechanisms of AgNPs in vitro by flow-cytometry and molecular analyses. To improve bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake and efficacy.Results AgNPs reduced viability of CLL primary cells and HG-3 cell line by activating intrinsic apoptotic pathway characterized by Bax/Bcl-2 unbalance, caspase activation and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib and Bepridil. In vitro, AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and in vivo, they strongly prolonged survival of CLL xenograft models compared to each unconjugated single agent.Conclusions AgNPs showed a strong anti-leukemic activity in CLL with the potential to clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs non-specific distribution and for increasing their efficacy.