B-Chronic Lymphocytic Leukemia Autophagyc Cell Death by the Use of Manganese Doped Zinc Oxide Nanoparticles and Photo-Dynamic Therapy.

Peña Luengas Sandra, Marín Gustavo H., Rodríguez Nieto Felipe, Dreon Marcos, Roque Gustavo, Núñez Luis, Sanchez Fransisco,Tarditti Adrian, Schinella Guillermo, Pistaccio Luis, Goya Rodolfo, Tau Jose Maria, Ichim Thomas, Riordan Neil, Rivera-Montalvo Luis, Mansilla Eduardo.

B-Chronic Lymphocytic Leukemia (B-CLL) usually follows an adverse, relentless clinical course by slowly developing drug resistance to fludarabine and other chemo-therapeutic agents, as well as by acquiring new different genetic abnormalities.  As these cells spontaneously produce high amounts of Reactive Oxygen Species (ROS) having an altered redox state in relation to that of normal B lymphocytes, we decided to probe different metal Zinc nanoparticles (ZnNPs), quantifying the levels of Singlet Oxigen (SO) and see if variations of its intracellular concentrations could execute and accelerate deadly programs in leukemic cells when applied with Photodynamic Therapy (PDT), producing almost no significant damage on normal B lymphocytes. In this way, we developed and tested a variety of metal ZnNPs of which one made of 0.5% Manganese Doped Zinc Oxide (MnZnO) was finally selected for further testing as it had the best killing activity in fludarabine resistant B-CLL cells, specially when combined with PDT. An interesting and rapidly dying process of B-CLL cells, known as autophagy, was seen under Transmission Electronic Microscopy (TEM) when incubated with these 0.5% Mn doped ZnO NPs. This phenomenon correlated well with those intracellular increases of SO when PDT was administered, and measured by a novel method first described by us. As this therapy seems to be very specific to fludarabine resistant B-CLL cells, without much harm to normal lymphocytes, it could contribute in the near future as a new innovative targeted strategy to be delivered in the clinical setting, for the definitive benefit of these bad prognostic patients.

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