Novel RNAi Prodrugs Targeting Plk1 Induce Specific mRNA Cleavage in Pediatric Acute B-Cell Lymphoblastic Leukemia

Context Acute B-cell lymphoblastic leukemia (B-cell ALL) is a predominant malignancy among children of different ages. Despite the efficiency of the existing drugs, up to 20% of children are primarily resistant to approved therapies or relapse after the standard treatment. Moreover, patients struggle from acute toxicities and long-term side effects, such as infertility, osteoporosis, and cardiovascular morbidities. Objective Therefore, there is a necessity in novel efficient treatments with minimal side effects. Design Pololike kinases (Plk) belong to the serine-threonine family and are key players in the cell cycle. One of them, Plk1, is expressed at a low level in healthy peripheral blood mononuclear cells (PBMCs), but on a comparatively higher level in malignant lymphoblasts. Therefore, Plk1 is seen as a promising target in hematological malignancies. RNA interference (RNAi) technology has a high potential in cancer treatment due to its specificity. However, the delivery of short interfering ribonucleic acids (siRNAs), which induce RNAi, is a major issue. Setting In this project, we used siRNAs modified into self-delivering short interfering ribonucleic neutrals (siRNNs) in order to overcome the issue of the intracellular siRNA delivery. Once inside the cytoplasm, siRNNs are processed into siRNAs and induce RNAi with a consequent mRNA cleavage of a target protein. Patients or other participants Therefore, Plk1 siRNNs were used to target Plk1 mRNA in the primary B-cells from pediatric B-ALL patients diagnosed and treated at Astrid Lindgren\u0027s Children Hospital (Karolinska University Hospital). Results The results showed that the treatment of primary peripheral blood and bone marrow samples from patients cultured ex vivo with Plk1 siRNNs for 24 and 48 h resulted in a significant (p Conclusions We demonstrate for the first time that siRNNs targeting Plk1 can enter pediatric B-cell ALL patient cells without a transfection reagent and induce significant Plk1 knockdown, resulting in G2/M-arrest, apoptosis, and double-strand DNA breaks. Therefore, Plk1 siRNNs have the potential to be used as selective therapeutic drugs in pediatric B-cell ALL. Grant acknowledgements Swedish Foundation for Strategic Research (C.P.A), the Swedish Childhood Cancer Foundation (C.P.A), Ake Olsson Foundation (C.P.A), Ake Wiberg Foundation (C.P.A), Magnus Bergvall Foundation (C.P.A), Karolinska Institutets Forskningsstiftelser (C.P.A).