A novel in vivo nanoparticle-mediated delivery for microRNA in a CLL mouse model: identification of miR-26a as a potential therapeutic agent

Purpose. Chronic lymphocytic Leukemia (CLL) is an indolent but incurable disease. MicroRNAs emerged as promising therapeutic molecules. However, the in vivo delivery of microRNAs is challenging. The purpose of this work is to develop an efficient novel delivery system for microRNAs in CLL mouse model and to identify new microRNAs as potential therapeutic agents. Results. We have successfully developed efficient immune-liposomes formulation composed of anionic lipoplex coupled to antiCD38 (mAb) to specifically target CLL cells. Interestingly, the developed nanoparticles (named CD38-NP) demonstrated approximately 70-fold increase in the level of miR-181b in leukemic splenocytes compared with the cationic polymer PEI. Among tested microRNAs, we successfully identify miR-26a as a potential therapeutic agent in CLL. First, miR-26a selected as a candidate among the group of miR/Anti-miRs tested in vitro and in vivo and viability/apoptosis measured. Second, its anti-leukemic role was validated in a long term treatment in mice with established leukemia. A protocol that included three weeks treatment with miR-26a mimics demonstrated a significant increase in the level of miR-26a in the leukemic splenocytes, accompanied by the down-modulation of the level of its target CDK6 protein. More importantly, a delay in the leukemic cell expansion (LE) was detected at the end of miR26a treatment. Conclusions. These results provide a novel delivery approach, which improves efficiency and specificity of delivery to CD38+ leukemic cells. In addition, we report for the first time that miR-26a exhibit a significant activity in reducing leukemic cells expansion.