Lipopolymer Mediated siRNA Delivery Targeting Aberrant Oncogenes for Effective Therapy of Myeloid Leukemia

Abstract

Abstract In contrast to exploiting proteins as targets like most conventional drugs and tyrosine kinase inhibitors (TKI), that are rendered futile in the face of emerging drug resistance, RNA Interference (RNAi) exerts its therapeutic action towards disease-driving aberrant genes. To realize the potential of RNAi, the major challenge is to efficiently deliver the therapeutic mediator of RNAi, small interfering RNA (siRNA) molecules. In this study, we explored the feasibility of using aliphatic lipid-grafted polymers (lipopolymers) for the delivery of siRNAs against the FLT3 oncogene in acute myeloid leukemia (AML) and BCR-ABL oncogene in chronic myeloid leukemia (CML). The lipopolymer delivered siRNA potently suppressed the proliferation AML and CML cells via silencing of the targeted oncogenes. In mouse subcutaneous xenograft models, intravenously administered lipopolymer/siRNA complexes displayed significant inhibitory effect on tumor growth. Combining siFLT3 complexes with gilteritinib allowed for reduction of effective drug dosage, longer duration of remission, and enhanced survival after relapse. Anti-leukemic activity of siBCR-ABL complexes was similar in wild-type and TKI-resistant cells, and therapeutic efficacy was confirmed in vivo through prolonged survival of the NCG hosts systemically implanted with TKI-resistant cells. These results demonstrate the preclinical efficacy of lipopolymer facilitated siRNA delivery, providing a novel therapeutic platform for myeloid leukemias.