Lipopolymer mediated siRNA delivery targeting aberrant oncogenes for effective therapy of myeloid leukemia in preclinical animal models

• Published in: Journal of controlled release 2024-03, Vol.367, p.821-836
• Main Authors: Ansari, Aysha S., K.C., Remant, Morales, Luis C., Nasrullah, Mohammad, Meenakshi Sundaram, Daniel Nisakar, Kucharski, Cezary, Jiang, Xiaoyan, Brandwein, Joseph, Uludağ, Hasan
• Format: Article
• Language: English
• Subjects: Aniline Compounds; Animals; dodecanoic acid; drug resistance; Drug Resistance, Neoplasm; drugs; Fusion Proteins, bcr-abl - genetics; Humans; intravenous injection; landscapes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; linoleic acid; Lipopolymers for siRNA delivery; Mice; Models, Animal; myeloid leukemia; Myeloid leukemia therapy; Oncogenes; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrazines; relapse; remission; RNA; RNA interference; RNA, Small Interfering; RNAi therapy; siRNA delivery; tyrosine; xenotransplantation
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2024.02.018

The clinical development of tyrosine kinase inhibitors (TKI) has led to great strides in improving the survival of chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) patients. But even the new generation TKIs are rendered futile in the face of evolving landscape of acquired mutations leading to drug resistance, necessitating the pursuit of alternative therapeutic approaches. In contrast to exploiting proteins as targets like most conventional drugs and TKIs, 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 (linoleic acid and lauric acid)-grafted polymers (lipopolymers) for the delivery of siRNAs against the FLT3 oncogene in AML and BCR-ABL oncogene in CML. The lipopolymer delivered siRNA potently suppressed the proliferation AML and CML cells via silencing of the targeted oncogenes. In both AML and CML subcutaneous xenografts generated in NCG mice, 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, compared to gilteritinib monotherapy. 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. [Display omitted] •Lipopolymers showed superior siRNA delivery in ‘hard-to-transfect’ leukemia cells.•Lipopolymer/siFLT3 complexes demonstrated therapeutic efficacy in FLT3-ITD AML animal models as monotherapy and in combination with gilteritinib.•Treatment with lipopolymer/siBCR-ABL complexes enhanced survival in mice bearing imatinib-resistant CML xenografts.