2. Academic Validation
  3. Lipopolymer mediated siRNA delivery targeting aberrant oncogenes for effective therapy of myeloid leukemia in preclinical animal models

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

  • J Control Release. 2024 Feb 15:367:821-836. doi: 10.1016/j.jconrel.2024.02.018.
Aysha S Ansari 1,  Remant K C 1,  Luis C Morales 1,  Mohammed Nasrullah 2,  Daniel Nisakar Meenakshi Sundaram 1,  Cezary Kucharski 1,  Xiaoyan Jiang 3,  Joseph Brandwein 4,  Hasan Uludağ 5
Affiliations

Affiliations

  • 1 Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton T6G 1H9, Alberta, Canada.
  • 2 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2H1, Alberta, Canada.
  • 3 Department of Molecular Genetics and Terry Fox Labs, University of British Columbia, Vancouver V5Z 1L3, British Columbia, Canada.
  • 4 Division of Hematology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton T6G 2E1, Alberta, Canada.
  • 5 Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton T6G 1H9, Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2H1, Alberta, Canada. Electronic address: huludag@ualberta.ca.
PMID: 38360178 DOI: 10.1016/j.jconrel.2024.02.018
Abstract

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.

Keywords

Lipopolymers for siRNA delivery; Myeloid leukemia therapy; RNAi therapy; siRNA delivery.

Figures
Products