Synthetic diblock copolymer micelles as vectors for siRNA delivery to knockdown RUNX1/ETO in acute myeloid leukaemia cells

Knockdown of RUNX1/ETO using short interfering ribonucleic acids (siRNAs) in vitro has been shown to inhibit acute myeloid leukaemia (AML) cell growth and proliferation. Due to the poor pharmacokinetic properties of siRNA a delivery system is required for therapeutic use in vivo. We propose a polymeric nanoparticle (PNP) system consisting of two diblock copolymers which allow for rapid determination of structure-activity relationships involving gene knockdown and toxicity using a luciferase reporter assay. This high throughput screening method allows rapid determination of the optimum PNP formulation under specific conditions. In the SKNO-1 cell line the optimum PNP formulation was able to knockdown the RUNX1/ETO fusion protein by ˜60% at an mRNA level and ˜40% at a protein level compared to cells treated with PNPs loaded with a non-targeting siRNA. In order to target acute myeloid leukaemia cells in vivo an anti-CD33 scFv has been conjugated to the PNP to increase association with the target tissues. This PNP system offers a flexible method of establishing the optimum particle formulation under a specific set of conditions but requires further development before testing in vivo.