CXCR4-antagonistic peptide-decorated lipid nanoparticles for co- delivery of AML1-ETO siRNA to enhance chemotherapy in refractory AML.

Fusion protein AML1-ETO and chemokine receptor CXCR4 are crucial therapeutic targets for AML, the former plays a key role in differentiation blockade and leukemogenesis, and the latter is closely associated with drug resistance and relapse. This work developed a unified platform (referred as to E5-LNP@siAE) to integrate AML1-ETO-targeted RNA interference (RNAi) and CXCR4 antagonism by employing lipid nanoparticle (LNP) technology and antagonistic peptide E5 modification. The E5-LNP@siNC was slightly negative charged with 121.8 nm in diameter, showing homogenous spherical morphology and stability in PBS and 10% FBS. The E5-LNP@siAE could be specifically taken up by Kasumi-1 cells, down regulated levels of AML1-ETO, p-Erk and p-p38, and E5-LNP@siNC inhibited the CXCL12-mediated migration. In a refractory AML mouse model, E5-LNP@siAE monotherapy significantly reduced AML cells in peripheral blood, as well as infiltrations in the liver, lung and spleen. The expressions of CD11b, CD41a and Ter119 were upregulated while c-Kit decreased in the spleen of AML mice received E5-LNP@siAE treatment. The differentiation inductive effects were also observed in bone marrow mononuclear cells separated from AML patients with t(8;21) translocation. Moreover, E5-LNP@siAE significantly enhanced the therapeutic efficacy of doxorubicin (DOX) in the AML mice, evidenced by the reduced AML cells in peripheral blood, bone marrow and multiple organs, meanwhile, did not bring negative impacts on the counts of red blood cells and platelets. Consequently, the combination regimen achieved the much better result of survival prolongation than E5-LNP@siAE monotherapy, and the other control groups did not show therapeutic effects on the survival of the AML mice.