CXCR4 and CD44 dual-targeted Prussian blue nanosystem with daunorubicin loaded for acute myeloid leukemia therapy

Abstract

Chemotherapy has been major and standard strategy that is widely used in the treatment of acute myeloid leukemia (AML). However, for the lack of specificity of free drugs, patients are suffering from the non-specific toxicity and high recurrence rate. The C-X-C chemokine receptor type 4 (CXCR4) and cluster determinant 44 (CD44) are becoming highly appealing target candidates as the markers for AML relapse. Here, we designed and fabricated pH-responsive CXCR4 and CD44 dual-targeted nanosystems, based on Prussian blue nanoparticles (PBNPs) for AML therapy. The polyethylene glycol-grafted polyethylenimine with benzoic-imine bond modified PBNPs were synthesized and then functionalized with CXCR4 targeting peptide E5 and CD44 targeting moiety hyaluronic acid (HA). Daunorubicin (DNR) was selected as a model anti-AML drug. The dual-targeted PBNPs achieved not only effective endosomal escape but also prolonged blood retention time in physiological condition. Moreover, the cleavage of PEG chain in the endosome enabled to rapidly release DNR. The dual-targeted PBNPs exhibited increased internalization, improved anti-HL60 cells effect, and reduced HL60 cells migration and adhesion induced by bone marrow stroma cells compared with mono-targeted PBNPs. The in vivo results showed that DNR-loaded dual-targeted PBNPs displayed more powerful capability to block the proliferation of leukemia blasts in bone marrow, peripheral blood and spleen in AML mice xenograft model. More importantly, the dual-targeted PBNPs also inhibited leukemia blasts metastatic to liver and spleen, reversed splenomegaly, and extended the overall survival. Therefore, the dual-targeted PBNPs represent a promising strategy for advancing therapeutics for AML therapy.