A Dual-Function\nLipoAraN-E5 Coloaded with <i>N</i><sup>4</sup>‑Myristyloxycarbonyl-1-β‑d‑arabinofuranosylcytosine (AraN) and a CXCR4 Antagonistic\nPeptide (E5) for Blocking the Dissemination of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematological malignancy\nwith\na high recurrence rate. The interaction of chemokine receptor 4/chemokine\nligand 12 (CXCR4/CXCL12) mediates homing and adhesion of AML cells\nin bone marrow, leading to minimal residual disease in patients, which\nbrings a hidden danger for future AML recurrence. Ara-C is a nonselective\nchemotherapeutic agent against AML. Due to its short half-life and\nsevere side effects, a lipid-like Ara-C derivative (AraN) was synthesized\nand a dual-function LipoAraN-E5 (135 nm, encapsulation efficiency\n99%) was developed, which coloaded AraN and E5, a peptide of the CXCR4\nantagonist. LipoAraN-E5 effectively improved the uptake, enhanced\nthe inhibition of leukemia cell proliferation, migration, and adhesion\nto stromal cells in bone marrow, and mobilized the leukemia cells\nfrom bone marrow to peripheral blood via interfering with the CXCR4/CXCL12\naxis. LipoAraN-E5 prolonged the plasma half-life of AraN (8.31 vs\n0.56 h) and was highly enriched in peripheral blood (3.67 vs 0.05\nμmol/g at 8 h) and bone marrow (379 vs 148 μmol/g at 24\nh). LipoAraN-E5 effectively prevented the infiltration of leukemia\ncells in peripheral blood, bone marrow, spleen, and liver, prolonged\nthe mice survival, and showed outstanding antineoplastic efficacy\nwith negligible toxicity, which were attributed to the ingenious design\nof AraN, the use of a liposomal delivery carrier, and the introduction\nof E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate\nagainst AML.