Bone Marrow Microenvironment-Responsive Nanomedicine Promotes Anti-Leukemia Activity In Vivo

Abstract

Background: Leukemia escape and relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). Work over the past decades has demonstrated that the CD47- signal-regulatory protein α (SIRPa) interaction mediated cancer cell immune escape. Although CD47-SIRPα interaction blockade contributes to cancer cell clearance by macrophages, how to deliver the anti-CD47 to bone marrow niche through an efficient drug delivery strategy and improve the cytotoxic activity of macrophages is an important issue that needs to be addressed. Methods: Here, we performed immunohistochemical (IHC) analysis and flow cytometry analysis of TIM-3 expression using samples of bone marrow from patients with or without relapse. In addition, according to the natural “myeloid niche homing” characteristic of AML cells and the low-oxygen microenvironment in bone marrow, we constructed β-cyclodextrin azobenzene linker (AZO-β-CD)-modified fusion protein and amantadine-modified HSA protein (HSA-ADA), followed by the addition of anti-CD47. Furthermore, the nanogel TIM3-targeting antibodies were modified on the surface of the nanogel to finally construct the supramolecular nanogel delivery system. Moreover, we detected the effect of target nanomedicine in a leukemia xenograft mouse model. Results: We demonstrated that in the bone marrow microenvironment of patients with relapse, the expression of TIM-3 significantly increased, especially in the CD34 +CD38 + leukemic progenitors, but not in the HSCs. Furthermore, we verified using nanomedicine could significantly increase the number of macrophages in the bone marrow. Importantly, the blockade of CD47-SIRPα signaling using nanomedicine markedly improved the anti-tumor activity in a leukemia xenograft mouse model. Conclusion: Thus, our findings reveal that nanomedicine could inhibit CD47-SIRPα signaling and contribute to anti-leukemia function effectively, which may be a new strategy for preventing and treating the recurrence of AML after transplantation.