International journal of nanomedicine
Liposomal-Mitoxantrone Overcomes Acquired Resistance and Enhances Venetoclax Synergy in AML-Mechanistic Insights and Preliminary Clinical Evidence
By Luo K, Hui Y, Shen H and 7 others.
Abstract
Introduction
Liposomal drug delivery has emerged as a promising strategy to improve the efficacy and safety of chemotherapeutic agents, yet whether and how liposomal reformulation fundamentally reshapes therapeutic response and resistance evolution remains unclear. This study compared liposomal mitoxantrone with free mitoxantrone and examined their effects on antileukemic activity, hematologic toxicity, resistance development, and cell-death pathways.
Methods
Liposomal and free mitoxantrone were evaluated in an MLL-AF9-driven acute myeloid leukemia mouse model by survival analysis and peripheral blood measurements. Secondary transplantation experiments were performed to evaluate the sensitivity of residual leukemia cells. Single-cell RNA sequencing was used to characterize transcriptional features of residual leukemia cells. Drug combination with venetoclax and the cell killing pattern of the two drugs were explored based on MOLM13 cell line. Exploratory clinical observations were additionally obtained from four patients who received liposomal mitoxantrone in combination with venetoclax.