Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes

• Published in: Molecular pharmaceutics Vol. 20; no. 8; pp. 3937 - 3946
• Main Authors: Nguyen, Thao M., Jambhrunkar, Manasi, Wong, Sook S., Ross, David M., Joyce, Paul, Finnie, John W., Manavis, Jim, Bremmell, Kristen, Pitman, Melissa R., Prestidge, Clive A.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.08.2023
• Subjects: Animals; Cell Line, Tumor; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Liposomes - therapeutic use; Mice; Phosphotransferases (Alcohol Group Acceptor); Tissue Distribution; nanomedicine; acute myeloid leukemia; liposomal drug encapsulation; sphingosine kinase 1
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.3c00078

Acute myeloid leukemia (AML) kills 75% of patients and represents a major clinical challenge with a need to improve on current treatment approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor, MP-A08, induces cell death in AML. However, limitations in MP-A08’s “drug-like properties” (solubility, biodistribution, and potency) hinder its pathway to the clinic. This study demonstrates a liposome-based delivery system of MP-A08 that exhibits enhanced MP-A08 potency against AML cells. MP-A08-liposomes increased MP-A08 efficacy against patient AML cells (>140-fold) and significantly prolonged overall survival of mice with human AML disease (P = 0.03). The significant antileukemic property of MP-A08-liposomes could be attributed to its enhanced specificity, bioaccessibility, and delivery to the bone marrow, as demonstrated in the pharmacokinetic and biodistribution studies. Our findings indicate that MP-A08-liposomes have potential as a novel treatment for AML.