Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.
Thao M NguyenManasi JambhrunkarSook S WongDavid M RossPaul JoyceJohn W FinnieJim ManavisKristen BremmellMelissa R PitmanClive A PrestidgePublished in: Molecular pharmaceutics (2023)
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.
Keyphrases
- acute myeloid leukemia
- drug delivery
- allogeneic hematopoietic stem cell transplantation
- cell death
- induced apoptosis
- cell cycle arrest
- bone marrow
- drug release
- end stage renal disease
- endothelial cells
- chronic kidney disease
- ejection fraction
- mesenchymal stem cells
- signaling pathway
- emergency department
- case report
- acute lymphoblastic leukemia
- endoplasmic reticulum stress
- computed tomography
- newly diagnosed
- skeletal muscle
- risk assessment
- induced pluripotent stem cells
- cell proliferation
- insulin resistance
- tyrosine kinase
- heavy metals
- pi k akt
- smoking cessation
- climate change
- structural basis
- human health
- health risk assessment