Nanoparticle‐Mediated Delivery of Micheliolide Analogs to Eliminate Leukemic Stem Cells in the Bone Marrow
- 8 October 2021
- journal article
- research article
- Published by Wiley in Advanced Therapeutics
- Vol. 5 (1), 2100100
- https://doi.org/10.1002/adtp.202100100
Abstract
Micheliolide (MCL) is a naturally occurring sesquiterpene lactone that selectively targets leukemic stem cells (LSCs), which persist after conventional chemotherapy for myeloid leukemias, leading to disease relapse. To overcome modest MCL cytotoxicity, analogs with ≈two–threefold greater cytotoxicity against LSCs are synthesized via late-stage chemoenzymatic C─H functionalization. To enhance bone marrow delivery, MCL analogs are entrapped within bone-targeted polymeric nanoparticles (NPs). Robust drug loading capacities of up to 20% (mg drug mg−1 NP) are obtained, with release dominated by analog hydrophobicity. NPs loaded with a hydrolytically stable analog are tested in a leukemic mouse model. Median survival improved by 13% and bone marrow LSCs are decreased 34-fold following NPMCL treatments versus controls. Additionally, selective leukemic cell and LSC cytotoxicity of the treatment versus normal hematopoietic cells is observed. Overall, these studies demonstrate that MCL-based antileukemic agents combined with bone-targeted NPs offer a promising strategy for eradicating LSCs.Keywords
Funding Information
- National Institutes of Health (P30 AR069655, R01 AR064200, R01 AR056696, R01 GM098628, UL1 TR002001, F31 CA228391)
This publication has 47 references indexed in Scilit:
- Synthesis of Micheliolide Derivatives and Their Activities against AML Progenitor CellsMolecules, 2013
- How close are we to targeting the leukemia stem cell?Best Practice & Research Clinical Haematology, 2012
- Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemiaBlood, 2012
- Overcoming the barriers in micellar drug delivery: loading efficiency,in vivostability, and micelle–cell interactionExpert Opinion on Drug Delivery, 2009
- Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor, DMAPT (LC-1)Bioorganic & Medicinal Chemistry Letters, 2009
- Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)‐block‐polycaprolactone diblock copolymer micelles: Theoretical and experimental data and correlationsJournal of Pharmaceutical Sciences, 2008
- Drug diffusion from polymer core–shell nanoparticlesSoft Matter, 2007
- Polymer–drug compatibility: A guide to the development of delivery systems for the anticancer agent, ellipticineJournal of Pharmaceutical Sciences, 2004
- Strategy for the treatment of acute myelogenous leukemia based on folate receptor β–targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acidBlood, 2002
- Sesquiterpene Lactones Specifically Inhibit Activation of NF-κB by Preventing the Degradation of IκB-α and IκB-βOnline Journal of Public Health Informatics, 1998