Nanoparticle-Mediated Delivery of Micheliolide Analogs to Eliminate Leukemic Stem Cells in the Bone Marrow.

Autor: Ackun-Farmmer MA; University of Rochester, Department of Biomedical Engineering, 308 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627, USA., Alwaseem H; University of Rochester, Department of Chemistry, 418 Hutchison Hall, RC Box 270216, Rochester, NY 14627-0216, USA., Counts M; University of Rochester, Department of Biomedical Engineering, 308 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627, USA., Bortz A; University of Rochester, Department of Chemistry, 418 Hutchison Hall, RC Box 270216, Rochester, NY 14627-0216, USA., Giovani S; University of Rochester, Department of Chemistry, 418 Hutchison Hall, RC Box 270216, Rochester, NY 14627-0216, USA., Frisch BJ; University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, 601 Elmwood Ave, Box 704, Rochester, NY 14642, USA., Fasan R; University of Rochester, Department of Chemistry, 418 Hutchison Hall, RC Box 270216, Rochester, NY 14627-0216, USA., Benoit DSW; University of Rochester Medical Center. Department of Orthopaedics. 308 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627, USA.
Jazyk: angličtina
Zdroj: Advanced therapeutics [Adv Ther (Weinh)] 2022 Jan; Vol. 5 (1). Date of Electronic Publication: 2021 Oct 08.
DOI: 10.1002/adtp.202100100
Abstrakt: 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 NP MCL 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.
Competing Interests: Conflict of Interest The MCL analogs and TRAP binding peptides described here are part of patent applications, WO2019040335A1 and WO2014152451, respectively, filed by the University of Rochester.
Databáze: MEDLINE
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