Novel (1S,3R)-RSL3-Encapsulated Polyunsaturated Fatty Acid Rich Liposomes Sensitise Multiple Myeloma Cells to Ferroptosis-Mediated Cell Death

Ali Habib; Rachel L Mynott; Oliver G Best; Isabella A Revesz; Clive A Prestidge; Craig T Wallington-Gates

doi:10.3390/ijms26146579

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Novel (1S,3R)-RSL3-Encapsulated Polyunsaturated Fatty Acid Rich Liposomes Sensitise Multiple Myeloma Cells to Ferroptosis-Mediated Cell Death

Journal article

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Novel (1S,3R)-RSL3-Encapsulated Polyunsaturated Fatty Acid Rich Liposomes Sensitise Multiple Myeloma Cells to Ferroptosis-Mediated Cell Death

Ali Habib, Rachel L Mynott, Oliver G Best, Isabella A Revesz, Clive A Prestidge and Craig T Wallington-Gates

International Journal of Molecular Sciences, Vol.26(14), pp.1-23

2025

DOI: https://doi.org/10.3390/ijms26146579

PMID: 40724829

Appears in Cancer Research Cluster Research Collection

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Abstract

cancer

haematology

multiple myeloma

ferroptosis

phospholipids

fatty acids

saturated

unsaturated

nanotechnology

nanoparticles

liposomes

Multiple myeloma (MM) is an incurable malignancy of plasma cells that accounts for 10% of all haematological malignancies diagnosed worldwide. The poor outcome of patients with MM highlights the ongoing need for novel treatment strategies. Ferroptosis is a recently characterised form of non-apoptotic programmed cell death. Phospholipids (PLs) containing polyunsaturated fatty acids (PUFAs) play a crucial role as ferroptosis substrates when oxidised to form toxic lipid reactive oxygen species (ROS). Using a range of scientific techniques, we demonstrate a strong correlation between the PL profile of MM and diffuse large B cell lymphoma (DLBCL) cells with their sensitivity to ferroptosis. Using this PL profiling, we manufacture liposomes that are themselves composed of PL-PUFA ferroptosis substrates relatively deficient in MM cells, with and without the GPX4 inhibitor, RSL3, for investigation of their ferroptosis-inducing potential. PL-PUFAs were more abundant in DLBCL than MM cell lines, consistent with greater ferroptosis sensitivity. In contrast, MM cells generally contained a significantly higher proportion of PLs containing monounsaturated fatty acids. Altering the lipid composition of MM cells through exogenous supplementation with PL-PUFAs induced ferroptosis-mediated cell death and further sensitised these cells to RSL3. Liposomes predominantly comprising PL-PUFAs were subsequently manufactured and loaded with RSL3. Uptake, cytotoxicity and lipid ROS studies demonstrated that these novel liposomes were readily taken up by MM cells. Those containing RSL3 were more effective at inducing ferroptosis than empty liposomes or free RSL3, resulting in IC values an average 7.1-fold to 14.5-fold lower than those for free RSL3, from the micromolar to nanomolar range. We provide a better understanding of the mechanisms associated with ferroptosis resistance of MM cells and suggest that strategies such as liposomal delivery of relatively deficient ferroptosis-inducing PL-PUFAs together with other targeted agents could harness ferroptosis for the personalised treatment of MM and other cancers.

Details

Title: Novel (1S,3R)-RSL3-Encapsulated Polyunsaturated Fatty Acid Rich Liposomes Sensitise Multiple Myeloma Cells to Ferroptosis-Mediated Cell Death
Authors: Ali Habib - Flinders University
Rachel L Mynott - Flinders University
Oliver G Best - Flinders University
Isabella A Revesz - University of South Australia
Clive A Prestidge - University of South Australia
Craig T Wallington-Gates (Corresponding Author) - University of the Sunshine Coast, Queensland, Cancer Research Cluster
Publication details: International Journal of Molecular Sciences, Vol.26(14), pp.1-23
Publisher: MDPI AG
Date published: 2025
DOI: 10.3390/ijms26146579
ISSN: 1422-0067; 1661-6596
PMID: 40724829
Copyright note: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Data Availability: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Grant note: A.H. was funded by a Jane Watson Ramsey Myeloma Research PhD Scholarship. R.L.M. was funded by an Australian Government Research Training Program (RTP) Scholarship and Margaret Fay Fuller Foundation Scholarship Top-Up. C.W.G was funded by a Cancer Council SA Clinical Investigator Grant and Flinders Foundation Cancer Seed Grant.
Organisation Unit: Cancer Research Cluster
Language: English
Record Identifier: 991153711202621
Output Type: Journal article

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Collaboration types: Domestic collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Chemistry, Multidisciplinary