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Theranostics 2019; 9(20):5924-5936. doi:10.7150/thno.36320 This issue Cite

Research Paper

TRAIL acts synergistically with iron oxide nanocluster-mediated magneto- and photothermia

Hanene Belkahla^1,2,3, Eva Mazarío¹, Anouchka Plan Sangnier⁴, John S. Lomas¹, Tijani Gharbi², Souad Ammar¹, Olivier Micheau^3✉, Claire Wilhelm^4✉, Miryana Hémadi^1✉

1. Université de Paris, ITODYS, CNRS-UMR 7086, 15 rue J.-A. de Baïf, F-75013 Paris, France.
2. Nanomedicine, Imagery and Therapeutics, EA 4662, Université de Bourgogne Franche-Comté, UFR Sciences & Techniques, 16 Route de Gray, 25030 Besançon Cedex, France.
3. Lipides nutrition cancer, INSERM-UMR 1231, Université de Bourgogne Franche-Comté, UFR Science de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France.
4. Laboratoire Matières et Systèmes Complexes, Université de Paris, CNRS-UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France.

✉ Corresponding authors: Miryana Hémadi, PhD, ITODYS Laboratory, Université de Paris, CNRS-UMR 7086, 15 rue Jean-Antoine de Baïf, 75205 Paris Cedex 13, France. hemadifr, Tel: +33-1-55278839; Claire Wilhelm, PhD, MSC Laboratory, Université de Paris, CNRS-UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France. claire.wilhelmfr, Tel: +33-1-55276253; Olivier Micheau, PhD, LNC, INSERM-UMR 1231, Université de Bourgogne Franche-Comté, UFR Science de santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France. olivier.micheaufr, Tel: +33-3-80393468. More

Abstract

Targeting TRAIL (Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand) receptors for cancer therapy remains challenging due to tumor cell resistance and poor preparations of TRAIL or its derivatives. Herein, to optimize its therapeutic use, TRAIL was grafted onto iron oxide nanoclusters (NCs) with the aim of increasing its pro-apoptotic potential through nanoparticle-mediated magnetic hyperthermia (MHT) or photothermia (PT).

Methods: The nanovector, NC@TRAIL, was characterized in terms of size, grafting efficiency, and potential for MHT and PT. The therapeutic function was assessed on a TRAIL-resistant breast cancer cell line, MDA-MB-231, wild type (WT) or TRAIL-receptor-deficient (DKO), by combining complementary methylene blue assay and flow cytometry detection of apoptosis and necrosis.

Results: Combined with MHT or PT under conditions of “moderate hyperthermia” at low concentrations, NC@TRAIL acts synergistically with the TRAIL receptor to increase the cell death rate beyond what can be explained by the mere global elevation of temperature. In contrast, all results are consistent with the idea that there are hotspots, close to the nanovector and, therefore, to the membrane receptor, which cause disruption of the cell membrane. Furthermore, nanovectors targeting other membrane receptors, unrelated to the TNF superfamily, were also found to cause tumor cell damage upon PT. Indeed, functionalization of NCs by transferrin (NC@Tf) or human serum albumin (NC@HSA) induces tumor cell killing when combined with PT, albeit less efficiently than NC@TRAIL.

Conclusions: Given that magnetic nanoparticles can easily be functionalized with molecules or proteins recognizing membrane receptors, these results should pave the way to original remote-controlled antitumoral targeted thermal therapies.

Keywords: iron oxide nanoclusters, TRAIL, photothermal therapy, magnetic hyperthermia, apoptosis

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