Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Pascal Clerc (1, 2) , Pauline Jeanjean (1, 2) , Nicolas Hallali (1) , Michel Gougeon (3) , Bernard Pipy (4) , Julian Carrey (1) , Daniel Fourmy (1, 2) , Véronique Gigoux (1, 2)

1 LPCNO - Laboratoire de physique et chimie des nano-objets
2 INSERM - Institut National de la Santé et de la Recherche Médicale
3 CIRIMAT - Centre interuniversitaire de recherche et d'ingenierie des matériaux
4 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement

Therapeutic strategies using drugs which cause Lysosomal Cell Death have been proposed for eradication of resistant cancer cells. In this context, nanotherapy based on Magnetic Intra-Lysosomal Hyperthermia (MILH) generated by magnetic nanoparticles (MNPs) that are grafted with ligands of receptors overexpressed in tumors appears to be a very promising therapeutic option. However, mechanisms whereby MILH induces cell death are still elusive. Herein, using Gastrin-grafted MNPs specifically delivered to lysosomes of tumor cells from different cancers, we provide evidences that MILH causes cell death through a non-apoptotic signaling pathway. The mechanism of cell death involves a local temperature elevation at the nanoparticle periphery which enhances the production of reactive oxygen species through the lysosomal Fenton reaction. Subsequently, MILH induces lipid peroxidation, lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol, including Cathepsin-B which activates Caspase-1 but not apoptotic Caspase-3. These data highlight the clear potential of MILH for the eradication of tumors overexpressing receptors.

Mots clés: Magnetic hyperthermia; Lysosome membrane permeabilization; Cell death; Cancer; Caspase-1; Cathepsin-B

Domaines: Pharmacologie

Pascal Clerc, Pauline Jeanjean, Nicolas Hallali, Michel Gougeon, Bernard Pipy, et al.. Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death. Journal of Controlled Release, 2018, 270, pp.120-134. ⟨10.1016/j.jconrel.2017.11.050⟩. ⟨hal-02319530⟩