Novel Chemical Tools to Study The Role of

il y a 3 jours

Marseille, France AMU Institut de chimie radicalaire Temps plein

**Novel chemical tools to study the role of mitochondrial superoxide in cancer cell death**:

- Réf **ABG-123668**
- Sujet de Thèse- 04/05/2024- Autre financement public- AMU Institut de chimie radicalaire- Lieu de travail- Marseille - Provence-Alpes-Côte d'Azur - France- Intitulé du sujet- Novel chemical tools to study the role of mitochondrial superoxide in cancer cell death- Champs scientifiques- Chimie
- Biochimie
- Matériaux
- Mots clés- Organic chemistry, reaction kinetics, mitochondria, reactive oxygen species (ROS), superoxide, cancer, probes for ROS detection, spin trapping, fluorescent probes, hydroethidine**Description du sujet**:
**Introduction-Context**

The generation of free radicals in biological systems was discovered about 60 years ago. Radicals are chemical species with an unpaired electron resulting in a high reactivity and thus, a short lifetime. Cellular radicals are involved in physiological processes regulating redox signalling or immune defense. Increased production of free radicals may, however, result in the structural damage to biomolecules, leading to lipid peroxidation, posttranslational modification of proteins, and DNA damage. Among the biological radicals, superoxide radical anion (O2--) is the primary radical species that can initiate the reactive oxygen species (ROS) cascade. There are several recognized pathways of cellular O2-- production, both enzymatic (e.g., from mitochondrial OXPHOS proteins, NADPH oxidases) and non-enzymatic (e.g., radiation, photochemistry, xenobiotics).1,2

Increased generation of mitochondrial O2-- has been implicated in numerous diseases, including neurodegeneration, cardiovascular diseases and cancer. However, in most cases, it is experimentally challenging to define the actual mechanistic role of O2--. The inability to selectively detect O2-- or to modulate its production are clear limiting factors. In fact, for most pathologies the mechanisms involved and the role of ROS remain not fully understood. The discrepancy between many reports on the role of ROS in a specific disorder may be attributed to differences in: (_i_) the species detected (identity); (_ii_) the amount (level), and (_iii_) the localization of ROS production at the subcellular level (location). **Due to the transient nature of ROS, addressing those three variables is not trivial and requires the development of novel tools for rigorous detection, identification, and quantitative analyses of ROS at the subcellular level. **Despite the advances in the understanding of the chemical biology of ROS and tremendous effort devoted to the development of sensors for ROS, reliable detection and quantification of O2-- remain a challenge.

**Objectives**:There are several **scientific and technical barriers **in the detection of subcellular O2--. Mitochondrial O2-- detection and quantification remain a significant conundrum in redox biology which hamper the progress in our understanding of mitochondrial redox biology. New tools for modulation of mitochondrial O2-- production and for the specific detection of O2-- at the subcellular level are desperately needed to understand its role in cancer cell proliferation and for the development of novel redox-based anticancer strategies.3 Rigorous detection of superoxide requires the use of probes that produce specific, marker products formed only in the presence of superoxide.4,5 These include cyclic nitrone spin traps (e.g., DIPPMPO) and hydroethidine (HE) fluorogenic probe. Laboratories of Drs. Hardy and Zielonka have been involved in the development and characterization of mitochondria-targeted probes, including mitochondria-targeted spin traps or HE, as evidenced by numerous joint publications. This PhD thesis project will also benefit from both labs’ experience gained in previous studies on the development of novel mitochondria-targeted agents, to delineate the role of mitochondrial O2-- in cancer cell proliferation and anticancer therapies.6-8

**This proposed thesis is aimed at developing new chemical biology tools to detect mitochondrial superoxide in cell-free and cellular systems. The developed chemical probes will be applied to the studies of the role of mitochondrial superoxide in cancer cell proliferation and in anticancer strategies.**

**Methodology**
- **Aim 1. Preparation of nanoparticles and mitochondria-targeted nanoparticles precursors**

Aim 1 of the thesis will focus on the synthesis of biologically compatible bis-functionalized hybrid **m**esoporous **s**ilica **n**anoparticles (MSNs) allowing the grafting of the probes (Aims 2 & 3) knowing the accessibility to the porosity. MSNs have been used previously as nanocarriers for mitochondrial drug delivery, 9 but few studies proposed their use for ROS detection. The triphenylphosphonium (TPP) cationic moiety is one of the most adaptable targeting group used to conjugate molecule of interest to lipophilic cations to target the molecule/particle to mitochondria.10 Aim 1 will

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