Iron chelators as mitophagy agents: Potential and limitations.

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.

PEGylated Molybdenum-Iodine Nanocluster as a Promising Radiodynamic Agent against Prostatic Adenocarcinoma.

The combination of photodynamic therapy and radiotherapy has given rise to a modality called radiodynamic therapy (RDT), based on reactive oxygen species-producing radiosensitizers. The production of singlet oxygen, O2(1Δg), by octahedral molybdenum (Mo6) clusters upon X-ray irradiation allows for simplification of the architecture of radiosensitizing systems. In this context, we prepared a radiosensitizing system using copper-free click chemistry between a Mo6 cluster bearing azido ligands and the homo-bifunctional linker bis-dPEG11-DBCO. The resulting compound formed nanoparticles, which featured production of O2(1Δg) and efficient cellular uptake, leading to remarkable photo- and radiotoxic effects against the prostatic adenocarcinoma TRAMP-C2 cell line. Spheroids of TRAMP-C2 cells were also used for evaluation of toxicity and phototoxicity. In vivo experiments on a mouse model demonstrated that subcutaneous injection of the nanoparticles is a safe administration mode at a dose of up to 0.08 g kg-1. The reported results confirm the relevancy of Mo6-based radiosensitizing nanosystems for RDT.

A Cell Membrane Targeting Molybdenum-Iodine Nanocluster: Rational Ligand Design toward Enhanced Photodynamic Activity.

The development of singlet oxygen photosensitizers, which target specific cellular organelles, constitutes a pertinent endeavor to optimize the efficiency of photodynamic therapy. Targeting of the cell membrane eliminates the need for endocytosis of drugs that can lead to toxicity, intracellular degradation, or drug resistance. In this context, we utilized copper-free click chemistry to prepare a singlet oxygen photosensitizing complex, made of a molybdenum-iodine nanocluster stabilized by triazolate apical ligands. In phosphate-buffered saline, the complex formed nanoaggregates with a positive surface charge due to the protonatable amine function of the apical ligands. These nanoaggregates targeted cell membranes and caused an eminent blue-light phototoxic effect against HeLa cells at nanomolar concentrations, inducing apoptotic cell death, while having no dark toxicity at physiologically relevant concentrations. The properties of this complex were compared to those of a negatively charged parent complex to highlight the dominant effect of the nature of apical ligands on biological properties of the nanocluster. These two complexes also exerted (photo)antibacterial effects on several pathogenic strains in the form of planktonic cultures and biofilms. Overall, we demonstrated that the rational design of apical ligands toward cell membrane targeting leads to enhanced photodynamic efficiency.