Photoactivatable Osmium Complexes for Selective Lipid Peroxidation in Cellular Membranes

• Grant number: 25/21172-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2026
• End date: April 30, 2028
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Mauricio da Silva Baptista
• Grantee: Luca Michael Sihn
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

This project proposes the development of a new class of heteroleptically coordinated osmium(II) complexes of the type [Os(terpy)(bipy)(L)]², designed for application in Photodynamic Therapy (PDT). The central hypothesis is that the combination of near-infrared (NIR) absorption with a selective ligand photodissociation mechanism can provide an integrated solution to two fundamental challenges of PDT: the need for activation within the biological optical window (650-900 nm) and the lack of stable anchoring mechanisms in cellular membranes.The strategy involves using light to trigger the controlled dissociation of a monodentate photolabile ligand, thereby exposing a coordination site capable of binding to lipid unsaturations. Once anchored, the complex is expected to act as a localized photosensitizer, generating singlet oxygen (¹O2) in the immediate environment and inducing lipid peroxidation, a process that compromises membrane integrity and leads to cell death via oxidative stress. This "activation-anchoring-catalysis" approach remains largely unexplored and may significantly enhance the spatial and temporal selectivity of PDT.The work plan is organized into three main stages: (i) synthesis and structural/photophysical characterization of a library of Os(II) complexes with varied photolabile and targeting ligands; (ii) mechanistic investigation of ligand photodissociation and lipid peroxidation in biomimetic systems, using time-resolved spectroscopies and analysis of oxidative products; and (iii) validation in tumor and non-tumor cell models, evaluating uptake, subcellular localization, viability, and cell death pathways.The expected outcome is the establishment of general design principles for osmium-based photosensitizers with improved selectivity and control over photoinduced activity, contributing both to advances in PDT for solid tumors and to a deeper understanding of oxidative processes in biological membranes. (AU)