BPS2026 – pH-sensitive and biomimetic polymers interacting with endosomal model membranes in the context of drug delivery

For a rational design and selection of suitable polymers for drug delivery applications, we need to understand the underlying membrane biophysics of the interactions. During endolysosomal development the endosomal pH is lowered, and the quantity of negatively charged, fusogenic lipid BMP is raised. These properties are aimed to be used to selectively permeabilize endosomal membranes. We study two polymers that can be positively charged depending on the pH, and have different transfection efficiencies. To represent the different membranes and maturation stages of endo-lysosomal development, different membrane models, simplified lipid compositions, and different pH values were used. Using various methods, such as fluorescence (time correlated single photon counting-TCSPC), monolayer methods, and zeta potential, as well as microcalorimetry (DSC) and dynamic light scattering (DLS), we examined membrane perturbations like leakage, fusion, or destabilization caused by the interactions with the pH-sensitive polymers. Membrane leakage, electrostatic lipid clustering (the local enrichment of negatively charged lipids by positively charged polycations), and membrane fusion can play important roles for membrane permeabilization and thus for the endosomal escape. We are approaching the point of revealing possible mechanisms behind the interactions and have answered some questions that have been pending.