Cleavable Carbosilane Dendrimers Modulate the Thermodynamical Properties of DMPC/DPPG Lipid Membrane and Conformation of Human Serum Albumin.
TL;DR
Study of cationic carbosilane dendrimers interact with both DMPC/DPPG lipid bilayers and HSA in a manner that is generation-dependent and concentration-dependent, suggesting that their generation and charge density are key determinants of their behavior toward biological membranes and plasma proteins.
Abstract
Cationic carbosilane dendrimers are promising nonviral vectors for the delivery of drugs and nucleic acids, however, their interaction with bloodstream molecules is incompletely understood. In this study, we investigated the interactions of a novel family of pH-tunable charge cationic carbosilane dendrimers of three generations G1: ArG₁(NMe₂HCl)₆, G2: ArG₂(NMe₂HCl)₁₂ and G3: ArG₃(NMe₂HCl)₂₄ with model 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) lipid membranes and human serum albumin (HSA), using dynamic light scattering, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), fluorescence spectroscopy, circular dichroism, and isothermal titration calorimetry (ITC). All three kinds of dendrimers formed stable complexes with negatively charged liposomes, inducing generation-dependent changes in hydrodynamic diameter and surface charge. DSC analysis demonstrated that G1 dendrimer destabilized the DMPC/DPPG bilayer in a concentration-dependent manner, perturbing both the polar headgroup region and the hydrophobic hydrocarbon chain region of the membrane. TEM imaging revealed generation-dependent differences in the extent of membrane disruption. Interactions with HSA were confirmed by tryptophan fluorescence quenching and circular dichroism, which showed a generation-dependent decrease in α-helix content indicative of partial protein unfolding. ITC analysis of the G1/HSA interaction demonstrated a spontaneous, exothermic binding process. In conclusion, studied dendrimers interact with both DMPC/DPPG lipid bilayers and HSA in a manner that is generation-dependent (DLS, zeta potential, TEM, CD, fluorescence) and concentration-dependent (DSC, ITC, characterized for the representative G1 dendrimer), suggesting that their generation and charge density are key determinants of their behavior toward biological membranes and plasma proteins.