The origin of neural stem cells impacts their interactions with targeted-lipid nanocapsules: Potential role of plasma membrane lipid composition and fluidity.

The adsorption of a peptide (NFL-TBS.40-63 peptide (NFL)) known to induce neural stem cells (NSC) differentiation in vitro, at the surface of lipid nanocapsules (LNC) provides a targeting drug delivery system (NFL-LNC) that penetrates subventricular zone-neural stem cells (SVZ-NSC) but not central canal-NSC (CC-NSC). We hypothesized preferential interactions could explaine, at least partially, the different properties of SVZ- and CC-NSC plasma membranes. The objective of this work was to compare SVZ- and CC-NSC plasma membrane lipid composition, fluidity and permeability. Plasma membranes of SVZ- and CC-NSC were isolated and analyzed by LC-MS for their lipid content. Membrane fluidity was evaluated by measuring the generalized polarization (GP) of Laurdan and membrane permeability by fluorescent dextran penetration. Liposomes with different lipid compositions and steady state fluidities were prepared. ΔGP was measured after incubation with NFL-LNC. A significantly higher proportion of cholesterol, ceramides, sphingomyelins, phosphatidylethanolamines and a lower proportion of phosphatidylcholines and sulfatides were observed in SVZ- compared to CC-NSC. Fluidity, probably more than lipid composition, drove NFL-LNC and NSC interactions, and SVZ-NSC were more sensitive to NFL permeabilization than CC-NSC. We demonstrated that NSC membrane lipid composition and fluidity depended of NSC origin and that these features could play a role in the specific interactions with NFL-LNC.

Changes in membrane biophysical properties induced by the Budesonide/Hydroxypropyl-ß-cyclodextrin complex.

Budesonide (BUD), a poorly soluble anti-inflammatory drug, is used to treat patients suffering from asthma and COPD (Chronic Obstructive Pulmonary Disease). Hydroxypropyl-ß-cyclodextrin (HPßCD), a biocompatible cyclodextrin known to interact with cholesterol, is used as a drug-solubilizing agent in pharmaceutical formulations. Budesonide administered as an inclusion complex within HPßCD (BUD:HPßCD) required a quarter of the nominal dose of the suspension formulation and significantly reduced neutrophil-induced inflammation in a COPD mouse model exceeding the effect of each molecule administered individually. This suggests the role of lipid domains enriched in cholesterol for inflammatory signaling activation. In this context, we investigated the effect of BUD:HPßCD on the biophysical properties of membrane lipids. On cellular models (A549, lung epithelial cells), BUD:HPßCD extracted cholesterol similarly to HPßCD. On large unilamellar vesicles (LUVs), by using the fluorescent probes diphenylhexatriene (DPH) and calcein, we demonstrated an increase in membrane fluidity and permeability induced by BUD:HPßCD in vesicles containing cholesterol. On giant unilamellar vesicles (GUVs) and lipid monolayers, BUD:HPßCD induced the disruption of cholesterol-enriched raft-like liquid ordered domains as well as changes in lipid packing and lipid desorption from the cholesterol monolayers, respectively. Except for membrane fluidity, all these effects were enhanced when HPßCD was complexed with budesonide as compared with HPßCD. Since cholesterol-enriched domains have been linked to membrane signaling including pathways involved in inflammation processes, we hypothesized the effects of BUD:HPßCD could be partly mediated by changes in the biophysical properties of cholesterol-enriched domains.