Lipid Bilayer Disruption by Polycationic Polymers:  The Roles of Size and Chemical Functional Group

Abstract

Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell. The highly polydisperse nature of many of these materials makes obtaining a mechanistic understanding of the disruption processes difficult. To design an effective mechanistic study, a monodisperse class of polycationic polymers, poly(amidoamine) (PAMAM) dendrimers, has been studied in the context of supported dimyristoylphosphatidylcholine (DMPC) lipid bilayers using atomic force microscopy (AFM). Aqueous solutions of amine-terminated generation 7 (G7) PAMAM dendrimers caused the formation of 15-40-nm-diameter holes in lipid bilayers. This effect was significantly reduced for smaller G5 dendrimers. For G3, no hole formation was observed. In addition to dendrimer size, surface chemistry had a strong influence on dendrimer-lipid bilayer interactions. In particular, acetamide-terminated G5 did not cause hole formation in bilayers. In all instances, the edges of bilayer defects proved to be points of highest dendrimer activity. A proposed mechanism for the removal of lipids by dendrimers involves the formation of dendrimer-filled lipid vesicles. By considering the thermodynamics, interaction free energy, and geometry of these self-assembled vesicles, a model that explains the influence of polymer particle size and surface chemistry on the interactions with lipid membranes was developed. These results are of general significance for understanding the physical and chemical properties of polycationic polymer interactions with membranes that lead to the transport of materials across cell membranes.

Nanoparticle Interaction with Biological Membranes: Does Nanotechnology Present a Janus Face?

“…3-5). 24,26,27 In this case, a literal hole in the bilayer membrane exists (Fig 7b). Questions to be answered regarding such holes include the distribution of sizes, density in the membrane, and lifetime.…”

Physico-chemical Studies on the Interaction of Dendrimers with Lipid Bilayers. 1. Effect of Dendrimer Generation and Liposome Surface Charge

“…This class of dendrimers can cause bilayer disruption easily and their activities are generation dependent 21,24 . Biocompatibilities of PAMAM dendrimers have encouraged several research groups to study their effect on lipid bilayers 27 31 .…”

A mechanistic view of lipid membrane disrupting effect of PAMAM dendrimers

“…The interaction between cell membranes and nanocarriers, such as dendrimers, is very important, because in the most cases carriers have to get across the lipid bilayer without disrupting it. Previous studies based on atomic force microscopy (AFM) [12][13][14][15][16][17] isothermal titration calorimetry (ITC), fluorescence correlated spectroscopy (FCS) [17][18], in vitro experiments [13,[19][20] and molecular dynamics simulations (MD) [14,17,[21][22][23][24] showed that cationic dendrimers disrupt lipid bilayers by forming holes on the bilayer surface and may remove lipids from it. The degree of the disruption depends on the size and charge of the dendrimer.…”

“…Mecke and coworkers have made thermodynamic calculations and proposed that G7 PAMAM dendrimers (d ≈ 8 nm) are big enough to have a closed lipid bilayer wrapping them [14]. Although the diameter of G5 (d ≈ 5.5 nm) dendrimers is too small for this, they still remove lipids from PC membranes.…”