Molecular analysis of interactions between dendrimers and asymmetric membranes at different transport stages

Abstract

Studying dendrimer-biomembrane interactions is important for understanding drug and gene delivery. In this study, coarse-grained molecular dynamics simulations were performed to investigate the behaviors of polyamidoamine (PAMAM) dendrimers (G4 and G5) as they interacted with asymmetric membranes from different sides of the bilayer, thus mimicking different dendrimer transport stages. The G4 dendrimer could insert into the membrane during an equilibrated state, and the G5 dendrimer could induce pore formation in the membrane when the dendrimers interacted with the outer side (outer interactions) of an asymmetric membrane [with 10% dipalmitoyl phosphatidylserine (DPPS) in the inner leaflet of the membrane]. During the interaction with the inner side of the asymmetric membrane (inner interactions), the G4 and G5 dendrimers only adsorbed onto the membrane. As the membrane asymmetry increased (e.g., increased DPPS percentage in the inner leaflet of the membrane), the G4 and G5 dendrimers penetrated deeper into the membrane during the outer interactions and the G4 and G5 dendrimers were adsorbed more tightly onto the membrane for the inner interactions. When the DPPS content reached 50%, the G4 dendrimer could completely penetrate through the membrane from the outer side to the inner side. Our study provides molecular understanding and reference information about different dendrimer transport stages during drug and gene delivery.

Different patterns of nuclear and mitochondrial penetration by the G3 PAMAM dendrimer and its biotin–pyridoxal bioconjugate BC-PAMAM in normal and cancer cells in vitro

“…Considering the similar levels of total cellular FITC-BC-PAMAM accumulation (Figure 8), the controlled transport of bioconjugated dendrimers into the nucleus might only proceed at nontoxic cellular dendrimer concentrations. At higher toxic concentrations, the direct interaction of cationic dendrimers with elements of the nuclear envelope may cause lipid membrane perforation as previously described 22,64,65 and concentration-dependent dendrimer entry into nucleus by simple diffusion.…”

PAMAM dendrimer - cell membrane interactions

“…The interactions between cationic G4 and G5 PAMAM dendrimers and asymmetric DPPC/DPPE/DPPS membranes have also been studied by He et al using CG simulations [126]. When the outer leaflet of the membrane contained 10% DPPS and the inner leaflet contained 50% DPPS, it was found that the G4 dendrimer inserted into the outer membrane and the G5 dendrimer caused pore formation.…”

Getting Drugs Across Biological Barriers

“…[83, 85–86] They have been reported to further improve the flux enhancement seen with small molecule CPEs such as isopropyl myristate. [80, 83] Although coarse-grained molecular dynamic simulation showed that larger dendrimers with generation numbers greater than four can penetrate biomembranes, [87] this has not been borne out experimentally. [83–84, 88] Cationic dendrimers can disrupt the lipid bilayers by forming nanoscale pores.…”