Modeling Cell Membrane Transport:  Interaction of Guanidinylated Poly(propylene imine) Dendrimers with a Liposomal Membrane Consisting of Phosphate-Based Lipids

Abstract

Mixed anionic liposomes consisting of dihexadecyl phosphate, phosphatidylcholine, and cholesterol were employed as model systems for assessing the ability of a series of functionalized dendrimers, bearing a varying number of guanidinium groups at their surface, to translocate across the liposomal bilayers. At low guanidinium/phosphate molar ratios or when weakly guanidinylated dendrimeric derivatives were employed, the dendrimeric derivative acted as a kind of "molecular glue" leading to a simple adhesion of the liposomes. Liposomal fusion occurred to a certain extent at high guanidinium/phosphate molar ratios or when highly guanidinylated dendrimeric derivatives were employed. Furthermore, translocation of these dendrimeric derivatives to the liposomal core was observed for low to medium guanidinylation and at low guanidinium/phosphate molar ratios which was, however, enhanced when the lipid bilayer was in its fluid liquid-crystalline phase. Thus, an optimum balance is required between the binding strength of guanidinium with the phosphate groups and the degree of hydrophilicity of the guanidinylated dendrimers for the transport of the latter to the liposomal core to occur.

Interactive Transport of Guanidinylated Poly(propylene imine)‐Based Dendrimers through Liposomal and Cellular Membranes

“…On the other hand, guanidinylated poly(propylene imine) dendrimers, in addition to having the potential to bear an appropriate number of guanidinium moieties, also exhibit the socalled adaptive solubility behavior. This, as has recently been discussed, [24] facilitates their transport through the hydrophobic membrane.…”

“…[24] On the basis of these results, coupled with the structural features of the dendritic derivatives, an interactive transport mechanism was proposed, [24] and this constitutes the basis of the present study. In this context, further "decoration" of the dendrimeric surface was performed; poly(propylene imine) dendrimers of the third and fourth generation, employed as starting materials, were functionalized through the introduction of guanidinium groups with or without spacers (Scheme 1), while in the latter case the partially guanidinylated surfaces were rendered less hydrophilic through the introduction of acetate groups.…”

“…Functionalization of the surface amino groups of poly(propylene imine) dendrimers is crucial for affecting [24] interaction and transport through bilayer membranes. Thus, poly(propylene imine) dendrimers of the third and fourth generation were partially acetylated to reduce hydrophilicity and to assess whether this modification affects translocation.…”

“…The issue of membrane transport is, in general, a subject of great interest, [20] and specifically for dendrimers it has recently been addressed by employing either cells [21,22] or model liposomal systems. [23,24] In the latter case, surface amino groups of poly(propylene imine) dendrimers have been modified, being guanidinylated for interaction with the phosphate moieties of liposomal lipids. In this manner, adhesion between the interacting parties is induced as a result of combined hydrogen-bonding and electrostatic forces.…”

“…In this manner, adhesion between the interacting parties is induced as a result of combined hydrogen-bonding and electrostatic forces. [25][26][27] This idea of applying guanidinylated poly(propylene imine) dendrimers [23,24] as transporting agents for drug delivery originated from the application of arginine-rich peptides. [28][29][30][31][32][33][34][35][36][37][38][39] Due to the presence of an appropriate number of guanidinium groups, these proved to exhibit enhanced translocation.…”