The Effects of Substituent Grafting on the Interaction of pH-Responsive Polymers with Phospholipid Monolayers

Abstract

pH-responsive amphiphilic polymers with suitable graftings have demonstrated highly efficient cell membrane activity and hence are promising applicants for drug-delivery. Grafting the hydrophobic amino acid l-phenylalanine and the hydrophilic methoxy poly(ethylene glycol) amine onto the pendant carboxylic acid moieties of a linear polyamide, poly(l-lysine isophthalamide), can effectively modify the amphiphilicity and conformation of the amphiphilic polymers. Here, the interactions of these polymers with phospholipid monolayers adsorbed on mercury (Hg) electrodes have been studied. AC voltammetry (ACV), rapid cyclic voltammetry (RCV), and electrochemical impedance spectroscopy (EIS) have been applied to monitor phospholipid monolayer associations with different polymer concentrations under different pH values. The polymers interact reversibly with the monolayer shown by altering the monolayer capacitance and inhibiting the phospholipid reorientation in electric field. Polymer grafting enhances the pH-mediated conformational change of the polymers which in turn increases their phospholipid monolayer activity. The most significant monolayer interactions have been observed with the polymer grafted with hydrophobic l-phenylalanine. A low level of PEGylation of the backbone also increases the monolayer activity. The polymer/DOPC interactions have been represented with an impedance model, which takes account of the interaction giving rise to an increase in monolayer capacitance and inhomogeneity and a Debye type dielectric relaxation. The extent of penetration of the polymers into the monolayer is inversely related to the electrical resistance they give rise to during the Debye relaxation. The cell membrane activities of these amphiphilic polymers have been successfully mirrored in this supported DOPC monolayer system, isolating the key parameters for biomembrane activities and giving insight into the mechanism of the interactions. The conclusions from this study provide strategic directions in material design catering to different requirements in biomedical applications.

Role of electrolyte in the occurrence of the voltage induced phase transitions in a dioleoyl phosphatidylcholine monolayer on Hg

“…A glass syringe was used to transfer the lipid solution to the electrolyte surface in the electrochemical cell. DOPC monolayers were prepared by spreading about 15 mdm 3 of the DOPC working solution at the argonelectrolyte interface in the electrochemical cell [60][61][62][63]. A period of about 5-10 minutes was required for the pentane to evaporate.…”

A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

“…This is consistent with our recent report that the main driving force for the association of PP75 with the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) monolayer model membrane is the hydrophobic interaction. 33 Side-chain modification with Phe, the most hydrophobic amino acid in nature with an aromatic residue, could facilitate the anchoring of the polymer into the liposomal membrane. This is in agreement with the report that aromatic residues in peptide structures can cause a dramatic increase in their interaction with the lipid membrane.…”

pH-Responsive, Lysine-Based, Hyperbranched Polymers Mimicking Endosomolytic Cell-Penetrating Peptides for Efficient Intracellular Delivery

“…The linear, metabolite-derived, parent 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 polymer, poly(L-lysine iso-phthalamide), only displayed the limited membrane-lytic capacity at lysosomal pH. Hydrophobic amino acids or alkyl chains were grafted onto its pendant carboxyl groups to manipulate its pH-responsive conformational change and endosomolytic activity [27][28][29][30][31] , thus enabling efficient cytoplasmic delivery of small-molecule model drugs and bioactive macromolecules (e.g. therapeutic proteins and siRNA) in vitro and in vivo [32][33][34] .…”