Abstract
Cell penetrating peptides (CPPs)
have been established as excellent
candidates for mediating drug delivery into cells. When designing
synthetic CPPs for drug delivery applications, it is important to
understand their ability to penetrate the cell membrane. In this paper,
anionic or zwitterionic phospholipid monolayers at the air–water
interface are used as model cell membranes to monitor the membrane
insertion potential of synthetic CPPs. The insertion potential of
CPPs having different cationic and hydrophobic amino acids were recorded
using a Langmuir monolayer approach that records peptide adsorption
to model membranes. Fluorescence microscopy was used to visualize
alterations in phospholipid packing due to peptide insertion. All
CPPs had the highest penetration potential in the presence of anionic
phospholipids. In addition, two of three amphiphilic CPPs inserted
into zwitterionic phospholipids, but none of the hydrophilic CPPs
did. All the CPPs studied induced disruptions in phospholipid packing
and domain morphology, which were most pronounced for amphiphilic
CPPs. Overall, small changes to amino acids and peptide sequences
resulted in dramatically different insertion potentials and membrane
reorganization. Designers of synthetic CPPs for efficient intracellular
drug delivery should consider small nuances in CPP electrostatic and
hydrophobic properties.