Many drugs and molecular biology reagents require drug delivery agents, like cell penetrating peptides (CPPs), that can shuttle the drugs into cells.  In these delivery systems it is important to control the CPPs' translocation mechanism to avoid endosomal degradation and harmful side effects. There is currently much controversy whether these agents can directly penetrate lipid membranes or not. Here we demonstrate that atomic force microscopy (AFM) with 'd'-functionalized probes can characterize a CPP's tendency to directly penetrate cells.  To mimic cell membrane translocation, CPP-functionalized probes are pushed through stacks of lipid membranes.  The position of the CPP during translocation, as well as the energy barrier to bilayer penetration, indicate: whether CPPs reduce the energy barrier to penetration; whether CPPs disrupt lipid bilayers; and the energy landscape during translocation.  We describe the results for three different CPPs to show that AFM can differentiate between drug delivery agents that are likely to spontaneously penetrate lipid bilayers (penetratin) and those that do not (TAT and a lysine oligomer).

Energetics and dynamics of direct cell-penetrating peptide translocation using atomic force microscopy

243rd National Meeting (2012)

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