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Recent successes in the pharmaceutical industry have yielded a variety of new drugs based on proteins and nucleic acids. While these drugs are very promising, they are only effective once they are inside cells. Unfortunately, transporting drugs into cells tends to be challenging because cell membranes provide a protective barrier. However, there is hope for these drugs since researchers have identified many drug delivery agents that can shuttle drugs past this barrier. Cell penetrating peptides (CPPs) are particularly promising delivery agents due to their low toxicity and ability to deliver a wide number of therapeutic agents. However there are challenges to using CPPs, because their delivery mechanisms cannot yet be controlled. Engineering new CPPs that use specific, known translocation mechanisms would be a key achievement that could increase delivery efficiency and prevent unwanted side effects. Accomplishing this goal requires new experimental methods for determining the factors that control a CPP's translocation mechanisms. In this thesis I present new atomic force microscopy (AFM) methods for studying CPPs and other cell membrane active species. I first present a theoretical model that shows how results from AFM can indicate whether CPPs change the energy barrier to bilayer penetration. I then describe new experimental AFM methods we developed for examining CPP transduction mechanisms.

Recent successes in the pharmaceutical industry have yielded a variety of new drugs based on proteins and nucleic acids. While these drugs are very promising, they are only effective once they are inside cells. Unfortunately, transporting drugs into cells tends to be challenging because cell membranes provide a protective barrier. However, there is hope for these drugs since researchers have identified many drug delivery agents that can shuttle drugs past this barrier. Cell penetrating peptides (CPPs) are particularly promising delivery agents due to their low toxicity and ability to deliver a wide number of therapeutic agents. However there are challenges to using CPPs, because their delivery mechanisms cannot yet be controlled. Engineering new CPPs that use specific, known translocation mechanisms would be a key achievement that could increase delivery efficiency and prevent unwanted side effects. Accomplishing this goal requires new experimental methods for determining the factors that control a CPP's translocation mechanisms. In this thesis I present new atomic force microscopy (AFM) methods for studying CPPs and other cell membrane active species. I first present a theoretical model that shows how results from AFM can indicate whether CPPs change the energy barrier to bilayer penetration. I then describe new experimental AFM methods we developed for examining CPP transduction mechanisms.