Probing the mechanism of drug delivery by cyclic peptide-polymer nanotubes

Cyclic octapeptides containing residues with alternating D- and L- stereochemistry which are capable of self-assembling into so-called ‘nanotubes’ which can be further modified by the grafting of hydrophilic polymers, resulting in water-soluble cyclic peptide-polymer nanotubes (CPPNs) with additional functionalities imparted by polymer chains. Our current work involves the use of CPPNs as drug delivery vectors, where controlled assembly and disassembly and is required to tune drug uptake, release and bioavailability. In the case of mammalian cells, our initial studies indicate cellular uptake proceeds by means of adsorption to the cell surface and subsequent endocytosis, resulting in CPPNs encapsulated within low-pH lysosomes. In order to exploit the subcellular encapsulation of CPPNs, we have engineered their chemistry such that the stabilising polymers are removed by the low-pH conditions experiencced within the lysosome. One the polymers are removed, the cyclic peptide is highly efficient in membrane lysis leading to lysosomal escape and subsequent delivery to the cell cytoplasm. Here, we propose to use NR at the solid-liquid interface using mammalian model membranes to investigate multiple responsive CPPNs with different physicochemical properties to study the role of the cyclic peptide sequence in cell surface binding and lysosomal escape.