| A successful drug delivery vehicle has to facilitate the internalization and intracellular trafficking of its cargo to a desired organelle along a characterized pathway, a process described as 'vectorial delivery.' The present work focuses on the design of peptide-based drug delivery vehicles based on the principle of multivalency. The tetramerization domain of the human p53 protein (hp53tet) served as the structural scaffold for multivalent intracellular trafficking vehicles. Cationic import signal (IS) sequences and the nuclear localization sequence (NLS) from SV40 large T-antigen were incorporated at the N-terminus of the hp53 tet peptides. This approach generated peptide constructs able to relocate into cells and facilitate macromolecular cargos transport with significantly enhanced efficiency resulted from their tetrameric arrangement. This enhancement was particularly dramatic in the case of deca-arginine containing constructs. These deca-arginyl constructs were found to enter through a clathrin-mediated process after binding to cell surface glycosaminoglycans, specifically heparan sulfates. |
