| Popis: |
Nowadays, cancer still remains one of the leading causes of death in the world. Therefore, cancer research is a present and central topic. Current drawbacks in cancer therapeutics are the lack of tumor specificity and the inefficient drug accumulation in cancer cells, resulting in non-specific agents that also affect healthy cells and thus their application provokes many side effects. Many possibilities for cancer cell-selective targeting of drugs are currently in focus. One includes the use of cell-penetrating peptides (CPPs), which are able to overcome the plasma membrane barrier and to transport various cargoes inside cells. Recently, it was shown for some CPPs, that they can specifically target cancer cells and therefore be used to promote the effective transport of anticancer drugs into various neoplastic cells. Furthermore, a certain intracellular targeting feature to various organelles was presented in the last years, which is important for the successful delivery of certain drugs to their point of action. This makes these amino acid sequences a promising research field in cancer treatment. In this study, the focus was set to the development and characterization of specific cancer-selective peptides that accumulate in the cell nuclei and can moreover be used to deliver various cargoes to cancer cells. The design of the CPPs was based on the C-terminal domain of the cationic antimicrobial peptide CAP18 (sC18), which was modified in various ways. For instance, it could be demonstrated that dimerization of the sequence and the N-terminally introduction of nuclear targeting sequences led to higher uptake rates of the CPP. Furthermore, the branched variant (sC18)2 exhibited a certain cancer cell-selectivity and was able to disrupt the neoplastic plasma membranes resulting in higher cytotoxicity. Next to this, the combination of sC18 with N50 and NrTP - two sequences that specifically target the cell nuclei - are approving the intracellular trafficking into the cell nucleus in cancer cells. Furthermore, an application as drug delivery system in breast cancer cells was elucidated. |
