Engineering Ionophore Gramicidin-Inspired Self-Assembled Peptides for Drug Delivery and Cancer Nanotherapeutics

Nature-inspired self-assembled peptide-based nanoscale materials are of great interest for biomedical applications. Here, ionophore gramicidin-inspired designed nanoscale materials for drug delivery and cancer nanotherapeutics are reported. The length dependent formation of diverse nanoarchitectures by experimental and computational studies from gramicidin-inspired sequences is explored and their therapeutic potential is evaluated. Mechanistic studies revealed that gramicidin A (gA) and gramicidin-inspired octapeptide (LD8) induce cytotoxic effects, mitochondrial depolarization, and apoptotic cell death against metastatic breast cancer cell line MDA-MB-231. Doxorubicin loaded LD8 peptide (LD8-Dox-NP) and doxorubicin loaded gramicidin (gA-Dox-NP) show cytotoxicity determined by MTT assay and apoptosis as evidenced by DNA fragmentation study and Western blot analysis of poly (ADP-ribose) polymerase (PARP) expression and cleavage. gA-Dox-NP and LD8-Dox-NP treated MDA-MB-231 cells show upregulation of tumor suppressor protein p53, which can inhibit cell proliferation. Interestingly, cell cycle analysis suggests that gA-Dox-NP and LD8-Dox-NP induce S and G2 phase cell cycle arrest, respectively. These data establish gA and LD8 peptide as new potential anticancer therapeutics against metastatic breast cancer and suggest that gA-Dox-NP and LD8-Dox-NP can be potentially used as two-in-one nanomedicine for treating breast cancer.