Development of an artificial helical polypeptide for cancer targeting and therapy

Abstract

Development of an artificial helical polypeptide has a remarkable attention to biomedical fields because an artificial helical polypeptide provides various biomedical applications such as delivery agent and peptide therapeutic. In this thesis, new artificial helical polypeptide were developed for cancer targeting and therapy. In chapter 2, helical peptides are naturally-occurring ordered conformations that mediate various biological functions essential for biotechnology. However, it is difficult for natural helical polypeptides to be applied in biomedical fields due to low bioavailability. To avoid these problems, synthetic alpha-helical polypeptides have recently been introduced by further modifying pendants in the side chain. In spite of an attractive biomimetic helical motif, these systems cannot be tailored for targeted delivery mainly due to nonspecific binding events. To address these issues, we created a conformation-transformable polypeptide capable of eliciting a pH-activated cell-penetrating property solely at the cancer region. The developed novel polypeptide showed that the bare helical conformation has a “stealth” function at physiological conditions while the pH-induced helical motif provided an active cell-penetrating characteristic at a tumor extracellular matrix pH. The unusual conformation-transformable system can elicit bioactive properties exclusively at the desirable site, thereby accomplishing “unprecedented cancer-guided systems”. In chapter 3, An artificial cationic helical peptide possessed the enhanced cell-penetrating property. However, the cell-penetrability was not converted by cellular environmental changes, resulting in nonspecific uptake. In this study, pH-sensitive anion-donating group were introduced in the helical polypeptide to simultaneously attain tumor targeting and pro-apoptotic activity. The mitochondria-destabilizing helical polypeptide undergoing pH-dependent conformational transitions selectively targeted cancer cells and then, disrupt the mitochondrial membranes, thereby provoking apoptosis. This work suggests a promising peptide therapeutic systems for cancer therapy. In chapter 4, Perturbation of potassium homeostasis can affect various cell functions, and lead to the onset of programmed cell death. In this study, an artificial potassium ion-depleting helical polypeptide can disturb potassium electrochemical gradient, thereby initiating the onset of cell death-mediated signaling. The unbalance of potassium electrochemical gradients provokes endoplasmic reticulum stress resulting from activated calcium signaling. Stressed endoplasmic reticulum fosters the amplified oxidative conditions and strongly promoted apoptotic-signaling pathways, resulting in the exacerbation of various cell functions. This study provides the first experimental evidence that a potassium homeostasis-perturbing polypeptide strongly suppresses various cell functions.