Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors

• Published in: Scientific reports 2023-01, Vol.13 (1), p.518-518, Article 518
• Main Authors: Sakamoto, Kotaro, Qi, Yun, Miyako, Eijiro
• Format: Article
• Language: English
• Subjects: 631/154/152; 631/154/433; 639/925/352; 692/4028/67; Amino acids; Antitumor activity; Cancer; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Fluorescent indicators; Humanities and Social Sciences; Humans; Intravenous administration; K-Ras protein; Kidneys; multidisciplinary; Mutation; Nanoparticles; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Peptides; Peptides - genetics; Phosphorylation; Proto-Oncogene Proteins p21(ras) - genetics; Science; Science (multidisciplinary); Solubility; Syngeneic grafts; Tumors; Western blotting
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-27825-8

Single amino acid mutations of Ras occur in 30% of human cancers. In particular, K-Ras(G12D) has been detected in the majority of intractable colorectal and pancreatic cancers. Although efforts to target K-Ras(G12D) are currently underway, no effective drugs are available. We previously found that the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 exhibits antitumor activity against syngeneic colon and orthotopic grafted pancreatic tumors; however, pristine KS-58 is difficult to handle because of low water solubility and it requires frequent administration to obtain sufficient antitumor activity. In this study, we used a nanoformulation of KS-58 prepared with the highly biocompatible surfactant Cremophor ® EL (CrEL) to improve water solubility and reduce the dosing frequency. Nanoformulations of KS-58 with CrEL dramatically improved its water solubility and increased its stability. Weekly intravenous administration of KS-58 nanoparticles (NPs) suppressed the growth of CT26 and PANC-1 cell-derived tumors in vivo, and fluorescent bioimaging indicated that the NP-encapsulated near-infrared fluorescent probe indocyanine green selectively accumulated in the tumor and was safely excreted through the kidneys following intravenous injection. Histopathological analysis of CT26 tumors and Western blotting of PANC-1 tumors revealed that KS-58 NPs reduced ERK phosphorylation, a downstream signal of K-Ras(G12D). Our results suggest that KS-58 NPs represent a novel therapeutic agent for treating colorectal and pancreatic cancers.