Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors
Open accessAbstract
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.
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Sakamoto et al. developed KS-58, a KRAS G12D-selective inhibitory peptide.
“Sakamoto et al. have developed KS-58, a KRAS G12D-selective inhibitory peptide, which has gained considerable attention [79,80].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [80]
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- Authors
- Sakamoto, K., Qi, Y., & Miyako, E.
- Affiliations
- Ichimaru Pharcos (Japan) (JP)
- Japan Advanced Institute of Science and Technology (JP)
- Corresponding author
- Sakamoto, Kotaro
- Miyako, Eijiro
- Venue
- Scientific Reports
- Published
- 2023-01-10
- Volume
- 13
- Issue
- 1
- Pages
- 518-518
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC9832047
- OpenAlex
- W4315490318
- Cited by
- 14
- References
- 33
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 4
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12D, bicyclic peptides, nanoformulations, nanoparticles, Cremophor EL, water solubility, colorectal cancer, pancreatic cancer, ERK1/2 phosphorylation, near-infrared fluorescent probe, indocyanine green, tumor targeting, anticancer activity
- MeSH terms
- Humans, Mutation, Pancreatic Neoplasms, Peptides, Peptides, Cyclic, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor
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