Cited by 15Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryProtein Kinase Regulation and GTPase Signaling

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

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Sakamoto, Kotaro, Qi, Yun, Miyako, Eijiro·2023·Scientific Reports

Abstract

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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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)
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
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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