Targeting Pancreatic Cancer with 64Cu-Labeled KRAS PNA-Peptide Chimera for PET Imaging

A novel agent, 64Cu-WT4351, has been engineered for the purpose of PET imaging to detect pancreatic cancer. This compound is a fusion of a peptide and peptide nucleic acid (PNA) designed to bind specifically to the IGF1 receptor, which is often overexpressed in pancreatic cancer cells, and to hybridize with the mRNA of the KRAS oncogene, a common mutation in this type of cancer.

Pancreatic cancer is a leading cause of cancer-related deaths, with the KRAS gene frequently mutated in affected patients. The detection of this mutation is crucial for early diagnosis. Radiolabeled antisense oligonucleotides are useful for in vivo identification of specific mRNAs, but challenges such as nonspecific binding and susceptibility to enzymatic degradation exist.

PNAs are synthetic molecules that mimic DNA/RNA and offer enhanced stability and specificity. However, their cellular uptake is limited, necessitating strategies like receptor-specific peptides to improve internalization. Tian et al. have shown that attaching a receptor-specific peptide to PNAs can enhance their uptake in vitro and in vivo. This approach has been successfully applied to target the IGF1R overexpressed in certain cancers.

Building on this, Chakrabarti et al. developed a 64Cu-labeled chimera to target KRAS mRNA for imaging pancreatic cancer. The uptake mechanism was validated through the use of IGF1 blocking in breast cancer models. This research highlights the potential of targeted PNA-peptide chimeras for early cancer detection and imaging.