The aim of our project is to develop innovative tumor-specific approaches for transport of bioactive compounds in tumor cells for targeted therapy in cancer. Tumor Penetrating Peptides (TPP) are a subclass of tumor homing peptides that penetrate extravascular tumor tissue and specifically internalize into tumor cells. TPP are defined by the presence of the C-end rule (CendR) motif. This CendR motif must be at the C-terminus of the sequence to be able to bind to the cell and tissue penetration receptor Neuropilin-1 (NRP-1), which is over-expressed in tumor vasculature and in a variety of tumor cells in vitro and in vivo. In addition, it has been shown that NRP-1 is specifically expressed in B cells from Chronic Lymphocytic Leukemia (CLL) patients.
We have tested here five different TPPs as fluorophore-labeled peptides and as nanoparticles targeting ligand for binding. The tumor specificity has been demonstrated using human primary B cells isolated from blood of healthy donors or from patients suffering from CLL. In addition, we validate also its tumoral selectivity using primary human healthy hepatocytes or tumoral hepatocytes isolated from non-viral induced hepatocarcinomas.
We observed that there is a tumoral-specific penetration of all five TPPs in B cells isolated from CLL patients. On the contrary, the TPPs are not internalized in healthy B cells. Similarly, the TPPs were also tested in healthy and tumoral hepatocytes, showing a similar result, with very week or absence of penetration in healthy hepatocytes and high level of internalization in malignant hepatocytes. Similar results were obtained when the TPP were administrated bound to the surface of nanoparticles. Finally, the TPPs did not interact with healthy human red blood cells.
These results strongly suggest that the tested TPPs specifically internalize in malignant primary B cells and hepatocytes.
Audience Take Away:
• Protein/protein interactions (PPIs) are well recognized as promising therapeutic targets. Consequently, interfering peptides capable of interfering PPIs are receiving increasing attention. In addition, progress on peptide administration, stability, biodelibery and safety are also encouraging the interest in peptide drug development. We consider that our results are of interest for the scientific community working on cancer, cell penetrating peptides, interfering peptides, apoptosis and new therapies against cancer.