R. Nechushtai, R. Elber
PD&E Therapeutic Inc,
United States
Keywords: cancer, peptides, chemotherapy, delivery
Summary:
PEX is a new synthetic family of peptides designed by PD&E Therapeutics Inc. that is patent-protected. The design is inspired by human proteins, which are present in every cell of our body. Remarkably, PEX peptides show anti-cancer activities and permeate efficiently across the plasma membranes of malignant but not normal cells. This observation was verified experimentally in many cancer types. For example, triple-negative breast (MDA-MB-231), melanoma (A375), pancreatic cancer (PANC 04.03), and ovarian cancer (SKOV03). Simulation and modeling indicate that the acidic environment near cancer cells and the higher content of negatively charged phospholipids in the outer layer of the cancer plasma membrane led to a two-step permeation mechanism: (i) overall electrostatic attraction between the positively charged peptide and the membrane surface and (ii) the transient formation of membrane defect (not a pore) that allows charged peptides to permeate across the lipid center of the membrane. A hydrophobic N terminal segment of the peptide further supports the membrane defect. These peptides are non-toxic to normal cells in culture and to mice. Experiments show that mice treated with PEX continue to gain weight compared to a control group, demonstrating that the peptides are not toxic. The PEX family is also unique since, inside the cell, the peptides target specific organelles. Following their cell permeation, the peptides target the intracellular mitochondria and endoplasmic reticulum (ER) organelles, the native cellular localization of the protein they were derived from and inspired by. Upon reaching these organelles, they disrupt their integrity and facilitate cell death pathways that lead to apoptosis. To further enhance PEX's toxicity toward cancer cells, we consider attaching chemotherapeutic agents to the permeating peptide. The peptide directs the agent to the cancer cells and assists in translocation. PE1, a member of the PEX family, was conjugated to Doxorubicin (DOX). Experimentally, we observed selective and efficient permeation of DOX-PE1 into PANC cells by confocal microscopy, following the red fluorescence of DOX. DOX-PE1 showed significant cytotoxicity toward PANC 04.03 cells. These results suggest that in addition to their anti-cancer activity, we can use the PEX peptides to specifically deliver other anti-cancer agents to cancer cells, avoiding normal cells and facilitating a bi-functional drug activity.