Anti-cancer therapies that utilize cell penetrating peptides

Abstract

Cell penetrating peptides (CPPs) are 9-35mer cationic and/or amphipathic peptides that are rapidly internalized across cell membranes. Importantly, they can be linked to a variety of cargo, including anti-cancer therapeutics, making CPPs an efficient, effective and non-toxic mechanism for drug delivery. In this review, we discuss a number of CPP conjugated therapies (CTTs) that are either patented are in the progress of patenting, and show strong promise for clinical efficacy. The CTTs discussed here target a number of different processes specific to cancer progression, including proliferation, survival and migration. In addition, many of these CTTs also increase sensitivity to current anti-cancer therapy modalities, including radiation and other DNA damaging chemotherapies, thereby decreasing the toxic dosage required for effective treatment. Mechanistically, these CTTs function in a dominant-negative manner by blocking tumor-specific protein-protein interactions with the CPP-conjugated peptide or protein. The treatment of both cell lines and mouse models demonstrates that this method of molecular targeting results in equal if not greater efficacy than current standards of care, including DNA damaging agents and topoisomerase inhibitors. For the treatment of invasive carcinoma, these CTTs have significant clinical potential to deliver highly targeted therapies without sacrificing the patient's quality of life.

Fig. (1).. Mechanism of Peptide Membrane Transduction.

1) CPP-Cargo peptide is delivered to the site of disease. 2) The CPP’s highly cationic amino acids interact with proteoglycans (left) or glycolipids (right) on the cell surface. Note: There is an evidence that the CPP-cargo directly enters the cell (center arrow) 3) The peptide is endocytosed via clathrin or caveoloae or it is macropinocytosed. 4) Endosomal escape of peptide. 5) Interaction with target protein.

Fig. (2).. Mechanism of CTT Anti-Cancer Therapy.

1) The CPP portion of the CTT attaches to the plasma membrane and directly inhibits ECM Receptor/ECM interaction. This inhibits the ability of metastatic cancer cells to establish secondary tumor sites. 2) CTTs block cancer dependent protein-protein interactions, resulting in the inhibition of proliferation, angiogenesis, and chemoresistance. 3) Additionally, inhibition of protein interactions can modulate nuclear translocation of oncogenic transcription factors.