Abstract
Cell membranes with their selective permeability play important functions in the tight control of molecular exchanges between the cytosol and the extracellular environment as the intracellular membranes do within the internal compartments. For this reason the plasma membranes often represent a challenging obstacle to the intracellular delivery of many anti-cancer molecules. The active transport of drugs through such barrier often requires specific carriers able to cross the lipid bilayer. Cell penetrating peptides (CPPs) are generally 5–30 amino acids long which, for their ability to cross cell membranes, are widely used to deliver proteins, plasmid DNA, RNA, oligonucleotides, liposomes and anti-cancer drugs inside the cells. In this review, we describe the several types of CPPs, the chemical modifications to improve their cellular uptake, the different mechanisms to cross cell membranes and their biological properties upon conjugation with specific molecules. Special emphasis has been given to those with promising application in cancer therapy.
Highlights
Cell penetrating peptides (CPPs), formerly defined as protein transduction domains, are a large class of short amino acid sequences (5–30 residues) able to traverse biological membranes and to deliver numerous compounds including small molecules, nucleic acids, proteins, viruses, imaging agents and drugs inside the cells [1,2].The discovery of the first protein crossing the cell membrane was made independently by two research groups in 1988 [3,4]
This review describes the advances in the development and use of CPPs mainly as carriers for anticancer therapeutics
CPPs are classified as: (1) protein-derived CPPs, including the Tat protein and Penetratin; (2) chimeric CPPs, such the Transportan derived from the binding of the neuropeptide galanin N-terminus to the Mastoparan toxin; and (3) synthetic CPPs, comprising oligoarginines and numerous peptide nucleic acids (PNAs) formed by synthetic nucleic acid analogues bound to pseudopeptide backbone [12,13]
Summary
Cell penetrating peptides (CPPs), formerly defined as protein transduction domains, are a large class of short amino acid sequences (5–30 residues) able to traverse biological membranes and to deliver numerous compounds including small molecules, nucleic acids, proteins, viruses, imaging agents and drugs inside the cells [1,2]. The discovery of the first protein crossing the cell membrane was made independently by two research groups in 1988 [3,4]. The α-helical domain of Tat protein spanning the residues 48 to 60, mainly composed of basic amino acids, was found as the main determinant for cell internalization and nucleus translocation [5,6]. The 16 amino acid peptide (RQIKIWFQNRRMKWKK) of the third helix of the Antennapedia homeodomain, namely Penetratin peptide, was able to efficiently cross the cell membranes with an energy-independent mechanism [9]. Several experimental approaches have been used to produce active molecules able to reach cancer cells and deliver their cargo of anticancer drugs inside the cells.
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