Toward Targeting Antitumor Agents to Cancer Cells: Disulfide Conjugation of Cytotoxic Complexes to Cell Penetrating Peptides

As chemotherapy is a leading cancer treatment, many studies aim to address its main limitations, namely, lack of selectivity to tumor tissue and severe toxic effects. Therefore, development of targeted chemotherapeutic agents to cancer cells is essential.

Disulfide bridges, namely S­­­­­­–S bonds, serve as well-known practice for conjugation of different compounds. This linkage has a marked advantage for applications in biological environment: the disulfide bridge is cleavable as it is reduced in the cell due to the high concentration of glutathione in the cytoplasm. Thus, disulfide linkage opens opportunities for improving properties by combination of different compounds. In particular, disulfide bridges enable conjugation of an antitumor complex to peptides with cysteine residues. The peptide, which is often antibody or cell-penetrating peptide (CPP), increases the selectivity or permeability. For instance, the TAT peptide of HIV-1, which serves as a leading CPP, delivers its cargo into the cell by translocation of the plasma membrane. After penetration of the conjugated compound to the cancer cell, the disulfide bridge breaks due to the reducing environment and the complex is released. Therefore, the cytotoxic effect of an antitumor compound should increase.

Herein we present a new family of salan-based ligands that bear free thiol moieties and modified TAT peptide to include the desired cystein residue. The ligands and the modified peptide promote the development of disulfide linkage of cytotoxic complexes to CPPs. The CPP conjugated complex may overcome penetration and solubility problems and facilitate cellular uptake of the cytotoxic complex. Aspects of synthesis and cytotoxicity will be discussed.