TOWARD TARGETING ANTITUMOR AGENTS TO CANCER CELLS: DISULFIDE CONJUGATION OF CYTOTOXIC COMPLEXES TO OTHER ACTIVE SITES AND DELIVERY ENTITIES

As chemotherapy is a leading method for 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.

One of the possible targeting strategies utilizes disulfide bridges, which serve as well-known practice for conjugation of different compounds. Such conjugations have marked advantage for applications in biological environment: the disulfide bridge is cleavable, as it is reduced in the cancer cell due to the high concentration of glutathione in the cytoplasm. Thus, disulfide linkage opens new opportunities for improving properties by combination of different compounds. For instance, disulfide bridges with cysteine residues enable conjugation of antitumor complex to peptides. The peptide, which is often an antibody or cell-penetrating peptide (CPP), increases the selectivity or penetrability. After penetration of the conjugated compound to cancer cell, the disulfide bridge is broken due to the reducing environment and the active complex is released.

Herein we present a new family of salan-based ligands that bear free thiol moieties. These ligands promote the disulfide linkage of cytotoxic complexes to antibodies or CPPs; for instance, the TAT peptide of HIV-1. This peptide delivers its cargo into the cell by translocation of the plasma membrane. 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.