Selective Delivery of Clinically Approved Tubulin Binding Agents through Covalent Conjugation to an Active Targeting Moiety.

The efficacy and tolerability of tubulin binding agents are hampered by their low specificity for cancer cells like most clinically used anticancer agents. To improve specificity, tubulin binding agents have been covalently conjugated to agents that target cancer cells to give actively targeted drug conjugates. These conjugates are designed to increase uptake of the drug by cancer cells while having limited uptake by normal cells, thereby improving efficacy and tolerability. Approaches used include an attachment to small molecules, polysaccharides, peptides, proteins, and antibodies that exploit the overexpression of receptors for these substances. Antibody targeted strategies have been the most successful to date, with six such examples having gained clinical approval. Many other conjugate types, especially those targeting the folate receptor, have shown promising efficacy and toxicity profiles in pre-clinical models and in early-stage clinical studies. Presented herein is a discussion of the success or otherwise of the recent strategies used to form these actively targeted conjugates.