Targeted Drug Conjugates in Cancer Therapy: Challenges and Opportunities

Traditional chemotherapy is often accompanied by off-target toxicity, resulting in adverse side effects and driving the development of targeted therapies. Targeted drug conjugates (TDCs) typically comprise targeting ligands, such as specific antibodies, peptides, or small molecules, attached to a cytotoxic agent via a chemical linker. In this study, we briefly discussed the molecular aspects of the key components of TDCs and the mechanisms by which these key factors exert their activity. Moreover, we reviewed FDA-approved TDCs and promising candidates in clinical trials and discussed current challenges and future directions for TDC development, providing insights for the research and development of novel cancer therapeutics using TDCs. TDCs combine the advantages of highly specific targeting and a potent killing effect, enabling accurate and efficient cancer cell elimination. Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) have shown good efficacy in treating various cancers; however, they still present limitations such as immunogenicity, hematotoxicity, and complex pharmacokinetics. Smaller peptide-drug conjugates (PDCs) and small molecule-drug conjugates (SMDCs) may combine the advantages of ADCs while overcoming some of their limitations, thereby presenting more efficacious and safer alternatives. TDCs enhance the therapeutic effects of cytotoxic agents and reduce their adverse effects. However, tumor heterogeneity, limited transmembrane permeability, and drug resistance pose significant challenges for TDCs, potentially affecting their therapeutic efficacy. Nevertheless, TDCs are a promising therapeutic approach for cancer treatment, achieving precise drug delivery while minimizing toxicity and side effects on normal cells.