Bioorthogonal Chemistry in Drug Discovery: Techniques and Applications in Targeted Cancer Therapy

Abstract

Bioorthogonal chemistry represents a transformative platform in modern biomedical research, enabling chemical reactions to occur within living systems without interfering with native biochemical pathways. These reactions have provided powerful tools for selective drug activation, non-invasive imaging, and precise biomolecular labeling. In oncology, bioorthogonal strategies offer unique opportunities for targeted drug delivery, pretargeted imaging, and the development of antibody–drug conjugates with improved safety profiles. Key reaction classes—including strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron demand Diels–Alder (IEDDA) ligation, and sulfur fluoride exchange (SuFEx)—have shown distinct advantages in terms of speed, selectivity, and compatibility with physiological environments. This review summarizes the fundamental principles, reaction mechanisms, and recent advances in bioorthogonal chemistry, with a particular emphasis on applications in targeted cancer therapy. Current challenges, such as reagent stability, delivery efficiency, and translational barriers, are critically discussed. Future perspectives highlight integration with nanotechnology, artificial intelligence, and immunotherapy, which may accelerate the clinical translation of bioorthogonal strategies into precision oncology.