Conventional cancer chemotherapy is limited by the fact that small organic cytotoxic agents typically do not preferentially localize at the tumor site, causing unwanted toxicities to normal organs and limiting dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the tumor environment. While traditionally internalizing ligands have been used for such targeting applications, increasing experimental evidence suggests that the ligand-based delivery of anticancer drugs to the extracellular space in the tumor, followed by suitable release strategies, may mediate a potent anticancer activity. In this review, we outline the main requirements for the development of noninternalizing targeted cytotoxics.
Keywords: antibody−drug conjugates; cancer; dosimetries; drug quantitative biodistribution; noninternalizing antibody−drug conjugates; small molecule drug conjugates.