Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy

The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris® and Kadcyla® made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's “magic bullet”. However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy.