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Innovative linker strategies for tumor-targeted drug conjugates.

The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small-molecules represents a well-known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side-effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) which connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this review, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions).