In contrast, cleavable linkers possess a chemical trigger that can be cleaved in the specific environment of cancer (typically intracellularly). Often a self-immolative spacer is combined with a cleavable linker that facilitates the release of unmodified payload. Common cleavable linkers include: acid-labile hydrazones, which target the acidic pH of the lysosome; reducible disulfides, targeting the elevated concentrations of glutathione in the cytosol of cancer cells and; enzyme-cleavable linkers, such as Valine-Citrulline (Val-Cit) dipeptides, that can be cleaved by the elevated levels of cathepsin proteases present in cancer (Fig. 4A). Many other cleavable linkers have been described,5 but will not be discussed in detail in this review.

In contrast, cleavable linkers possess a chemical trigger that can be cleaved in the specific environment of cancer (typically intracellularly). Often a self-immolative spacer is combined with a cleavable linker that facilitates the release of unmodified payload. Common cleavable linkers include: acid-labile hydrazones, which target the acidic pH of the lysosome; reducible disulfides, targeting the elevated concentrations of glutathione in the cytosol of cancer cells and; enzyme-cleavable linkers, such as Valine-Citrulline (Val-Cit) dipeptides, that can be cleaved by the elevated levels of cathepsin proteases present in cancer (Fig. 4A). Many other cleavable linkers have been described,5 but will not be discussed in detail in this review.