Table 5.

Common linkers in drug conjugates

Chemical trigger	Structure	Payload	Characteristics
Noncleavable linker	6-Aminocaproic acid, Transmembrane peptide TAT, Triazole, Oxime, Short peptide, Fragment CGGW, PEG linkers with intermediates of alkyne, triazole and piperazine, Mal-PAB linker	MMAE, PBD Dimer, TRMRA	No linker cleavage. A polypeptide or carbon composed mostly of 4 amino acids, in which the main chain contains 5 to 8 carbon atoms. It is chemically stable and can regulate the polarity of tumor-targeting PDCs [160, 161]
GSH-cleavable linker	Disulfide trigger	DM1, DM3, MMAE	Linker cleavage depends on a threshold level of GSH in the cytoplasm [138, 162]
pH-sensitive linker	Hydrazone, Carbonate, Silyl ether trigger	Calicheamicin, SN-38, MMAE	The linker is not cleaved when entering the circulatory system, but once it reaches the tumor tissue, it is cleaved under the acidic environment and releases the drug [139]
Enzyme-sensitive linker	Glycosidase, Phosphatase, Sulfatase, Dipeptide or tripeptide, Carbamate, Ester and Amide	MMAE, Budesonide DDAE, Paclitaxel	The valine–citrulline (Val–Cit) linker exhibits widespread sensitivity to a variety of cathepsins, thought to be highly expressed in cancer cells, and the widespread sensitivity to other cathepsins could induce off-target toxicity in normal cells [156, 163–166]
Fe(II) cleavable trigger	1,2,4-Trioxolane, PLGLAG, Val–Cit	MMAE, DM1	Linker cleavage is dependent on a threshold level of Fe(II) [155]
Redox-sensitive linker	Disulfide bond	DM1	The disulfide bond is cleaved by glutathione in the tumor tissue, and the cytotoxic load is released
Cathepsin-cleavable linker	Dipeptide trigger, Triglycyl (CX) trigger, cBu-Cit trigger	MMAE, DM1, PBD	Linker cleavage by cathepsin in lysosomes [167]
Phosphatase-cleavable linker	Pyrophosphate trigger	Budesonide	Linker cleavage by phosphatase and pyrophosphate in lysosomes [157]
Sulfatase-cleavable linker	Arylsulfate trigger	MMAE	Linker cleavage by sulfatase in lysosomes [165]
Photoresponsive cleavable linker	Heptamethine cyanine fluorophore trigger, O-Nitrobenzyl trigger, PC4AP trigger	CA-4, MMAE, DOX	Linker cleavage by irradiation with NIR light (λ = 650–900 nm), UV light (λ = 365 nm) or UV light (λ = 365 nm), respectively [158, 168, 169]
Bioorthogonally cleavable linker	dsProc trigger	DOX	Linker cleavage by the bioorthogonal cleavage pair Cu(I)-BTTAA/dsProc [170]

PDC peptide drug conjugate, GSH glutathione, MMAE Monomethyl auristatin E, PBD pyrrolobenzodiazepines