From: Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice
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, 163,164,165,166] |
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] |