Table 3 Classification of different linkers used in PDC
Classification | Advantages | Limitations | Key design principles | Representative examples |
|---|---|---|---|---|
Enzyme-cleavab-le linkers | selective cleavage in the tumor microenviron-ment or in the lysosomes | sometimes cleavage occurs prior to reaching the target site | targeted drug release by enzymes active in tumor environment | dipeptide (Val-Cit) cathepsin B sensitive linker [38]; GPLG, MMP-2 sensitive linker [123] |
Acid cleavable linkers | selective cleavage primarily in the acidic tumor microenvironment or acidic cellular compartments | plasma stability has been variable despite good stability in buffer solutions (pH 7.4) | relatively stable in serum and targeted drug release in acidic tumor microenvironment | acid-sensitive hydrazone [132] |
Reducible disulfide linkers | selective cleavage in the excessive reductive environment in tumor cells and may be further augmented due to oxidative stress and hypoxia environment | Sometimes very slow drug release efficiency | selective drug release in the excessive reductive environment in tumor cells | disulfide linker [38] |
Noncleavable linkers | not cleavage in the plasma before reaching the target | not release the drug at tumor sites | relatively long circulation half-life | succinimidyl thioether [139] |