Design and synthesis of releasable folate–drug conjugates using a novel heterobifunctional disulfide-containing linker

Cellular uptake of vitamin folic acid occurs via folate-receptor mediated endocytosis. Many types of cancer cells express high levels of folate receptors as they need continuous supply of this vitamin for their proliferation. With an objective to use folic acid as a ‘Trojan Horse’ to transport anticancer drugs into cancer cells, a novel heterobifunctional disulfide-containing linker was synthesized and utilized to covalently link an amino- and hydroxyl-containing anticancer drug, and an appropriately functionalized folic acid to create novel targetable folate–drug conjugates that are shown to release free drugs under biologically relevant pH via sulfhydryl-assisted cleavage of the self-immolative disulfide-containing linker.

Graphical abstractA novel heterobifunctional disulfide-containing linker 3 was synthesized and utilized to create targetable folate–drug conjugates 1 that were shown to release free drugs under biologically relevant pH via sulfhydryl-assisted cleavage.Figure optionsDownload full-size imageDownload as PowerPoint slide