Dithio-bis(ethyl 1H-imidazole-1-carboxylate) crosslinks with protein amine groups. The dissulfide gets reduced in the cellular environment.
Researchers are always looking for ways to improve the cellular delivery of drugs. Many times they use polymers or protein particles. Protein particles offer immediate biocompatibility, but since they are water soluble they tend to break up rapidly once they enter the bloodstream. Now researchers have applied crosslinking to allow protein particles together until they enter a cell, where they are then dissolved. From C&EN:
His team achieved this solubility switch by stitching together the proteins once they had formed a particle. They used a compound called dithio-bis(ethyl 1H-imidazole-1-carboxylate) (DIC), which crosslinks proteins via their amine groups. This crosslinking holds the proteins together and prevents the particle from dissolving. But the crosslinking compound contains a disulfide bond that breaks in reducing environments, such as inside a cell, explains DeSimone. So once the particle slips into a cell, it breaks apart, dissolves, and releases its cargo. In addition, when the disulfide bonds break, the remaining halves of the DIC molecule fall off the amine groups, restoring the proteins to their unmodified state.
To test the protein-stitching technique, the researchers first made protein particles using a method they had developed previously (J. Am. Chem. Soc., DOI: 10.1021/ja8014428). They combined bovine serum albumin, an inexpensive protein, with glycerol and α-D-lactose, which act as glues to hold the protein matrix together. As test cargo, they mixed in a large RNA molecule that codes for the enzyme chloramphenicol acetyltransferase. To form the particles, the researchers poured this mixture into a mold to solidify. They pulled the protein particles from their molds with sticky paper and then dissolved the adhesive to release the particles.