SPOC synthesis of linker-dolastatin 10 derivatives for antibody driven targeted drug delivery.

This work describes the development of targeted drug delivery (TDD) tools to treat cancer. One possibility to overcome the side effects of chemotherapy is delivering the drugs by specific carriers that target mainly cancer cells. As a toxic payload we develop a dolastatinol, the derivative of sub-nanomolar microtubule toxin – DOLASTATIN 10. It differs from the parent peptide by methylene hydroxyl tether at C-terminus and synthesized by solid phase peptide synthesis (SPPS). Evidently, the linkage of the drug to the carrier is done via linker. The nature of the linker dictates the release of the drug in the presence of a proteolytic factor that dominates in cancer cells. In this study, a biodegradable disulfide linker was chosen in order to disintegrate in the presence of elevated levels of glutathione and subsequently release the payload dolastatinol. The linker bears three functional groups: one carboxylic group and two orthogonally protected amines The second amine, allows addition of fluorescent dye for monitoring a drug release at the target by imaging. The conjugation of dolastatinol to Ab is in process in our lab.