Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects conventional chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through linker that releases drug inside or proximity cell, represents key component final therapeutic effect conjugate. Here, we show replacement Val-Ala- p -aminobenzyloxycarbamate with Gly-Pro-Leu-Gly- (GPLG-PABC) sequence as enzymatically cleavable SMDC bearing cyclo [DKP -iso DGR] α V β 3 integrin ligand monomethyl auristatin E (MMAE) led 4-fold more potent anti-tumoral conjugate on different cell lines. addition, synthesized resulted be significantly than free MMAE when tested following “kiss-and-run” protocol, relative potency were clearly consistent expression receptor considered vitro enzymatic cleavage tests showed GPLG-PABC cleaved by lysosomal enzymes, released observable already after 15 min incubation. Although additional data are needed fully characterize releasing capacity linker, our findings significance since introducing an alternative other well-established sensitive peptide sequences might used future generating efficient less toxic delivery systems.