Hydrazone-like linkers

A recent trend is to design polymers with multiple functions including cationic units to bind nucleic acids as well as pH-sensitive carboxylic acids for endosomal dismption. Using a block copolymer architecture, comb-like polymers with cationic grafts were extended from aspartic acid units via a hydrazone linkers.The second block was composed of... 

The linker used to attach the antibody and cytotoxic agent was greatly under-appreciated in early ADC research, but has become a central focus for more recent conjugate research efforts. The broadest activity for ADCs has been obtained with cleavable linkers that contain disulfides, peptides, or acyl hydrazones that, when properly chosen, all have acceptable stability in circulation but are successfully cleaved under conditions encountered intra-cellularly. The peptides and hydrazones are most likely cleaved in the lysosomes while most disulfides are believed to be reduced in the cytosol. This approach has the additional advantage that the species released can be predicted, controlled, and modified, albeit within the limits of the linker technology. All of these approaches can be used in a self-immolative mode that cleaves off any residual linker to release a specific desired derivative in un-derivatized form. ... 

MED-2220, which are attached to antibodies with lysines thiolated by 2-IT (2-iminothiolane, Trout s reagent Figure 7.12). The phenol in the open form of the CBI alkylating unit is protected as a carbamate of tV-methyl piperazine, which likely increases stability and adds solubility. The cyclopropane precursor contains a bromine instead of chlorine for undisclosed reasons. The linker is attached via an acyl hydrazone similar to the AcBut linker in several cali-cheamicin conjugates. The linker contains a short PEG unit that would also likely improve solubility. 

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