Multifunctional Chemical Cross-linkers for Drug Carriers and Molecular Probes

Abstract

Bioconjugates are an indispensable tool for molecular biology as well as an established modality for biomedical imaging and drug delivery. Broadly, bioconjugation is the use of a chemical cross-linker to covalently attach non-natural reporters, chemical handles, drug cargo, or targeting ligands to biologics to augment their innate properties and functions. Many bioconjugation strategies attach a single non-natural component to the biomolecule of interest. This limits the functional complexity of the resulting bioconjugate. Incorporating multiple functionalities and/or stimuli responsive units has the potential to enable new applications of bioconjugates as molecular probes and drug carriers. Herein, we present a survey of our work towards developing multifunctional bioconjugates. We develop a new strategy for the site-specific modification of native antibodies. This strategy enables dual “click” modification of native antibodies. We also develop new synthetic methods for the synthesis of oligothioetheramides. We apply this new synthesis to study the effect of cross-linker sequence on the biophysical properties of antibody-drug conjugates. Finally, we discuss our efforts to develop molecular probes to characterize the surface of extracellular vesicles and quantify endosomal escape for siRNA therapeutics. Taken together, these works highlight the importance of chemical cross-linkers in the design of multifunctional bioconjugates for a variety of applications.