Assembly of pH-Responsive Antibody-Drug-Inspired Conjugates.

With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates (ADCs). While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive linker, we devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate should ideally possess distinct features of ADCs such as (1) recognition sites that recognize cell receptor and are arranged on (2) distinct location on a high molecular weight protein scaffold, (3) a stimuli-responsive linker, as well as (4) an attached payload such as a drug molecule. These AD-like conjugates target cancer cells that overexpress somatostatin receptors, could enable controlled release in the microenvironment of cancer cells through a new pH-responsive biotin linker, and exhibit stability in biological media. This article is protected by copyright. All rights reserved.