Modular Assembly of Reversible Multivalent Cancer‐Cell‐Targeting Drug Conjugates

Herein is described a new modular platform for the construction of cancer‐cell‐targeting drug conjugates. Tripodal boronate complexes featuring reversible covalent bonds were designed to accommodate a cytotoxic drug (bortezomib), poly(ethylene glycol) (Peg) chains, and folate targeting units. The B‐complex core was assembled in one step, proved stable under biocompatible conditions, namely, in human plasma (half‐life up to 60 h), and underwent disassembly in the presence of glutathione (GSH). Stimulus‐responsive intracellular cargo delivery was confirmed by confocal fluorescence microscopy, and a mechanism for GSH‐induced B‐complex hydrolysis was proposed on the basis of mass spectrometry and DFT calculations. This platform enabled the modular construction of multivalent conjugates with high selectivity for folate‐positive MDA‐MB‐231 cancer cells and IC50 values in the nanomolar range. Getting together for group therapy: Tripodal boronate complexes accommodating the cytotoxic drug bortezomib (Btz), poly(ethylene glycol) (PEG) chains, and folate targeting units showed high selectivity for folate‐positive MDA‐MB‐231 cancer cells and stimulus‐responsive intracellular cargo delivery (see picture). The core structure was assembled in one step and was stable in human plasma but underwent disassembly in the presence of glutathione (GSH).