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

Abstract

Herein is described anew modular platform for the construction of cancer-cell-targeting drug conjugates.T ripodal boronate complexes featuring reversible covalent bonds were designed to accommodate ac ytotoxic drug (bortezomib), poly(ethylene glycol) (Peg) chains,a nd folate targeting units. The B-complex core was assembled in one step,proved stable under biocompatible conditions,n amely,i nh uman 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 am echanism for GSH-induced B-complex hydrolysis was proposed on the basis of mass spectrometry and DFT calculations.T his platform enabled the modular construction of multivalent conjugates with high selectivity for folate-positive MDA-MB-231 cancer cells and IC 50 values in the nanomolar range.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201703492. Scheme 1. A) Linear construction of TDCs;B)boron-promoted modular and reversible assemblyo fmultifunctional TDCs.

Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes

“…22 The binding complex is equipped with (1) small spatial requirement, (2) fast binding kinetics and (3) pH-responsiveness within the physiological range (5.0−7.4). 23 Hence, its dynamic covalent binding capabilities have been applied broadly in therapeutics, 24 biosensors, 25,26 stimulus responsive ligation tools 27 and as self-regenerative materials. 28,29 Herein, we propose that BA/ CA motifs in a binary sequence would encode molecular recognition in a stimulus responsive fashion.…”

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…Thus, 51 in the presence of glutathione releases 52 which will undergo oxidation and self-immolative cleavage to afford 50 (Scheme 10). 95 Again, the modular approach for assembling the molecules greatly facilitates development of a glutathione triggered release of the cytotoxic drug Bortezomid. 95 A model study identified the cleavage products (Scheme 11) and led to a proposal for the mechanism of release of the boronic acid.…”

“…95 Scheme 10 Glutathione/hydrogen peroxide induced self-immolative release of a fluorescent coumarin. 95 Scheme 9 Hydrogen peroxide induced self-immolative release of a nitrogen mustard. [91][92][93]…”

“…Thus, 51 in the presence of glutathione releases 52 which will undergo oxidation and self-immolative cleavage to afford 50 (Scheme 10). 95…”