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Modular Assembly of Reversible Multivalent Cancer‐Cell‐Targeting Drug Conjugates
Author(s) -
Santos Fábio M. F.,
Matos Ana I.,
Ventura Ana E.,
Gonçalves João,
Veiros Luís F.,
Florindo Helena F.,
Gois Pedro M. P.
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201703492
Subject(s) - chemistry , conjugate , covalent bond , glutathione , drug delivery , combinatorial chemistry , ethylene glycol , prodrug , peg ratio , cancer cell , biophysics , biochemistry , cancer , enzyme , organic chemistry , medicine , mathematical analysis , mathematics , finance , economics , biology
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 IC 50 values in the nanomolar range.