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

• Published in: Angewandte Chemie Vol. 129; no. 32; pp. 9474 - 9478
• Main Authors: Santos, Fábio M. F., Matos, Ana I., Ventura, Ana E., Gonçalves, João, Veiros, Luís F., Florindo, Helena F., Gois, Pedro M. P.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01.08.2017
• Subjects: Biocompatibility; Blood plasma; Boronsäuren; Bortezomib; Cancer; Cargo; Chemistry; Conjugates; Construction; Coordination compounds; Covalence; Covalent bonds; Cytotoxicity; Dismantling; Fluorescence; Fluorescence microscopy; Folic acid; Glutathione; Hydrolysis; Mass spectrometry; Mass spectroscopy; Microscopy; Modular construction; Multivalenz; Polyethylene glycol; Selectivity; Tumortherapeutika; Wirkstoffkonjugate; Wirkstofftransport
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201703492

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. Tripodale Boronatkomplexe aus dem cytotoxischen Wirkstoff Bortezomib (Btz), Polyethylenglykol(PEG)‐Ketten und Folat‐Erkennungseinheiten zeigen hohe Selektivität für Folat‐positive MDA‐MB‐231‐Krebszellen und ermöglichen den stimulusresponsiven intrazellulären Transport von molekularer Fracht (siehe Bild). Die Kernstruktur wurde in einem Schritt aufgebaut und ist in humanem Plasma stabil, zerfällt aber in der Gegenwart von Glutathion (GSH).