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

envie a um amigo share this

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

Segunda, 02.10.2017

Authors and Affiliations:

Fábio M. F. Santosa, Ana I. Matosa, Ana E. Venturaa, João Gonçalvesa, Luís F. Veirosb, Helena F. Florindoa, Pedro M. P. Goisa

a) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

b) Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa Portugal.

 

Abstract:

A new modular platform for the construction of cancer-cell-targeting drug conjugates was developed, in which 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.

 

Journal: Angewandte Chemie International Edition

 

Link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201703492/abstract