Modular Assembly of Reversible Multivalent Cancer-Cell-Targeting Drug Conjugates.
Fábio M F SantosAna I MatosAna E VenturaJoão GonçalvesLuís F VeirosHelena F FlorindoPedro M P GoisPublished in: Angewandte Chemie (International ed. in English) (2017)
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.
Keyphrases
- cancer therapy
- drug delivery
- mass spectrometry
- high throughput
- drug induced
- single molecule
- density functional theory
- adverse drug
- optical coherence tomography
- emergency department
- fluorescent probe
- oxidative stress
- liquid chromatography
- high glucose
- drug release
- breast cancer cells
- molecular dynamics simulations
- diabetic rats
- high speed
- molecular docking
- single cell
- stress induced