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

Angew Chem Int Ed Engl. 2017 Aug 1;56(32):9346-9350. doi: 10.1002/anie.201703492. Epub 2017 Jul 10.

Abstract

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.

Keywords: antitumor agents; boronic acids; drug delivery; multivalency; small-molecule-drug conjugates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Boronic Acids / chemistry*
  • Bortezomib / chemistry
  • Bortezomib / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Polyethylene Glycols / chemistry*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Polyethylene Glycols
  • Bortezomib