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

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 IC values in the nanomolar range.

Advances in targeting the folate receptor in the treatment/imaging of cancers

“…A bivalent folate targeting moiety was chosen to mimic the bivalent Fab regions present on immunoglobulin Gs (IgGs) that give rise to high affinity and specificity of antibodies for particular antigen epitopes. 47 Complex 10 exhibited an IC 50 value of 62 nM against MDA-MB-231 cancer cells, lower than that of free bortezomib, but superior selectivity for these FRα-overexpressing cells as compared to the free drug. As GluSH is present in millimolar concentrations in the cell, Gois et al investigated the GluSH-mediated cleavage mechanism by synthesising complex 11 , a less sterically hindered analogue of complex 10 .…”

Synthetic Cancer‐Targeting Innate Immune Stimulators Give Insights into Avidity Effects

“…Bispecific constructs have also been developed; these include CovX‐bodies, in which two peptides targeting the vascular endothelial growth factor (VEGF) and angiopoietin‐2 were fused to an antibody scaffold designed to provide long half‐life and biodistribution, and BiTE (bispecific T‐cell engaging) antibodies, single‐chain bispecific antibody (Bis‐scFv) constructs that target tumor cells and activate T‐cells . Synthetic constructs such as antibody‐recruiting molecules (ARMs) and synthetic antibody mimics (SyAMs) that mimic antibody properties have also been reported, as well as targeting drug conjugates (TDCs) based on core molecules to which targeting and cytotoxic moieties can be conjugated …”

Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker)

“…41 Gois et al modified this phenolic-based linker to release umbelliferone 12 upon self-immolative degradation. 42 Taking inspiration from both of these systems, we decided to apply a related, but novel, strategy to the thiophenol system of PD 4, which required the synthesis of umbelliferone-PD 13. To this end, we synthesised PD 8, which could be brominated using N-bromosuccinimde (NBS) 9 and azobisisobutyronitrile (AIBN) 10 to make di-bromo intermediate 11.…”