Synthesis and Biological Evaluation of Homogeneous Thiol‐Linked NHC*‐Au‐Albumin and ‐Trastuzumab Bioconjugates

Abstract

Targeted delivery of potent cytotoxic drugs to cancer cells minimizes systemic toxicity and several side effects. NHC*−Au−Cl has already been proven to be a potent anticancer agent. In this study, we explore a strategy based on chemoselective cysteine conjugation of NHC*−Au−Cl to albumin and trastuzumab (Thiomab LC‐V205C) to potentiate drug‐ligand ratio, pharmacokinetics, as well as drug efficacy and safety. This strategy is a step forward towards the use of gold‐based anticancer agents as targeted therapies.

Trastuzumab gold-conjugates: synthetic approach and in vitro evaluation of anticancer activities in breast cancer cell lines

“…16,17 AF is known for its redox enzymes inhibitory and ROS scavenging properties. 15 The first ADC based on a Nheterocyclic carbene gold fragment conjugated to an engineered Trastuzumab antibody, Thiomab, was reported recently by Bernardes et al 18 With an GI 50 in the low micromolar range, the anti-proliferative activity of this ADC in HER2 positive breast cancer cell line showed a promising moderate improvement as compared to the gold-complex drug. However, the direct conjugation of the gold atom to the free cysteine of Thiomab (Au-Scysteine bond) may pose in vivo stability issues.…”

Preparation of Titanocene–Gold Compounds Based on Highly Active Gold(I)‐N‐Heterocyclic Carbene Anticancer Agents: Preliminary in vitro Studies in Renal and Prostate Cancer Cell Lines

“…The antiproliferative activity of this ADC in HER2 positive breast cancer cell line showed a promising moderate improvement as compared to the gold-complex drug. [28] Compound b, described by Gust and co-workers in 2011, was found to be cytotoxic (low or sub-micromolar range) in breast and colon cancer cell lines. [21] We hypothesized that the incorporation of these highly cytotoxic gold(I) compounds and titanocene in the same molecule would improve their pharmacological profile.…”

Covalent and non-covalent albumin binding of Au(i) bis-NHCsviapost-synthetic amide modification

“…1A). 23,24 Unfortunately, this binding mode leads to sequestration of the gold centre via irreversible binding to the protein as inferred from studies involving foetal bovine serum. 4 The effect of such binding approach may underlie the reduced in vitro anticancer activity seen for Au(I) mono-NHCs relative to their Au(I) bis NHC counterparts.…”