N-Heterocyclic Carbene–Polyethylenimine Platinum Complexes with Potent in Vitro and in Vivo Antitumor Efficacy

Abstract

The current interest for platinum N-heterocyclic carbene complexes in cancer research stems from their impressive toxicity reported against a range of different human cancer cells. To date, the demonstration of their in vivo efficacy relative to that of established platinum-based drugs has not been specifically addressed. Here, we introduce an innovative approach to increase the NHC-Pt complex potency whereby multiple NHC-Pt(II) complexes are coordinated along a polyethylenimine polymer (PEI) chain. We show that such NHC-Pt(II)-PEI conjugates induce human cancer cell death in vitro and in vivo in a xenograft mouse model with no observable side effects in contrast to oxaliplatin. Additional studies indicate nucleus and mitochondria targeting and suggest various mechanisms of action compared to classical platinum-based anticancer drugs.

N-Heterocyclic Carbene-PEI Platinum Complexes Inducing Human Cancer Cell Death: Polymer Carrier Impact

“…We recently highlighted that polyethyleneimine (PEI), a polymer widely used as transfection agent, can be used as ligand for N-heterocyclic carbene platinum complexes to generate NHC-Pt-PEI conjugates that induce human cancer cell death in vitro and in vivo [10]. Interestingly, we showed that a part of the cytotoxicity induced by our compounds was independent of nucleus and seemed related to mitochondrial dysfunction.…”

N-Heterocyclic Carbene-Platinum Complexes Featuring an Anthracenyl Moiety: Anti-Cancer Activity and DNA Interaction.

“…This is also much higher than known platinum(II) N-heterocyclic carbene complexes thus confirming the positive impact of the anthracene moiety. Indeed, complexes of type (NHC)PtI2(L) have IC50 at a micromolar range typically from 0.5 to 5 µM [47,[50][51][52][53].…”

“…On the other hand, little is known about the intracellular cytotoxic mechanism of NHC-Pt complexes mainly due to their novelty [50,51]. We thus decided to conduct several studies on the interaction between DNA and such type of complexes.…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…50 In fact, measurements of the binding efficiency of the complexes to salmon testes DNA showed increased binding for 5a and 5b (2.03 pmol/µg and 1.03 pmol/µg, respectively) compared to Et3PAuCl (0.11 pmol/µg), but which was still weaker than cisplatin Furthermore, novel mechanistic behaviors were reported for a polymeric formulation of platinum(II) NHC fragments attached to a bidentate polyethylenimine ligand, a known transfection agent (7, Figure 5). 52 Notably, the complex is much more effective than cisplatin and oxaliplatin against HCT-116 (human colorectal adenocarcinoma) cells. Evaluation of the subcellular distribution of 7 demonstrated that only 16% of the total intracellular platinum accumulated in the nucleus while 20% was found in mitochondria.…”