Amphiphilic Triazine-Phosphorus Metallodendrons Possessing Anti-Cancer Stem Cell Activity.

Evgeny K Apartsin,Anne-Marie Caminade,Nadezhda Knauer,Ulf Dietrich Kahlert

doi:10.3390/pharmaceutics14020393

Abstract

Dendritic molecules bearing metal complexes in their structure (metallodendrimers and metallodendrons) are considered prospective therapeutic entities. In particular, metallodendrons raise interest as antitumor agents for the treatment of poorly curable or drug-resistant tumors. Herein, we have synthesized amphiphilic triazine-phosphorus dendrons bearing multiple copper (II) or gold (III) complexes on the periphery and a branched hydrophobic fragment at the focal point. Due to their amphiphilic nature, metallodendrons formed single micelles (mean diameter ~9 nm) or multi-micellar aggregates (mean diameter ~60 nm) in a water solution. We have tested the antitumor activity of amphiphilic metallodendrons towards glioblastoma, a malignant brain tumor with a notoriously high level of therapy resistance, as a model disease. The metallodendrons exhibit higher cytotoxic activity towards glioblastoma stem cells (BTSC233, JHH520, NCH644, and SF188 cell lines) and U87 glioblastoma cells (IC50 was 3–6 µM for copper-containing dendron and 11–15 µM for gold-containing dendron) in comparison with temozolomide (IC50 >100 µM)—the clinical standard of care for glioblastoma. Our findings show the potential of metallodendron-based nanoformulations as antitumor entities.

Highlights

Dendritic molecules, dendrimers and dendrons, are symmetric hyperbranched macromolecules consisting of a core and radially growing branches terminated with multiple functional groups exposed to the surface [1]
We have used a bifunctional AB5 -type phosphorus dendron consisting of a hexafunctional cyclotriphosphazene core bearing five hydroxybenzaldehyde substituents and a chlorine substituent [28]
Cyanuric chloride was modified with two dodecylamine moieties (Figure 1, i), the linker was introduced (Figure 1, ii) to graft the hydrophobic modifier to the focal point of a dendron

Summary

Introduction

Dendrimers and dendrons, are symmetric hyperbranched macromolecules consisting of a core and radially growing branches terminated with multiple functional groups exposed to the surface [1]. Thanks to this feature, along with a precisely defined molecular structure and monodispersity-by-design, dendrimers and dendrons are considered prospective nano-platforms for the development of therapeutic formulations, active both per se or as carriers for bioactive entities [2,3,4,5]. An important class of dendrimers with proven biological activity contains dendritic species bearing metal complexes on the periphery These dendrimers, referred to as metallodendrimers, consist of a dendritic scaffold (various architecture types reported) decorated with nitrogen-based or N-heterocyclic carbene ligands coordinating metal ions. The main field of biological applications of metallodendrimers is antitumor therapy [6,7,8].

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Results

Conclusion