Fine-Tuning the Interaction and Therapeutic Effect of Cu(II) Carbosilane Metallodendrimers in Cancer Cells: An In Vitro Electron Paramagnetic Resonance Study

Abstract

Copper(II) carbosilane metallodendrimers are promising nanosized anticancer metallodrugs. The precise control on their design enables an accurate structure-to-activity study. We hypothesized that different structural features, such as the dendrimer generation and metal counterion, modulate the interaction with tumor cells, and subsequently, the effectivity and selectivity of the therapy. A computeraided analysis of the electron paramagnetic resonance (EPR) spectra allowed us to obtain dynamical and structural details on the interactions over time between the dendrimers and the cells, the myeloid U937 tumor cells and peripheral blood mononuclear cells (PBMC). The intracellular fate of the metallodendrimers was studied through a complete in vitro evaluation, including cytotoxicity, cytostaticity, and sublethal effects regarding mitochondria function, lysosomal compartments, and autophagic organelle involvement. EPR results confirmed a higher membrane stabilization for chloride dendrimers and low generation complexes, which ultimately influence the metallodrug uptake and intracellular fate. The in vitro evaluation revealed that Cu(II) metallodendrimers are cytostatic and moderate cytotoxic agents for U937 tumor cells, inducing death processes through the mitochondria−lysosome axis as well as autophagic vacuole formation, while barely affecting healthy monocytes. The study provided valuable insight into the mechanism of action of these nanosized metallodrugs and relevant structural parameters affecting the activity.

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

“…1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR spectra were recorded on Bruker AV400PAS and AV300PAS (Bruker, Karlsruhe, Germany) instruments. 1 H and 13 C chemical shifts (δ, ppm) were measured relative to residual resonances of solvents.…”

“…1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR spectra were recorded on Bruker AV400PAS and AV300PAS (Bruker, Karlsruhe, Germany) instruments. 1 H and 13 C chemical shifts (δ, ppm) were measured relative to residual resonances of solvents. High-resolution mass spectra were recorded using GCT Premier (Waters, Milford, MA, USA) and UPLC Xevo G2 Q TOF (Waters, Milford, MA, USA) mass spectrometers for chemical ionization and electrospray ionization, respectively.…”

“…There are numerous examples of metallodendrimers having silicon-and phosphorusbased scaffolds. Carbosilane dendrimers functionalized with monodentate and bidentate ligands, coordinating ruthenium (II) [10,11] and copper (II) [12][13][14][15] complexes, have been reported to suppress the viability of cancer cell lines of different origin in micromolar concentrations. The cytotoxic activity of carbosilane metallodendrimers appears to be stronger than that of polyamidoamine dendrimers bearing metal complexes of similar structure [16,17].…”

Improvement in the Pharmacological Profile of Copper Biological Active Complexes by Their Incorporation into Organic or Inorganic Matrix

“…The corresponding system with Cu(OH 2 )Cl 2 moiety exhibits a moderate cytotoxicity in myeloid (U937) cancer cells. The system induces cell death through the mitochondria-lysosome system as well as vacuole formation through autophagy [129]. A comparative study of such G1 and G2 dendrimers conjugated with Cu(OH 2 )X 2 (27) (X: is ONO 2 ) and (28) (X is Cl) moieties (Figure 2) revealed that the increase in generation and changing nitrate with chloride, produced an increased in vitro cytotoxic effect in cervix (HeLa), normal and resistant breast cancer (MCF7 and HCC1806), advanced prostate cancer (PC3) and colorectal tumor (HT29) cell lines.…”

Combination of Copper Metallodendrimers with Conventional Antitumor Drugs to Combat Cancer in In Vitro Models

“…These modifications include the introduction of metal atoms that exhibit anticancer properties, for example, platinum, gold, silver, ruthenium or copper [ 6 , 20 ], into the dendrimer structure to improve their biomedical applications. In particular, carbosilane copper metallodendrimers bearing iminopyridine moieties have demonstrated outstanding anticancer activity in both solid tumors and myeloid cell lines [ 6 , 21 , 22 , 23 , 24 ].…”