ABSTRACT
A family of heterofunctional Schiff base carbosilane metallodendrons with [Ru(η5-C5H5)(PTA)Cl] (PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane) at the focal point and dimethylamino groups on the periphery are described. The new systems have proved their ability to interact with biological molecules such as Human Serum Albumin (HSA) without affecting its secondary structure and erythrocytes membranes, causing haemolysis in a dose and generation dependent way. The combination of two active functional groups in one single dendritic platform has shown a cooperative effect in the viability of HeLa and PC-3 cells, with the second generation derivative standing out as the most promising with the lowest IC50. Experiments focused on advanced prostate cancer have shown an antimetastasic activity for those metallodendrons, hindering the adhesion of cells in one of the main targets of metastasis, bones, and inhibiting cell migration. Finally, the second generation metallodendron with one single metal centre and four dimethylamino groups on the dendritic wedge, was selected for an ex vivo experiment in nude mice with advanced prostate cancer inhibiting the tumour growth in a 40% compared to control mice.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Prostatic Neoplasms/drug therapy , Ruthenium/chemistry , Ruthenium/pharmacology , Silanes/chemistry , Silanes/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Dendrimers/chemistry , Dendrimers/pharmacology , Dendrimers/therapeutic use , HeLa Cells , Humans , Male , Mice , Mice, Nude , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Organometallic Compounds/therapeutic use , PC-3 Cells , Prostatic Neoplasms/pathology , Ruthenium/therapeutic use , Silanes/therapeutic useABSTRACT
Metallodendrimers-dendrimers with included metals-are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case of using a dendrimer with a porphyrin core. In previous papers, we showed the promising anticancer effects of carbosilane ruthenium dendrimers. The present paper is devoted to studying biocompatibility and the cytotoxic effect on normal and cancer cells of carbosilane ruthenium dendrimers labelled with fluorescent probe fluorescein isothiocyanate (FITC). The addition of fluorescent probe allowed tracking the metallodendrimer in both normal and cancer cells. It was found that carbosilane ruthenium dendrimer labelled with FITC in concentration up to 10 µmol/L was more cytotoxic for cancer cells than for normal cells. Thus, FITC labelled carbosilane ruthenium dendrimer is a good candidate for diagnostic imaging and studying anticancer effects of metallodendrimers in cancer therapy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Dendrimers/chemistry , Fluorescein-5-isothiocyanate/chemistry , Ruthenium/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line , Cell Survival/drug effects , Dendrimers/chemical synthesis , Dendrimers/pharmacology , Drug Carriers/chemistry , Erythrocytes/cytology , Erythrocytes/drug effects , Erythrocytes/metabolism , Hemolysis/drug effects , Humans , Particle SizeABSTRACT
Coordination of ruthenium arene fragments on carbosilane dendrimers' surface greatly increases their antitumor properties. Newly synthetized ruthenium dendrimers are water-soluble, monodisperse and stable. Since carbosilane dendrimers are good carriers of drugs and genes, the presence of ruthenium in their structure makes them promising candidates for new drug delivery systems with improved antitumor potential. Carbosilane ruthenium dendrimers are more toxic to cancer cells than normal cells. Results of several in vitro studies applied here indicate that carbosilane ruthenium dendrimers induce apoptosis in promyelocytic leukemia HL-60 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Dendrimers/pharmacology , Leukemia, Promyelocytic, Acute/drug therapy , Organometallic Compounds/pharmacology , Ruthenium/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dendrimers/chemical synthesis , Dendrimers/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Leukemia, Promyelocytic, Acute/metabolism , Leukemia, Promyelocytic, Acute/pathology , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolism , Ruthenium/chemistry , Structure-Activity RelationshipABSTRACT
Dendrimers, which are considered as one of the most promising tools in the field of nanobiotechnology due to their structural organization, showed a great potential in gene therapy, drug delivery, medical imaging and as antimicrobial and antiviral agents. This article is devoted to study interactions between new carbosilane-based metallodendrimers containing ruthenium and anti-cancer small interfering RNA (siRNA). Formation of complexes between anti-cancer siRNAs and Ru-based carbosilane dendrimers was evaluated by transmission electron microscopy, circular dichroism and fluorescence. The zeta-potential and the size of dendriplexes were determined by dynamic light scattering. The internalization of dendriplexes were estimated using HL-60 cells. Results show that ruthenium dendrimers associated with anticancer siRNA have the ability to deliver siRNA as non-viral vectors into the cancer cells. Moreover, dendrimers can protect siRNA against nuclease degradation. Nevertheless, further research need to be performed to examine the therapeutic potential of ruthenium dendrimers as well as dendrimers complexed with siRNA and anticancer drugs towards cancer cells.
Subject(s)
Antineoplastic Agents/metabolism , Dendrimers/metabolism , Intercalating Agents/metabolism , Leukemia, Promyelocytic, Acute/metabolism , Models, Molecular , RNA, Small Interfering/metabolism , Ruthenium/metabolism , Absorption, Physiological , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Circular Dichroism , Dendrimers/administration & dosage , Dendrimers/chemistry , Drug Stability , Dynamic Light Scattering , HL-60 Cells , Humans , Intercalating Agents/administration & dosage , Intercalating Agents/chemistry , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/pathology , Microscopy, Electron, Transmission , Molecular Conformation , Molecular Dynamics Simulation , Molecular Structure , Particle Size , RNA Interference , RNA Stability , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/chemistry , RNA, Small Interfering/ultrastructure , Ruthenium/administration & dosage , Ruthenium/chemistry , Silanes/chemistry , Silanes/metabolism , Surface PropertiesABSTRACT
A series of new organometallic carbosilane dendrimers functionalized with Copper(II) complex on the surface were synthesized and characterized as potential anticancer agents. These metallodendrimers were synthesized through the reaction of dendritic ligands containing N,N- and N,O- donor atoms able to act as chelating agents with CuCl2 as metallic ion precursor. The structural characterization of these complexes was addressed through the use of different analytical and spectroscopical techniques. Particularly, an electron paramagnetic resonance study was performed to corroborate the coordination properties of these dendritic ligands. A preliminary study was carried out to establish the cytotoxicity of the new synthesized compounds in human prostate (PC3) and human cervical (HeLa) cancer cell lines in order to evaluate their potential as anticancer agents and compare their activity with other copper or analogous ruthenium metallodendrimers.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Copper/chemistry , Dendrimers/pharmacology , Silanes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dendrimers/chemical synthesis , Dendrimers/chemistry , Electron Spin Resonance Spectroscopy , Humans , Ligands , Silanes/chemical synthesis , Silanes/chemistryABSTRACT
A series of new organometallic carbosilane dendrimers (first and second generation) and the corresponding non-dendritic mononuclear based on ruthenium arene fragments are described. The metallodendrimers were prepared by reactions of the precursor [Ru(η(6)-p-cymene)Cl2]2 with carbosilane dendrimers functionalized with N-donor monodentate ligands such as NH2- and pyridine, or with N,O-, N,N-chelating imine ligands. While the dendrimer precursors are insoluble in DMSO or water, novel metallodendrimers are soluble in DMSO and some of them are even highly soluble in water. The molecular structure of the "Ru-NH2" mononuclear compound (zero generation) was determined by single-crystal X-ray crystallography. The cytotoxicity activity of these dendritic structures was evaluated in several human cancer cell lines and compared with that of the corresponding mononuclear ruthenium complexes. Most compounds display significant cytotoxic activities in the low micromolar range with the first generation ruthenium dendrimers being the most active compounds. The cell death type for selected compounds has been studied as well as their reactivity towards relevant biomolecules such as DNA, Human Serum Albumin (HSA) and Cathepsin-B. All the data point to a mode of action different from that of cisplatin for most complexes. First generation ruthenium dendrimers inhibit Cathepsin-B, which may suggest potential antimetastatic properties of these compounds.
