ABSTRACT
We report the [natMn/52Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(41R,42R,101R,102R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (52Mn, t1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [52Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [52Mn]Mn-PYAN has a distribution pattern similar to that of [52Mn]MnCl2, showing persistent radioactivity accumulation in the kidneys. Conversely, [52Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.
Subject(s)
Chelating Agents , Macrocyclic Compounds , Manganese , Positron-Emission Tomography , Animals , Mice , Positron-Emission Tomography/methods , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Manganese/chemistry , Chelating Agents/chemistry , Chelating Agents/chemical synthesis , Crystallography, X-Ray , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacokinetics , Tissue Distribution , Models, Molecular , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Drug StabilityABSTRACT
Direct interaction between iron oxide nanoparticles (IONs), modified with polyethylene glycol and an ionic liquid, and activated cisplatin drug resulted in a fast and high drug loading (up to 0.17 mol of platinum per gram of iron), and the payload does not strongly affect the magnetic properties of IONs and resists protein adsorption in human serum environment. For another, developmental metal-based drug, tris(8-quinolinolato)gallium(III), binding to the IONs allowed for overcoming the disadvantages of low solubility and incompatibility with intravenous administration. The potential of IONs as a magnetic nanoformulation for smart drug delivery has been confirmed by the release of both metallodrugs under conditions relevant to cancer cytosol.
Subject(s)
Coordination Complexes , Drug Delivery Systems , Gallium/chemistry , Magnetite Nanoparticles/chemistry , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Drug Liberation , Humans , Serum Albumin, Human/chemistryABSTRACT
One of the most widely used strategies for drug development is the coordination of bioactive ligands to transition metals, which could improve biological activity. Moreover, the incorporation of aromatic groups to ligands may allow an enhanced lipophilicity that can influence the cellular uptake and accumulation of the metallodrugs, thus increasing their activity. Herein, we have reported the synthesis and characterization of four Pt(II) complexes [PtCl2(L)], where L = 2-(1-pyrazolyl)-2-thiazoline (PzTn), 2-(1-pyrazolyl)-1,3-thiazine (PzTz), 2-(3,5-diphenyl-1-pyrazolyl)-2-thiazoline (DPhPzTn) or 2-(3,5-diphenyl-1-pyrazolyl)-1,3-thiazine (DPhPzTz). The study was aimed at analysing their potential anticarcinogenic ability in epithelial cervix carcinoma HeLa, human promyelocytic leukemia HL-60 and human histiocytic lymphoma U-937 tumour cell lines as well as checking whether the structural factors of the organic ligand may influence their biological activity. Our findings showed that PtDPhPzTn and PtDPhPzTz were far more effective in terms of cytotoxicity than their less lipophilic counterparts (PtPzTn and PtPzTz), especially in cells derived from solid cervical tumours, thereby suggesting that modulating the lipophilicity of the ligands can help improve the cytotoxic effect of the metal complexes.
Subject(s)
Antineoplastic Agents , Cell Proliferation/drug effects , Coordination Complexes , Neoplasms , Platinum , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Platinum/chemistry , Platinum/pharmacology , U937 CellsABSTRACT
In this work, new thiosemicarbazides (ECA-1, ECA-2) and their Cu (II) complexes (ECA-1-Cu, ECA-2-Cu) were synthesized and their structures were characterized by 1H NMR, 13C NMR, FT-IR, LC-MS, UV-Vis, and thermogravimetric analysis methods. Also, the surface morphology of the all compounds were examined by SEM (Scanning Electron Microscope). In the second stage, in vitro antioxidant capacity of the obtained compounds was investigated. The evaluation of the antioxidant properties of both synthesized ligands and complexes in this study was carried out by DPPH and FRAP methods. According to the results, both complexes exhibited more antioxidant capacity than the corresponding ligands. When antioxidant effects are compared for DPPH (SC50 = 5.27 ± 0.05 µM) and for FRAP (7845.69 ± 16.75 mmolTE/g), compound ECA-2-Cu appears to have the best inhibition effect. The complexes were found non-electrolytic in nature with melting point of above 250 °C, and electronic spectra and magnetic behavior demonstrated that the complexes were found to be tetrahedral geometry. Further, in silico the ADMET properties which studies are a significant role in improving and predicting drug compounds were calculated using web-based platforms. The theoretical calculations were made using the method of Density Functional Theory (Frontier molecular orbital analyze and Nonlinear optical properties). Also, molecular docking studies were performed to evaluate the binding interactions between the ligand and complex compounds and Human Peroxiredoxin 2. Both in vitro and in silico results indicated that synthesized compounds could act as potent antioxidant agents.
Subject(s)
Antioxidants/chemistry , Coordination Complexes/chemistry , Semicarbazides/chemistry , Antioxidants/chemical synthesis , Antioxidants/metabolism , Antioxidants/pharmacokinetics , Coordination Complexes/chemical synthesis , Coordination Complexes/metabolism , Coordination Complexes/pharmacokinetics , Copper/chemistry , Density Functional Theory , Humans , Ligands , Models, Chemical , Molecular Docking Simulation , Peroxiredoxins/metabolism , Protein Binding , Semicarbazides/chemical synthesis , Semicarbazides/metabolism , Semicarbazides/pharmacokineticsABSTRACT
Theranostic anticancer agents with dual functions of diagnosis and therapy are in highly demand for breast cancer. Herein, a triphenylphosphonium (TPP)-decorated aggregation-induced emission (AIE)-based Pt(IV) prodrug ACPt was developed, which exhibited superior anticancer performance with novel anticancer mechanism of dual modulation of apoptosis and autophagy inhibition. The experimental data showed that ACPt induced increased reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP). The morphology and function of mitochondria were also severely damaged and ACPt showed strong inhibition to both mitochondrial and glycolytic bioenergetics. Moreover, DNA damage and cell cycle arrest in the S-phase were also observed after the ACPt treatment, eventually leading to the apoptosis and autophagy inhibition of cancer cells. Furthermore, ACPt also indicated excellent anti-proliferation activity in 3D multicellular tumor spheroids (MCTSs), suggesting the potential to inhibit solid tumors in vivo. Our observation demonstrated that ACPt could serve as a promising anticancer theranostic agent toward breast cancers for prodrug activation monitoring and image-guided chemotherapy.
Subject(s)
Antineoplastic Agents , Apoptosis/drug effects , Autophagy/drug effects , Breast Neoplasms , Coordination Complexes , Drug Delivery Systems , Mitochondria/metabolism , Platinum , Prodrugs , A549 Cells , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , Female , Hep G2 Cells , Humans , MCF-7 Cells , Membrane Potential, Mitochondrial/drug effects , Platinum/chemistry , Platinum/pharmacokinetics , Platinum/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacologyABSTRACT
Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes' properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Gold , Neoplasm Proteins/antagonists & inhibitors , Neoplasms , Selenoproteins/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/therapeutic use , Gold/chemistry , Gold/pharmacokinetics , Gold/therapeutic use , Humans , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Selenoproteins/metabolismABSTRACT
The selection of technological parameters for nanoparticle formulation represents a complicated development phase. Therefore, the statistical analysis based on Box-Behnken methodology is widely used to optimize technological processes, including poly(lactic-co-glycolic acid) nanoparticle formulation. In this study, we applied a two-level three-factor design to optimize the preparation of nanoparticles loaded with cobalt (CoTPP), manganese (MnClTPP), and nickel (NiTPP) metalloporphyrins (MeP). The resulting nanoparticles were examined by dynamic light scattering, X-ray diffraction, Fourier transform infrared spectroscopy, MTT test, and hemolytic activity assay. The optimized model of nanoparticle formulation was validated, and the obtained nanoparticles possessed a spherical shape and physicochemical characteristics enabling them to deliver MeP in cancer cells. In vitro hemolysis assay revealed high safety of the formulated MeP-loaded nanoparticles. The MeP release demonstrated a biphasic profile and release mechanism via Fick diffusion, according to release exponent values. Formulated MeP-loaded nanoparticles revealed significant antitumor activity and ability to generate reactive oxygen species. MnClTPP- and CoTPP-nanoparticles specifically accumulated in tissues, preventing wide tissue distribution caused by long-term circulation of the hydrophobic drug. Our results suggest that MnClTPP- and CoTPP-nanoparticles represent the greatest potential for utilization in in anticancer therapy due to their effectiveness and safety.
Subject(s)
Coordination Complexes/pharmacokinetics , Metalloporphyrins/pharmacokinetics , Metals/chemistry , Nanoparticles/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Porphyrins/chemistry , Animals , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Liberation , Female , HeLa Cells , Hemolysis/drug effects , Humans , MCF-7 Cells , Metalloporphyrins/chemistry , Metalloporphyrins/pharmacology , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Nanoparticles/ultrastructure , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Tissue Distribution , X-Ray DiffractionABSTRACT
Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 µM) and P6 (6.52 and 14.45 µM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 µM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Cymenes , Ruthenium , Thioamides , Thiourea , A549 Cells , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Biological Availability , Cell Survival/drug effects , Coordination Complexes/administration & dosage , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Cymenes/administration & dosage , Cymenes/chemistry , Cymenes/pharmacokinetics , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Intestinal Absorption , Ligands , Male , Mice, Inbred ICR , Mitogen-Activated Protein Kinases/metabolism , Molecular Docking Simulation , Ruthenium/administration & dosage , Ruthenium/chemistry , Ruthenium/pharmacokinetics , Thioamides/administration & dosage , Thioamides/chemistry , Thioamides/pharmacokinetics , Thiourea/administration & dosage , Thiourea/chemistry , Thiourea/pharmacokineticsABSTRACT
α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Thiosemicarbazones , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/administration & dosage , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Copper/administration & dosage , Copper/chemistry , Copper/pharmacokinetics , Drug Liberation , Female , Humans , Liposomes , Methemoglobin/metabolism , Mice, Inbred BALB C , Thiosemicarbazones/administration & dosage , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacokineticsABSTRACT
Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately â¼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.
Subject(s)
Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Drug Carriers/chemistry , Nanocapsules/chemistry , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Line, Tumor , Cisplatin/chemistry , Cisplatin/pharmacokinetics , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Dendrimers/chemistry , Dendrimers/pharmacokinetics , Drug Carriers/pharmacokinetics , Drug Liberation , Humans , Mice, Inbred BALB C , Platinum/chemistry , Platinum/pharmacokinetics , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Polylysine/chemistry , Polylysine/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
Fe(III) macrocyclic complexes containing a macrocycle and three pendant groups including phosphonate (NOTP =1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid), carboxylate (NOTA = 1,4,7 - triazacyclononane - N,N',Nâ³ - triacetate) or hydroxypropyl (NOHP =(2S,2'S,2"S)-1,1',1â³-(1,4,7-triazonane-1,4,7-triyl)tris(propan-2-ol)) were studied in order to compare the effect of these donor groups on solution chemistry and water proton relaxivity. All three complexes, Fe(NOTP), Fe(NOHP) and Fe(NOTA), display a large degree of kinetic inertness to dissociation in the presence of phosphate and carbonate, under acidic conditions of 100 mM HCl or 1 M HCl or to trans-metalation with Zn(II). The r1 proton relaxivity of the complexes at 1.4 T, 33 °C is compared over the pH range of 1 to 10. At pH 7.4, 33 °C, 1.4 T, Fe(NOHP) has the largest relaxivity (1.5 mM-1 s-1), Fe(NOTP) is second at 1.0 mM-1 s-1, whereas Fe(NOTA) is the lowest at 0.61 mM-1 s-1. Fe(NOTP), Fe(NOHP) and Fe(NOTA) all show an increase in relaxivity at very acidic pH values (< 3) that is consistent with an acid-catalyzed process. Variable temperature 17O NMR studies at near neutral pH are consistent with the absence of an inner-sphere water molecule for Fe(NOTP) and Fe(NOHP), supporting second-sphere or outer-sphere water contributions to proton relaxation. Fe(NOTP) shows contrast enhancement in T1 weighted MRI studies in mice and clears through a renal pathway.
Subject(s)
Contrast Media/chemistry , Coordination Complexes/chemistry , Animals , Contrast Media/chemical synthesis , Contrast Media/pharmacokinetics , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacokinetics , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Iron/chemistry , Ligands , Magnetic Resonance Imaging , Mice, Inbred BALB C , Molecular Structure , Phosphorous Acids/chemical synthesis , Phosphorous Acids/chemistry , Phosphorous Acids/pharmacokinetics , Water/chemistryABSTRACT
Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-ß (Aß). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aß plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [TcâO]3+ and [ReâO]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aß1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [TcâO]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.
Subject(s)
Alzheimer Disease/diagnostic imaging , Coordination Complexes/chemistry , Organotechnetium Compounds/chemistry , Radiopharmaceuticals/chemistry , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Brain/diagnostic imaging , Coordination Complexes/chemical synthesis , Coordination Complexes/metabolism , Coordination Complexes/pharmacokinetics , Humans , Ligands , Mice , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/metabolism , Organotechnetium Compounds/pharmacokinetics , Peptide Fragments/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/metabolism , Pyridines/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/metabolism , Radiopharmaceuticals/pharmacokinetics , Rhenium/chemistry , Styrenes/chemical synthesis , Styrenes/chemistry , Styrenes/metabolism , Styrenes/pharmacokineticsABSTRACT
The search for alternatives to Gd-containing magnetic resonance imaging (MRI) contrast agents addresses the field of Fe(III)-bearing species with the expectation that the use of an essential metal ion may avoid the issues raised by the exogenous Gd. Attention is currently devoted to highly stable Fe(III) complexes with hexacoordinating ligands, although they may lack any coordinated water molecule. We found that the hexacoordinated Fe(III) complex with two units of deferasirox, a largely used iron sequestering agent, owns properties that can make it a viable alternative to Gd-based agents. Fe(deferasirox)2 displays an outstanding thermodynamic stability, a high binding affinity to human serum albumin (three molecules of complex are simultaneously bound to the protein), and a good relaxivity that increases in the range 20-80 MHz. The relaxation enhancement is due to second sphere water molecules likely forming H-bonds with the coordinating phenoxide oxygens. A further enhancement was observed upon the formation of the supramolecular adduct with albumin. The binding sites of Fe(deferasirox)2 on albumin were characterized by relaxometric competitive assays. Preliminary in vivo imaging studies on a tumor-bearing mouse model indicate that, on a 3 T MRI scanner, the contrast ability of Fe(deferasirox)2 is comparable to the one shown by the commercial Gd(DTPA) agent. ICP-MS analyses on blood samples withdrawn from healthy mice administered with a dose of 0.1 mmol/kg of Fe(deferasirox)2 showed that the complex is completely removed in 24 h.
Subject(s)
Contrast Media/chemistry , Coordination Complexes/chemistry , Deferasirox/analogs & derivatives , Animals , Binding Sites , Cell Line, Tumor , Contrast Media/metabolism , Contrast Media/pharmacokinetics , Coordination Complexes/metabolism , Coordination Complexes/pharmacokinetics , Deferasirox/metabolism , Deferasirox/pharmacokinetics , Female , Humans , Iron/chemistry , Magnetic Resonance Imaging , Mice, Inbred BALB C , Protein Binding , Serum Albumin, Human/chemistry , Serum Albumin, Human/metabolismABSTRACT
PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
Subject(s)
Coordination Complexes/pharmacokinetics , Menkes Kinky Hair Syndrome/drug therapy , Thiosemicarbazones/pharmacokinetics , Administration, Oral , Animals , Disease Models, Animal , Male , Mice , Mice, Inbred C3H , Particle SizeABSTRACT
Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(µ-atc-Me)}2µ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 µM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(µ-atc-Me)}2µ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (-11.11 and - 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.
Subject(s)
Antitubercular Agents/pharmacology , Coordination Complexes/pharmacology , Thiosemicarbazones/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacokinetics , Bacterial Proteins/metabolism , Coordination Complexes/chemical synthesis , Coordination Complexes/metabolism , Coordination Complexes/pharmacokinetics , Copper/chemistry , Ligands , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Mycobacterium avium/drug effects , Mycobacterium kansasii/drug effects , Mycobacterium tuberculosis/drug effects , Protein Binding , Structure-Activity Relationship , Thermodynamics , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/metabolism , Thiosemicarbazones/pharmacokineticsABSTRACT
Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.
Subject(s)
Contrast Media/pharmacokinetics , Coordination Complexes/pharmacokinetics , Edetic Acid/pharmacokinetics , Hepatocytes/metabolism , Magnetic Resonance Imaging , Manganese/pharmacokinetics , Animals , Cell Line , Cell Survival/drug effects , Contrast Media/chemical synthesis , Contrast Media/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Edetic Acid/chemistry , Hepatocytes/chemistry , Hepatocytes/drug effects , Humans , Hydrophobic and Hydrophilic Interactions , Manganese/chemistry , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
[Figure: see text].
Subject(s)
Heart Failure/diagnostic imaging , Macrophages/metabolism , Magnetic Resonance Imaging , Positron-Emission Tomography , Animals , Coordination Complexes/pharmacokinetics , Fibrosis , Male , Mice , Mice, Inbred C57BL , Myocardium/metabolism , Myocardium/pathology , Peptides, Cyclic/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Receptors, CXCR4/metabolismABSTRACT
Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Coordination Complexes , Dendrimers , Imidazoles , Platinum , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , Dendrimers/chemistry , Dendrimers/pharmacokinetics , Dendrimers/pharmacology , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , MAP Kinase Signaling System/drug effects , MCF-7 Cells , Neoplasm Proteins/metabolism , Platinum/chemistry , Platinum/pharmacokinetics , Platinum/pharmacologyABSTRACT
Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r1 of 6.7 mM-1 s-1 at 37 °C and 4.7 T or 3.3 mM-1 s-1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.
Subject(s)
Contrast Media/chemistry , Coordination Complexes/chemistry , Ferric Compounds/chemistry , Macrocyclic Compounds/chemistry , Magnetic Resonance Imaging , Animals , Contrast Media/chemical synthesis , Contrast Media/pharmacokinetics , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacokinetics , Ferric Compounds/pharmacokinetics , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Mice , Mice, Inbred BALB C , Molecular Structure , Serum Albumin, Human/chemistryABSTRACT
The development of Fe-coordination polymer-based nanoparticles, with safe and high anti-tumor effects, for the treatment of tumor is facing challenges such as limited resources and poor targeting. In this study, we prepared Fe-polyhydroxy coordination polymer nanoparticles (TA-Fe@MNPs), based on tartaric acid (TA)-Fe(III) coordination polymer as the new photothermal agent, mannose (M) as the target, and bovine serum albumin (BSA) and polyethyleneimine (PEI) as the carrier materials, and investigated them for targeting the multifunctional therapy of tumors. The TA-Fe@MNPs synthesized via a simple coordination of Fe3+ with TA, bovine serum albumin, and polyethyleneimine under ambient conditions exhibited an appropriate size (~125 nm), electrically neutral surfaces, good biocompatibility, and low normal cell toxicity. The TA-Fe@MNPs are the first to exhibit a remarkable photothermal performance. They also showed a pH-sensitive Fenton-like response that was further enhanced via glutathione response. Interestingly, after a single injection, the TA-Fe@MNPs could be retained at the tumor site for 36 h with an effective photothermal dose, which was attributed to the reduced protein adsorption and slow elimination in tumor cells with the aid of M modification and carrier materials, while that for the TA-Fe@NPs did so for only 2 h. Tumor ablation was demonstrated by in vivo photothermal and chemokinetic therapy using TA-Fe@MNPs, and their safety was evident from the weight changes and blood parameters. These results indicated that the TA-Fe@MNPs, as new photothermal and CDT agents, have the potential to be used in clinical tumor therapy nanoplatforms.