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Metal Ions in Life Sciences Feb 2018Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers.... (Review)
Review
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron-binding proteins and disrupt iron-dependent tumor cell growth. Gallium's mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth-inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Coordination Complexes; Drug Discovery; Gallium; Humans; Iron; Mitochondria; Molecular Structure; Neoplasms; Organometallic Compounds; Oxidative Stress; Structure-Activity Relationship
PubMed: 29394029
DOI: 10.1515/9783110470734-016 -
Biochimica Et Biophysica Acta Aug 2016Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain... (Review)
Review
Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain cancers and infectious microorganisms. By functioning as an iron mimetic, gallium perturbs iron-dependent proliferation processes in tumor cells. Gallium's action on iron homeostasis leads to disruption of ribonucleotide reductase, mitochondrial function, and the regulation of transferrin receptor and ferritin. In addition, gallium nitrate stimulates an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Gallium's anti-infective activity against bacteria and fungi results from disruption of microbial iron utilization through mechanisms which include gallium binding to siderophores and downregulation of bacterial iron uptake. Gallium compounds lack cross-resistance to conventional chemotherapeutic drugs and antibiotics thus making them attractive agents for drug development. This review will focus on the mechanisms of action of gallium with emphasis on its interaction with iron and iron proteins.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Biological Transport; Drug Evaluation; Drug Screening Assays, Antitumor; Gallium; Gallium Isotopes; Homeostasis; Humans; Iron; Mice; Mitochondria; Neoplasms; Nonheme Iron Proteins; Rats; Transferrin
PubMed: 27150508
DOI: 10.1016/j.bbamcr.2016.04.027 -
Acta Biomaterialia Sep 2022Amidst an ever-increasing demand for the enhancement of the lifestyle and the modulation of modern diseases, the functionalization of biomaterials is of utmost... (Review)
Review
Amidst an ever-increasing demand for the enhancement of the lifestyle and the modulation of modern diseases, the functionalization of biomaterials is of utmost importance. One of the leading materials for the aforementioned purpose have been calcium phosphates (CaPs). They have been widely used in bone regeneration displaying favourable regenerative potential and biological properties. Many studies have placed their entire focus on facilitating the osteogenic differentiation of stem cells and bone progenitor cells, while the aspect of antibacterial properties has been surmounted. Nevertheless, increasing antibiotic resistance of bacteria requires the development of new materials and the usage of alternative approaches such as ion doping. Gallium (Ga) has been the potential star on the rise among the ions. However, the obstacle that accompanies gallium is the scarcity of research performed and the variety of amalgamations. The question that imposes itself is how a growing field of therapeutics can be further entwined with advances in material science, and how will the incorporation of gallium bring a new outlook. The present study offers a comprehensive overview of state-of-the-art gallium containing calcium phosphates (GaCaPs), their synthesis methods, antibacterial properties, and biocompatibility. Considering their vast potential as antibacterial agents, the need for a methodical perspective is highly necessary to determine if it is a direction on the brink of recognition or a fruitless endeavour. STATEMENT OF SIGNIFICANCE: Although several studies have been published on various metal ions-containing calcium phosphates, to this date there is no systematic overview pointing out the properties and benefits of gallium containing calcium phosphates. Here we offer a critical overview, including synthesis, structure and biological properties of gallium containing calcium phosphates.
Topics: Anti-Bacterial Agents; Calcium Phosphates; Gallium; Ions; Osteogenesis; Phosphates
PubMed: 35933101
DOI: 10.1016/j.actbio.2022.07.063 -
Biomedical Engineering Online Jun 2022Although the powerful clinical effects of radiofrequency and microwave ablation have been established, such ablation is associated with several limitations, including a...
BACKGROUND
Although the powerful clinical effects of radiofrequency and microwave ablation have been established, such ablation is associated with several limitations, including a small ablation size, a long ablation time, the few treatment positioning, and biosafety risks. To overcome these limitations, biosafe and efficient magnetic ablation was achieved in this study by using biocompatible liquid gallium as an ablation medium and a contrast medium for imaging.
RESULTS
Magnetic fields with a frequency (f) lower than 200 kHz and an amplitude (H) × f value lower than 5.0 × 10 Am s were generated using the proposed method. These fields could generate an ablation size of 3 cm in rat liver lobes under a temperature of approximately 300 °C and a time of 20 s. The results of this study indicate that biomedical gallium can be used as a contrast medium for the positioning of gallium injections and the evaluation of ablated tissue around a target site. Liquid gallium can be used as an ablation medium and imaging contrast medium because of its stable retention in normal tissue for at least 3 days. Besides, the high anticancer potential of gallium ions was inferred from the self-degradation of 100 µL of liquid gallium after around 21 days of immersion in acidic solutions.
CONCLUSIONS
The rapid wireless ablation of large or multiple lesions was achieved through the simple multi-injection of liquid gallium. This approach can replace the currently favoured procedure involving the use of multiple ablation probes, which is associated with limited benefits and several side effects.
METHODS
Magnetic ablation was confirmed to be highly efficient by the consistent results obtained in the simulation and in vitro tests of gallium and iron oxide as well as the electromagnetic specifics and thermotherapy performance comparison detailed in this study Ultrasound imaging, X-ray imaging, and magnetic resonance imaging were found to be compatible with the proposed magnetic ablation method. Self-degradation analysis was conducted by mixing liquid gallium in acidic solutions with a pH of approximately 5-7 (to imitate a tumour-containing microenvironment). X-ray diffraction was used to identify the gallium oxides produced by degraded gallium ions.
Topics: Ablation Techniques; Animals; Catheter Ablation; Gallium; Liver; Magnetic Resonance Imaging; Rats; Ultrasonography
PubMed: 35715781
DOI: 10.1186/s12938-022-01003-9 -
Molecules (Basel, Switzerland) Dec 2022The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The... (Review)
Review
The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The synthesis of radiochemically pure gallium-68 radiopharmaceuticals relies on careful consideration of the coordination chemistry. The short half-life of 68 min necessitates rapid quantitative radiolabelling (≤10 min). Desirable radiolabelling conditions include near-neutral pH, ambient temperatures, and low chelator concentrations to achieve the desired apparent molar activity. This review presents a broad overview of the requirements of an efficient bifunctional chelator in relation to the aqueous coordination chemistry of gallium. Developments in bifunctional chelator design and application are then presented and grouped according to eight categories of bifunctional chelator: the macrocyclic chelators DOTA and TACN; the acyclic HBED, pyridinecarboxylates, siderophores, tris(hydroxypyridinones), and DTPA; and the mesocyclic diazepines.
Topics: Gallium; Chelating Agents; Radiopharmaceuticals; Gallium Radioisotopes; Positron-Emission Tomography
PubMed: 36615397
DOI: 10.3390/molecules28010203 -
Frontiers in Cellular and Infection... 2019There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions...
There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions of deaths/year. An unconventional approach to fight microbial infection is to exploit nutritional vulnerabilities of microorganism metabolism. The metal gallium can disrupt iron metabolism in bacteria and cancer cells, but it has not been tested against fungal pathogens such as and . Here, we investigate activity of gallium nitrate III [Ga(NO)] against these human pathogens, to reveal the gallium mechanism of action and understand the interaction between gallium and clinical antifungal drugs. Ga(NO) presented a fungistatic effect against azole-sensitive and -resistant strains (MIC = 32.0 mg/L) and also had a synergistic effect with caspofungin, but not with azoles and amphotericin B. Its antifungal activity seems to be reliant on iron-limiting conditions, as the presence of iron increases its MIC value and because we observed a synergistic interaction between gallium and iron chelators against . We also show that an mutant (Δ) unable to grow in the absence of iron is more susceptible to gallium, reinforcing that gallium could act by disrupting iron homeostasis. Furthermore, we demonstrate that gallium has a fungistatic effect against different species of ranging from 16.0 to 256.0 mg/L, including multidrug-resistant , and . Our findings indicate that gallium can inhibit fungal pathogens under iron-limiting conditions, showing that Ga(NO) could be a potential therapy not only against bacteria but also as an antifungal drug.
Topics: Antifungal Agents; Aspergillus fumigatus; Azoles; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Gallium; Kinetics; Microbial Sensitivity Tests
PubMed: 31921699
DOI: 10.3389/fcimb.2019.00414 -
Molecules (Basel, Switzerland) Jul 2015The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and... (Review)
Review
The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.
Topics: Gallium; Humans; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 26193247
DOI: 10.3390/molecules200712913 -
Acta Biomaterialia May 2024Bacterial infection remains a significant problem associated with orthopaedic surgeries leading to surgical site infection (SSI). This unmet medical need can become an...
Bacterial infection remains a significant problem associated with orthopaedic surgeries leading to surgical site infection (SSI). This unmet medical need can become an even greater complication when surgery is due to malignant bone tumor. In the present study, we evaluated in vitro titanium (Ti) implants subjected to gallium (Ga) and silver (Ag)-doped thermochemical treatment as strategy to prevent SSI and improve osteointegration in bone defects caused by diseases such as osteoporosis, bone tumor, or bone metastasis. Firstly, as Ga has been reported to be an osteoinductive and anti-resorptive agent, its performance in the mixture was proved by studying human mesenchymal stem cells (hMSC) and pre-osteoclasts (RAW264.7) behaviour. Then, the antibacterial potential provided by Ag was assessed by resembling "The Race for the Surface" between hMSC and Pseudomonas aeruginosa in two co-culture methods. Moreover, the presence of quorum sensing molecules in the co-culture was evaluated. The results highlighted the suitability of the mixture to induce osteodifferentiation and reduce osteoclastogenesis in vitro. Furthermore, the GaAg surface promoted strong survival rate and retained osteoinduction potential of hMSCs even after bacterial inoculation. Therefore, GaAg-modified titanium may be an ideal candidate to repair bone defects caused by excessive bone resorption, in addition to preventing SSI. STATEMENT OF SIGNIFICANCE: This article provides important insights into titanium for fractures caused by osteoporosis or bone metastases with high incidence in surgical site infection (SSI) because in this situation bacterial infection can become a major disaster. In order to solve this unmet medical need, we propose a titanium implant modified with gallium and silver to improve osteointegration, reduce bone resorption and avoid bacterial infection. For that aim, we study osteoblast and osteoclast behavior with the main novelty focused on the antibacterial evaluation. In this work, we recreate "the race for the surface" in long-term experiments and study bacterial virulence factors (quorum sensing). Therefore, we believe that our article could be of great interest, providing a great impact on future orthopedic applications.
Topics: Titanium; Silver; Humans; Gallium; Mice; Mesenchymal Stem Cells; Animals; Osteogenesis; Coculture Techniques; Pseudomonas aeruginosa; Bone Resorption; Surface Properties; RAW 264.7 Cells; Anti-Bacterial Agents; Bacterial Infections
PubMed: 38621600
DOI: 10.1016/j.actbio.2024.04.019 -
Molecules (Basel, Switzerland) Aug 2022Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive...
Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive compounds with improved antiproliferative action. Compounds were characterized by elemental analysis, IR, and NMR spectroscopy. Density functional theory calculations with Becke's 3-parameter hybrid functional and 6-31+G(d,p) basis set were carried out to investigate the structural features of the ligands and Ga(III) complexes. Cytotoxic screening by MTT-dye reduction assay was carried out using cisplatin and melphalan as reference cytotoxic agents. A general formula [Ga(HL)]NO for the complexes obtained was suggested. The complexes are mononuclear with the Ga(III) ions being surrounded by two ligands. The ligands acted as monoanionic tridentate (ONO) donor molecules. The analysis revealed coordination binding through deprotonated phenolic-oxygen, azomethine-nitrogen, and amide-oxygen atoms. The bioassay demonstrated that all compounds exhibited concentration-dependent antiproliferative activity at low micromolar concentrations against the acute myeloid leukemia HL-60 and T-cell leukemia SKW-3 cell lines. IC values of 5-bromo-derivative ligands and gallium (III) complexes are lower than those of cisplatin and much lower than these of melphalan. The coordination to gallium (III) additionally increased the cytotoxicity compared to the metal-free hydrazones.
Topics: Aldehydes; Antineoplastic Agents; Cisplatin; Coordination Complexes; Drug Screening Assays, Antitumor; Gallium; Humans; Ligands; Melphalan; Oxygen
PubMed: 36080261
DOI: 10.3390/molecules27175493 -
Molecules (Basel, Switzerland) Nov 2023In this study, we employed a chemical precipitation method to successfully synthesize nanoparticles of gallium-doped hydroxyapatite (Ga-HAp). The microstructure of...
In this study, we employed a chemical precipitation method to successfully synthesize nanoparticles of gallium-doped hydroxyapatite (Ga-HAp). The microstructure of Ga-HAp was precisely tailored by modulating the concentration of gallium ions. Our findings unequivocally demonstrate that gallium ions exert a pronounced inhibitory influence on the growth of HAp crystals, and this inhibitory potency exhibits a direct correlation with the concentration of gallium. Furthermore, gallium ions facilitate the metamorphosis of HAp nanoparticles, transitioning them from nanoneedles to nanosheets. It is worth noting, however, that gallium ions exhibit a limited capacity to substitute for calcium ions within the crystal lattice of HAp, with the maximum substitution rate capped at 4.85%. Additionally, gallium plays a pivotal role in constraining the release of ions from HAp, and this behavior remains consistent across samples with varying Ga doping concentrations. Our in vitro experiments confirm that Ga-doped HAp amplifies both the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.
Topics: Durapatite; Osteogenesis; Gallium; Cell Differentiation; Ions
PubMed: 37959798
DOI: 10.3390/molecules28217379