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Metal-Based Drugs: Updates and Perspectives

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 64289

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Special Issue Editors

Prof. Dr. Daniela Montesarchio

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Guest Editor

Department of Chemical Sciences, University of Naples Federico II, via Cintia 4, 80126 Naples, Italy
Interests: oligonucleotides; nucleoside analogues; unusual structures of DNA; G-quadruplex; Ru(III)-complexes; Pt(II)-complexes; metal–DNA interactions; small molecule–DNA interactions
Special Issues, Collections and Topics in MDPI journals

Dr. Domenica Musumeci

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Guest Editor

Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
Interests: oligonucleotide aptamers; oligonucleotide analogs; nucleopeptides; metal-based drugs; DNA-small molecule interaction; DNA-protein interaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The pharmaceutical potential of metals and their derivatives has been recognized for millennia in very different cultures, and with the advent of modern medicine, several metal-based drugs have been approved in clinic as effective therapeutic tools. Indeed, a large variety of metal compounds show significant bioactivity against a range of diseases, from the well-known anticancer activity of Pt(II)-complexes to the use of gold derivatives for the treatment of rheumatoid arthritis, just to name a few. Metal-based compounds can display an impressive chemical diversity, accompanied by a wide, easily and finely tunable reactivity, which allow their application as therapeutic and diagnostic tools in medicinal chemistry that is not readily accessible to the usual organic compounds.

This Special Issue of Pharmaceuticals on “Metal-Based Drugs: Updates and Perspectives” will include both regular articles and reviews focused on the most recent advances in the research into metals used in medicine, highlighting their pharmacological and diagnostic applications in several diseases. The major focus will be on the design, synthesis and optimization of novel complexes with higher efficacy and reduced toxic side effects compared to already existing metal-based drugs, on studies dealing with their mechanisms of action, the identification of their in vivo target, and approaches to validate their utility, along with their in vivo delivery, also taking advantage of specific or non-specific carriers (nanoparticles, liposomes, etc.).

With the aim of offering a dedicated forum open to all scientists engaged in this interdisciplinary research field, we particularly welcome contributions dealing with:

Metal-based complexes as therapeutic tools

Metallodrugs (design, synthesis, characterization, preclinical evaluation, pharmacokinetic studies, etc.) for the treatment of diseases, particularly with applications as:

anticancer, antimicrobial, antiparasitic, antibiotic, antiviral, anti-inflammatory, antiarthritic, antidiabetes, psychotropic, metallodrugs for the treatment of cardiovascular disorders, of metabolic diseases, of rare diseases, etc.

Metal-based complexes as diagnostic tools

Among others, diagnostic radiopharmaceuticals are powerful tools in the diagnosis of cancer, cardiological disorders, infections, kidney or liver abnormalities, neurological disorders, etc.

Studies of the mechanism of action of metallodrugs, with a special focus on the elucidation of their molecular targets
Studies on the biodistribution and fate of metallodrugs under in vivo conditions, including the physiological effects and toxicity issues.

Prof. Daniela Montesarchio
Dr. Domenica Musumeci
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

metallodrugs
anticancer
antimicrobial
antiparasitic
antibiotic
antiviral
anti-inflammatory
antiarthritic
antidiabetes
psychotropic
cardiovascular disorders
metabolic diseases
rare diseases, etc.

Related Special Issues

Selective Chelators for Metals on Cells and Cancer Chemotherapy in Pharmaceuticals (1 article)
Metallodrugs in Pharmaceuticals
Metal-Based Drugs in Pharmaceuticals (1 article)

Published Papers (14 papers)

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Research

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16 pages, 2360 KiB

Open AccessArticle

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd₂Spm) in Mice

by Martin Vojtek, Salomé Gonçalves-Monteiro, Edgar Pinto, Sára Kalivodová, Agostinho Almeida, Maria P. M. Marques, Ana L. M. Batista de Carvalho, Clara B. Martins, Helder Mota-Filipe, Isabel M. P. L. V. O. Ferreira and Carmen Diniz

Pharmaceuticals 2021, 14(2), 173; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020173 - 23 Feb 2021

Cited by 13 | Viewed by 3326

Abstract

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd₂Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd₂Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd₂Spm’s cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd₂Spm, which may become a promising pharmacological agent for cancer treatment. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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19 pages, 8008 KiB

Open AccessArticle

Biofabricated Fatty Acids-Capped Silver Nanoparticles as Potential Antibacterial, Antifungal, Antibiofilm and Anticancer Agents

by Mohammad Azam Ansari, Sarah Mousa Maadi Asiri, Mohammad A. Alzohairy, Mohammad N. Alomary, Ahmad Almatroudi and Firdos Alam Khan

Pharmaceuticals 2021, 14(2), 139; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020139 - 09 Feb 2021

Cited by 26 | Viewed by 3801

Abstract

The current study demonstrates the synthesis of fatty acids (FAs) capped silver nanoparticles (AgNPs) using aqueous poly-herbal drug Liv52 extract (PLE) as a reducing, dispersing and stabilizing agent. The NPs were characterized by various techniques and used to investigate their potent antibacterial, antibiofilm, antifungal and anticancer activities. GC-MS analysis of PLE shows a total of 37 peaks for a variety of bio-actives compounds. Amongst them, n-hexadecanoic acid (21.95%), linoleic acid (20.45%), oleic acid (18.01%) and stearic acid (13.99%) were found predominately and most likely acted as reducing, stabilizing and encapsulation FAs in LIV-AgNPs formation. FTIR analysis of LIV-AgNPs shows some other functional bio-actives like proteins, sugars and alkenes in the soft PLE corona. The zone of inhibition was 10.0 ± 2.2–18.5 ± 1.0 mm, 10.5 ± 2.5–22.5 ± 1.5 mm and 13.7 ± 1.0–16.5 ± 1.2 against P. aeruginosa, S. aureus and C. albicans, respectively. LIV-AgNPs inhibit biofilm formation in a dose-dependent manner i.e., 54.4 ± 3.1%—10.12 ± 2.3% (S. aureus), 72.7 ± 2.2%–23.3 ± 5.2% (P. aeruginosa) and 85.4 ± 3.3%–25.6 ± 2.2% (C. albicans), and SEM analysis of treated planktonic cells and their biofilm biomass validated the fitness of LIV-AgNPs in future nanoantibiotics. In addition, as prepared FAs rich PLE capped AgNPs have also exhibited significant (p < 0.05 *) antiproliferative activity against cultured HCT-116 cells. Overall, this is a very first demonstration on employment of FAs rich PLE for the synthesis of highly dispersible, stable and uniform sized AgNPs and their antibacterial, antifungal, antibiofilm and anticancer efficacy. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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25 pages, 5434 KiB

Open AccessArticle

Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents

by Valentin Studer, Nicoleta Anghel, Oksana Desiatkina, Timo Felder, Ghalia Boubaker, Yosra Amdouni, Jessica Ramseier, Martin Hungerbühler, Christoph Kempf, Johannes Thomas Heverhagen, Andrew Hemphill, Nico Ruprecht, Julien Furrer and Emilia Păunescu

Pharmaceuticals 2020, 13(12), 471; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120471 - 16 Dec 2020

Cited by 19 | Viewed by 3659

Abstract

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC₅₀ values ranging from 90 to 539 nM, and seven derivatives displayed IC₅₀ values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC₅₀ values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC₅₀ values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6–10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11–14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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21 pages, 3903 KiB

Open AccessArticle

Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity

by Henryk Mastalarz, Agnieszka Mastalarz, Joanna Wietrzyk, Magdalena Milczarek, Andrzej Kochel and Andrzej Regiec

Pharmaceuticals 2020, 13(12), 433; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120433 - 28 Nov 2020

Cited by 5 | Viewed by 2652

Abstract

A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with K₂PtCl₄ and characterized by elemental analysis, ESI MS spectrometry, ¹H NMR, ¹⁹⁵Pt NMR, IR and far IR spectroscopy. Thermal isomerization of cis-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 1 to trans-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 2 has been presented, and the structure of the compound 2 has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method. The trans complex 2 showed better antiproliferative activity than cisplatin for all the tested cancer cell lines. Additionally, trans-dichloridobis(1-methyl-5-nitropyrazole)platinum(II) 4 has featured a lower IC₅₀ value than reference cisplatin against MCF-7 cell line. To gain additional information that may facilitate the explanation of the mode of action of tested compounds cellular platinum uptake, stability in L-glutathione solution, influence on cell cycle progression of HL-60 cells and ability to apoptosis induction were determined for compounds 1 and 2. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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20 pages, 2531 KiB

Open AccessArticle

Synthesis, Antiproliferative Activity, and DNA Binding Studies of Nucleoamino Acid-Containing Pt(II) Complexes

by Claudia Riccardi, Domenica Capasso, Angela Coppola, Chiara Platella, Daniela Montesarchio, Sonia Di Gaetano, Giovanni N. Roviello and Domenica Musumeci

Pharmaceuticals 2020, 13(10), 284; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100284 - 30 Sep 2020

Cited by 6 | Viewed by 2143

Abstract

We here report our studies on the reaction with the platinum(II) ion of a nucleoamino acid constituted by the l-2,3-diaminopropanoic acid linked to the thymine nucleobase through a methylenecarbonyl linker. The obtained new platinum complexes, characterized by spectroscopic and mass spectrometric techniques, were envisaged to exploit synergistic effects due to the presence of both the platinum center and the nucleoamino acid moiety. The latter can be potentially useful to protect the complexes from early deactivation, as well as to facilitate their cell internalization. The biological activity of the complexes in terms of antiproliferative effects was evaluated in vitro on different cancer cell lines and healthy cells, showing the best results on human cervical adenocarcinoma (HeLa) cells along with good selectivity for cancer over normal cells. In contrast, the metal-free nucleoamino acid did not show any cytotoxicity on both normal and cancer cell lines. Finally, the ability of the novel Pt(II) complexes to bind various DNA model systems was investigated by circular dichroism (CD) spectroscopy and polyacrylamide gel electrophoresis analyses proving that the newly obtained compounds can potentially target DNA, similarly to other well-known anticancer Pt complexes, with a peculiar G-quadruplex vs. duplex selectivity. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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10 pages, 2310 KiB

Open AccessArticle

The Impact of Iron Supplementation for Treating Anemia in Patients with Chronic Kidney Disease: Results from Pairwise and Network Meta-Analyses of Randomized Controlled Trials

by Marcel Adler, Francisco Herrera-Gómez, Débora Martín-García, Marie Gavid, F. Javier Álvarez and Carlos Ochoa-Sangrador

Pharmaceuticals 2020, 13(5), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050085 - 30 Apr 2020

Cited by 4 | Viewed by 4074

Abstract

After relative erythropoietin deficiency, iron deficiency is the second most important contributing factor for anemia in chronic kidney disease (CKD) patients. Iron supplementation is a crucial part of the treatment of anemia in CKD patients, and intravenous (IV) iron supplementation is considered to be superior to per os (PO) iron supplementation. The differences between the available formulations are poorly characterized. This report presents results from pairwise and network meta-analyses carried out after a comprehensive search in sources of published and unpublished studies, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations (International prospective register of systematic reviews PROSPERO reference ID: CRD42020148155). Meta-analytic calculations were performed for the outcome of non-response to iron supplementation (i.e., hemoglobin (Hgb) increase of <0.5–1.0 g/dL, or initiation/intensification of erythropoiesis-stimulating agent (ESA) therapy, or increase/change of iron supplement, or requirements of blood transfusion). A total of 34 randomized controlled trials (RCT) were identified, providing numerical data for analyses covering 93.7% (n = 10.097) of the total study population. At the network level, iron supplementation seems to have a more protective effect against the outcome of non-response before the start of dialysis than once dialysis is initiated, and some preparations seem to be more potent (e.g., ferumoxytol, ferric carboxymaltose), compared to the rest of iron supplements assessed (surface under the cumulative ranking area (SUCRA) > 0.8). This study provides parameters for adequately following-up patients requiring iron supplementation, by presenting the most performing preparations, and, indirectly, by making it possible to identify good responders among all patients treated with these medicines. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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15 pages, 2942 KiB

Open AccessArticle

Peptide-Based Soft Hydrogels Modified with Gadolinium Complexes as MRI Contrast Agents

by Enrico Gallo, Carlo Diaferia, Enza Di Gregorio, Giancarlo Morelli, Eliana Gianolio and Antonella Accardo

Pharmaceuticals 2020, 13(2), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13020019 - 21 Jan 2020

Cited by 29 | Viewed by 4161

Abstract

Poly-aromatic peptide sequences are able to self-assemble into a variety of supramolecular aggregates such as fibers, hydrogels, and tree-like multi-branched nanostructures. Due to their biocompatible nature, these peptide nanostructures have been proposed for several applications in biology and nanomedicine (tissue engineering, drug delivery, bioimaging, and fabrication of biosensors). Here we report the synthesis, the structural characterization and the relaxometric behavior of two novel supramolecular diagnostic agents for magnetic resonance imaging (MRI) technique. These diagnostic agents are obtained for self-assembly of DTPA(Gd)-PEG8-(FY)3 or DOTA(Gd)-PEG8-(FY)3 peptide conjugates, in which the Gd-complexes are linked at the N-terminus of the PEG8-(FY)3 polymer peptide. This latter was previously found able to form self-supporting and stable soft hydrogels at a concentration of 1.0% wt. Analogously, also DTPA(Gd)-PEG8-(FY)3 and DOTA(Gd)-PEG8-(FY)3 exhibit the trend to gelificate at the same range of concentration. Moreover, the structural characterization points out that peptide (FY)3 moiety keeps its capability to arrange into β-sheet structures with an antiparallel orientation of the β-strands. The high relaxivity value of these nanostructures (~12 mM⁻¹·s⁻¹ at 20 MHz) and the very low in vitro cytotoxicity suggest their potential application as supramolecular diagnostic agents for MRI. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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15 pages, 2520 KiB

Open AccessFeature PaperArticle

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

by Daniele Florio, Ilaria Iacobucci, Giarita Ferraro, Ahmed M. Mansour, Giancarlo Morelli, Maria Monti, Antonello Merlino and Daniela Marasco

Pharmaceuticals 2019, 12(4), 154; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12040154 - 12 Oct 2019

Cited by 20 | Viewed by 3170

Abstract

The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2′-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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13 pages, 2120 KiB

Open AccessArticle

Colloidal Silver Induces Cytoskeleton Reorganization and E-Cadherin Recruitment at Cell-Cell Contacts in HaCaT Cells

by Elena Montano, Maria Vivo, Andrea Maria Guarino, Orsola di Martino, Blanda Di Luccia, Viola Calabrò, Sergio Caserta and Alessandra Pollice

Pharmaceuticals 2019, 12(2), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12020072 - 15 May 2019

Cited by 12 | Viewed by 11953

Abstract

Up until the first half of the 20th century, silver found significant employment in medical applications, particularly in the healing of open wounds, thanks to its antibacterial and antifungal properties. Wound repair is a complex and dynamic biological process regulated by several pathways that cooperate to restore tissue integrity and homeostasis. To facilitate healing, injuries need to be promptly treated. Recently, the interest in alternatives to antibiotics has been raised given the widespread phenomenon of antibiotic resistance. Among these alternatives, the use of silver appears to be a valid option, so a resurgence in its use has been recently observed. In particular, in contrast to ionic silver, colloidal silver, a suspension of metallic silver particles, shows antibacterial activity displaying less or no toxicity. However, the human health risks associated with exposure to silver nanoparticles (NP) appear to be conflicted, and some studies have suggested that it could be toxic in different cellular contexts. These potentially harmful effects of silver NP depend on various parameters including NP size, which commonly range from 1 to 100 nm. In this study, we analyzed the effect of a colloidal silver preparation composed of very small and homogeneous nanoparticles of 0.62 nm size, smaller than those previously tested. We found no adverse effect on the cell proliferation of HaCaT cells, even at high NP concentration. Time-lapse microscopy and indirect immunofluorescence experiments demonstrated that this preparation of colloidal silver strongly increased cell migration, re-modeled the cytoskeleton, and caused recruitment of E-cadherin at cell-cell junctions of human cultured keratinocytes. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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Review

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40 pages, 8763 KiB

Open AccessReview

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

by Mária Bodnár Mikulová and Peter Mikuš

Pharmaceuticals 2021, 14(2), 167; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020167 - 21 Feb 2021

Cited by 12 | Viewed by 2974

Abstract

Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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16 pages, 1597 KiB

Open AccessReview

The Protein-Binding Behavior of Platinum Anticancer Drugs in Blood Revealed by Mass Spectrometry

by Jingchen Wang, Jianmei Tao, Shuailong Jia, Meiqin Wang, Hongliang Jiang and Zhifeng Du

Pharmaceuticals 2021, 14(2), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020104 - 29 Jan 2021

Cited by 27 | Viewed by 3589

Abstract

Cisplatin and its analogues are widely used as chemotherapeutic agents in clinical practice. After being intravenously administrated, a substantial amount of platinum will bind with proteins in the blood. This binding is vital for the transport, distribution, and metabolism of drugs; however, toxicity can also occur from the irreversible binding between biologically active proteins and platinum drugs. Therefore, it is very important to study the protein-binding behavior of platinum drugs in blood. This review summarizes mass spectrometry-based strategies to identify and quantitate the proteins binding with platinum anticancer drugs in blood, such as offline high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC–ICP-MS) combined with electrospray ionization mass spectrometry (ESI-MS/MS) and multidimensional LC–ESI-MS/MS. The identification of in vivo targets in blood cannot be accomplished without first studying the protein-binding behavior of platinum drugs in vitro; therefore, relevant studies are also summarized. This knowledge will further our understanding of the pharmacokinetics and toxicity of platinum anticancer drugs, and it will be beneficial for the rational design of metal-based anticancer drugs. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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19 pages, 1836 KiB

Open AccessReview

Biological Applications of Thiocarbohydrazones and Their Metal Complexes: A Perspective Review

by Carmela Bonaccorso, Tiziano Marzo and Diego La Mendola

Pharmaceuticals 2020, 13(1), 4; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13010004 - 25 Dec 2019

Cited by 59 | Viewed by 5841

Abstract

Although organic compounds account for more than 99% of currently approved clinical drugs, the established clinical use of cisplatin in cancer or auranofin in rheumatoid arthritis have paved the way to several research initiatives to identify metal-based drugs for a wide range of human diseases. Nitrogen and sulfur donor ligands, characterized by different binding motifs, have been the subject in recent years of one of the main research areas in coordination chemistry. Among the nitrogen/sulfur compounds, very little is known about thiocarbohydrazones (TCH), the higher homologues of the well-known thiosemicarbazones (TSC), and their metal complexes. The extra hydrazine moiety provides the ligands of variable metal binding modes, structural diversity and promising biological implications. The interesting coordination chemistry of TCH has mainly been focused on symmetric derivatives, which are relatively simple to synthesize while few examples of asymmetric ligands have been reported. This informative review on TCHs and their metal complexes will be helpful for improving the design of metal-based pharmaceuticals for applications ranging from anticancer to antinfective therapy. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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46 pages, 10650 KiB

Open AccessReview

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

by Claudia Riccardi, Domenica Musumeci, Marco Trifuoggi, Carlo Irace, Luigi Paduano and Daniela Montesarchio

Pharmaceuticals 2019, 12(4), 146; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12040146 - 26 Sep 2019

Cited by 64 | Viewed by 6307

Abstract

The great advances in the studies on metal complexes for the treatment of different cancer forms, starting from the pioneering works on platinum derivatives, have fostered an increasingly growing interest in their properties and biomedical applications. Among the various metal-containing drugs investigated thus far, ruthenium(III) complexes have emerged for their selective cytotoxic activity in vitro and promising anticancer properties in vivo, also leading to a few candidates in advanced clinical trials. Aiming at addressing the solubility, stability and cellular uptake issues of low molecular weight Ru(III)-based compounds, some research groups have proposed the development of suitable drug delivery systems (e.g., taking advantage of nanoparticles, liposomes, etc.) able to enhance their activity compared to the naked drugs. This review highlights the unique role of Ru(III) complexes in the current panorama of anticancer agents, with particular emphasis on Ru-containing nanoformulations based on the incorporation of the Ru(III) complexes into suitable nanocarriers in order to enhance their bioavailability and pharmacokinetic properties. Preclinical evaluation of these nanoaggregates is discussed with a special focus on the investigation of their mechanism of action at a molecular level, highlighting their pharmacological potential in tumour disease models and value for biomedical applications. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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28 pages, 4363 KiB

Open AccessReview

Metal-Based Complexes as Pharmaceuticals for Molecular Imaging of the Liver

by Julia Greiser, Wolfgang Weigand and Martin Freesmeyer

Pharmaceuticals 2019, 12(3), 137; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12030137 - 16 Sep 2019

Cited by 11 | Viewed by 5185

Abstract

This article reviews the use of metal complexes as contrast agents (CA) and radiopharmaceuticals for the anatomical and functional imaging of the liver. The main focus was on two established imaging modalities: magnetic resonance imaging (MRI) and nuclear medicine, the latter including scintigraphy and positron emission tomography (PET). The review provides an overview on approved pharmaceuticals like Gd-based CA and ^99mTc-based radiometal complexes, and also on novel agents such as ⁶⁸Ga-based PET tracers. Metal complexes are presented by their imaging modality, with subsections focusing on their structure and mode of action. Uptake mechanisms, metabolism, and specificity are presented, in context with advantages and limitations of the diagnostic application and taking into account the respective imaging technique. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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