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Pharmaceutics
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Metallodrugs for Targeted Cancer Therapy
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Metallodrugs for Targeted Cancer Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (1 February 2022) | Viewed by 18796

Special Issue Editors

Dr. Elena Cerrada

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Guest Editor
Departamento de Química Inorgánica-Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), University of Zaragoza, C/ Pedro Cerbuna, 12, 50009 Zaragoza, Spain
Interests: bioinorganic chemistry; gold; silver; copper; PTA; colon cancer; metallodrugs
Dr. Vanesa Fernández-Moreira

E-Mail Website
Guest Editor
Departamento de Química Inorgánica-Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), University of Zaragoza, C/ Pedro Cerbuna, 12, 50009 Zaragoza, Spain
Interests: d6-metal complexes; gold chemistry; lanthanides; luminescence; bioactivity; antitumorals; cytotoxicity; bioimaging

Special Issue Information

Dear Colleagues,

DNA is considered as the primary target of platinum-based drugs, however, this DNA binding mechanism may damage normal cells and cause serious side effects. Recent research in the field of genomic and proteomics has identified different proteins or enzymes able to maintain the survival or progression of cancer cells. Most of these proteins are overexpressed in human tumors. Consequently, the design of anticancer agents able to target these proteins has become as an ideal approach for cancer treatment.

Many cancer-related proteins associated with the antimetastatic, antiangiogenic and antiproliferative activity have been identified as molecular targets for different metal complexes. Thus, metal complexes containing, e.g., ruthenium, osmium, rhodium, iridium, gold, copper, tin among others, could be turned out to be promising candidates in anticancer therapy, in addition to the platinum derivatives.

Metal complexes can easily modify ligands, oxidation states and coordination number in order to improve their biological activities. In addition, the excellent optical properties of luminescent metal complexes, such as long-lived phosphorescence, high photo stability and large Stokes shifts, allows their use as both imaging and therapeutic agents.

This Special Issue of Pharmaceutics, entitled “Metallodrugs for Targeted Cancer Therapy” welcomes original research focusing on the aspects of design, characterization, evaluation, development of metal complexes able to interact with biological targets, drug delivery and bioimaging in order to get cancer diagnoses and treatments.

Dr. Elena Cerrada
Dr. Vanesa Fernández-Moreira
Guest Editors

Manuscript Submission Information

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. Pharmaceutics 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

  • drug-design
  • mechanisms of cell death
  • drug uptake
  • structure-activity-relationships
  • toxicity
  • pharmacokinetics
  • metabolism
  • cancer treatment
  • clinical trials
  • metal-based drug delivery agents
  • metal-protein interactions
  • metal-nucleic acid interactions
  • phototherapic and photodiagnostic materials

Published Papers (7 papers)

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Research

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27 pages, 5197 KiB  
Article
The Anticancer Ruthenium Compound BOLD-100 Targets Glycolysis and Generates a Metabolic Vulnerability towards Glucose Deprivation
by Dina Baier, Beatrix Schoenhacker-Alte, Mate Rusz, Christine Pirker, Thomas Mohr, Theresa Mendrina, Dominik Kirchhofer, Samuel M. Meier-Menches, Katharina Hohenwallner, Martin Schaier, Evelyn Rampler, Gunda Koellensperger, Petra Heffeter, Bernhard Keppler and Walter Berger
Pharmaceutics 2022, 14(2), 238; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020238 - 20 Jan 2022
Cited by 17 | Viewed by 2484
Abstract
Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. [...] Read more.
Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. Insights into metabolic alterations underlying ruthenium-based chemotherapy resistance remain widely elusive. In this study, colon cancer HCT116 and pancreatic cancer Capan-1 cells were selected for resistance against the clinically evaluated ruthenium complex sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). Gene expression profiling identified transcriptional deregulation of carbohydrate metabolism as a response to BOLD-100 and in resistance against the drug. Mechanistically, acquired BOLD-100 resistance is linked to elevated glucose uptake and an increased lysosomal compartment, based on a defect in downstream autophagy execution. Congruently, metabolomics suggested stronger glycolytic activity, in agreement with the distinct hypersensitivity of BOLD-100-resistant cells to 2-deoxy-d-glucose (2-DG). In resistant cells, 2-DG induced stronger metabolic perturbations associated with ER stress induction and cytoplasmic lysosome deregulation. The combination with 2-DG enhanced BOLD-100 activity against HCT116 and Capan-1 cells and reverted acquired BOLD-100 resistance by synergistic cell death induction and autophagy disturbance. This newly identified enhanced glycolytic activity as a metabolic vulnerability in BOLD-100 resistance suggests the targeting of glycolysis as a promising strategy to support BOLD-100 anticancer activity. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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26 pages, 6573 KiB  
Article
Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal
by Ana R. Rubio, Rocío González, Natalia Busto, Mónica Vaquero, Ana L. Iglesias, Félix A. Jalón, Gustavo Espino, Ana M. Rodríguez, Begoña García and Blanca R. Manzano
Pharmaceutics 2021, 13(10), 1540; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101540 - 23 Sep 2021
Cited by 7 | Viewed by 2321
Abstract
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p [...] Read more.
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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18 pages, 2561 KiB  
Article
Histological Changes in Renal, Hepatic and Cardiac Tissues of Wistar Rats after 6 Weeks Treatment with Bipyridine Gold (III) Complex with Dithiocarbamate Ligands
by Ahmed Badar, Ayesha Ahmed, Dalal M. Al-Tamimi, Anvarhusein A. Isab, Muhammad Altaf and Sania Ahmed
Pharmaceutics 2021, 13(10), 1530; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101530 - 23 Sep 2021
Cited by 2 | Viewed by 1996
Abstract
Bipyridine gold (III) dithiocarbamate compounds are Gold-III complexes with promising cytotoxic properties. In this study, the subacute toxicity of a Gold (III) complex with dithiocarbamate ligand was evaluated. In the acute toxicity component, an initial LD50 (38.46 mg/kg) was calculated by the [...] Read more.
Bipyridine gold (III) dithiocarbamate compounds are Gold-III complexes with promising cytotoxic properties. In this study, the subacute toxicity of a Gold (III) complex with dithiocarbamate ligand was evaluated. In the acute toxicity component, an initial LD50 (38.46 mg/kg) was calculated by the administration of 50, 100, 200, 400, and 800 mg/kg of the compound to five groups of rats, respectively (n = 4 each). The sixth group was the control. The sub-acute toxicity component comprised the control group A (n = 6) and the study groups B (n = 10) and C (n = 4), which were administered 1 mL distilled water, 1/10 LD50 (3.8 mg/kg), and 1/5 LD50 (7.6 mg/kg), respectively, daily for 6 weeks. The alive animals were then sacrificed. Autopsy; preservation of renal, hepatic and cardiac tissue in buffered formalin; histopathological processing; microscopic evaluation; and comparison with the controls were sequentially conducted. In the subacute toxicity study at dosages of 3.8 mg/kg and 7.6 mg/kg, the renal tubules remained unaffected with no necrosis or vacuolization. Mild to moderate renal interstitial, hepatic capsular, lobular and portal inflammation along with mild focal hepatic vacuolization were present. At 3.8 mg/kg, the cardiac muscle fibers were unremarkable in 80% (n = 8) of the specimens, with mild focal hyalinization in 20% (n = 2) of the specimens. The same was observed in 50% (n = 2) of the specimens at 7.6 mg/kg. Variable congestion was evident in all of the groups. In the subacute toxicity study, the absence of renal tubular necrosis or vacuolization, the presence of mild inflammatory hepatic and renal alterations, and predominantly unremarkable cardiac muscle fibers suggest that Bipyridine gold (III)-dithiocarbamate is safe in animal studies and is a potential candidate for clinical trials. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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17 pages, 4023 KiB  
Article
Dual Emissive Ir(III) Complexes for Photodynamic Therapy and Bioimaging
by Marta Redrado, Andrea Benedi, Isabel Marzo, M. Concepción Gimeno and Vanesa Fernández-Moreira
Pharmaceutics 2021, 13(9), 1382; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091382 - 01 Sep 2021
Cited by 9 | Viewed by 3064
Abstract
Photodynamic therapy (PDT) is a cancer treatment still bearing enormous prospects of improvement. Within the toolbox of PDT, developing photosensitizers (PSs) that can specifically reach tumor cells and promote the generation of high concentration of reactive oxygen species (ROS) is a constant research [...] Read more.
Photodynamic therapy (PDT) is a cancer treatment still bearing enormous prospects of improvement. Within the toolbox of PDT, developing photosensitizers (PSs) that can specifically reach tumor cells and promote the generation of high concentration of reactive oxygen species (ROS) is a constant research goal. Mitochondria is known as a highly appealing target for PSs, thus being able to assess the biodistribution of the PSs prior to its light activation would be crucial for therapeutic maximization. Bifunctional Ir(III) complexes of the type [Ir(C^N)2(N^N-R)]+, where N^C is either phenylpyridine (ppy) or benzoquinoline (bzq), N^N is 2,2′-dipyridylamine (dpa) and R either anthracene (1 and 3) or acridine (2 and 4), have been developed as novel trackable PSs agents. Activation of the tracking or therapeutic function could be achieved specifically by irradiating the complex with a different light wavelength (405 nm vs. 470 nm respectively). Only complex 4 ([Ir(bzq)2(dpa-acr)]+) clearly showed dual emissive pattern, acridine based emission between 407–450 nm vs. Ir(III) based emission between 521 and 547 nm. The sensitivity of A549 lung cancer cells to 4 evidenced the importance of involving the metal center within the activation process of the PS, reaching values of photosensitivity over 110 times higher than in dark conditions. Moreover, complex 4 promoted apoptotic cell death and possibly the paraptotic pathway, as well as higher ROS generation under irradiation than in dark conditions. Complexes 2–4 accumulated in the mitochondria but species 2 and 4 also localizes in other subcellular organelles. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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13 pages, 2606 KiB  
Article
Alteration of Anticancer and Protein-Binding Properties of Gold(I) Alkynyl by Phenolic Schiff Bases Moieties
by Bandar A. Babgi, Jalal Alsayari, Hana M. Alenezi, Magda H. Abdellatif, Naser E. Eltayeb, Abdul-Hamid M. Emwas, Mariusz Jaremko and Mostafa A. Hussien
Pharmaceutics 2021, 13(4), 461; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040461 - 29 Mar 2021
Cited by 18 | Viewed by 2990
Abstract
A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R′) (R = PPh3, R′ = –CHO (1), R = PCy3, R′ = –CHO (2), R = PPh3, R′ = –N=CH-C [...] Read more.
A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R′) (R = PPh3, R′ = –CHO (1), R = PCy3, R′ = –CHO (2), R = PPh3, R′ = –N=CH-C6H4-2-OH (3), R = PPh3, R′ = –N=CH-C6H4-4-OH (4), R = PCy3, R′ = –N=CH-C6H4-2-OH (5)) were synthesized and characterized by elemental analysis, 1H-NMR spectroscopy, 31P-NMR spectroscopy, and mass spectrometry. The structures of complexes 2 and 5 were determined by X-ray crystallography. The effects of the structural modifications on the protein binding affinities and anticancer activities of the five gold complexes were assessed. Fluorescence quenching experiments to assess binding to human serum albumin (HSA) revealed that the Schiff base complexes (3, 4, and 5) had binding constants that were superior to their parent aldehyde complexes and highlighted the position of the hydroxy group because complex 4 (4-hydroxy) had a binding constant 6400 times higher than complex 3 (2-hydroxy). The anticancer activities of the complexes against the OVCAR-3 (ovarian carcinoma) and HOP-62 (non-small-cell lung) cancer cell lines showed that the Schiff bases (3–5) were more cytotoxic than the aldehyde-containing complexes (1 and 2). Notably, compound 4 had cytotoxic activity comparable to that of cisplatin against OVCAR-3, demonstrating the significance of the para position for the hydroxy group. Molecular docking studies against the enzyme thioredoxin reductase (TrxR) and human serum albumin were conducted, with docking scores in good agreement with the experimental data. The current study highlights how small structural modifications can alter physiochemical and anticancer properties. Moreover, this simple design strategy using the aldehyde group can generate extensive opportunities to explore new gold(I)-based anticancer drugs via condensation, cyclization, or nucleophilic addition reactions of the aldehyde. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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Review

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36 pages, 4123 KiB  
Review
Relevance of Fluorinated Ligands to the Design of Metallodrugs for Their Potential Use in Cancer Treatment
by José C. Páez-Franco, Miriam R. Zermeño-Ortega, Carmen Myriam de la O-Contreras, Daniel Canseco-González, Jesus R. Parra-Unda, Alcives Avila-Sorrosa, Raúl G. Enríquez, Juan M. Germán-Acacio and David Morales-Morales
Pharmaceutics 2022, 14(2), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020402 - 11 Feb 2022
Cited by 9 | Viewed by 2039
Abstract
Fluorination of pharmaceutical agents has afforded crucial modifications to their pharmacological profiles, leading to important advances in medicinal chemistry. On the other hand, metallodrugs are considered to be valuable candidates in the treatment of several diseases, albeit with the caveat that they may [...] Read more.
Fluorination of pharmaceutical agents has afforded crucial modifications to their pharmacological profiles, leading to important advances in medicinal chemistry. On the other hand, metallodrugs are considered to be valuable candidates in the treatment of several diseases, albeit with the caveat that they may exhibit pharmacological disadvantages, such as poor water solubility, low bioavailability and short circulating time. To surmount these limitations, two approaches have been developed: one based on the design of novel metallodrug-delivering carriers and the other based on optimizing the structure of the ligands bound to the metal center. In this context, fluorination of the ligands may bring beneficial changes (physicochemical and biological) that can help to elude the aforementioned drawbacks. Thus, in this review, we discuss the use of fluorinated ligands in the design of metallodrugs that may exhibit potential anticancer activity. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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17 pages, 2615 KiB  
Review
Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?
by Alain C. Jung, Fabien Moinard-Butot, Chloé Thibaudeau, Gilles Gasser and Christian Gaiddon
Pharmaceutics 2021, 13(11), 1788; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111788 - 26 Oct 2021
Cited by 11 | Viewed by 2487
Abstract
Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that [...] Read more.
Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers. PDT is based on a reaction involving a photosensitizer (PS), light, and oxygen, which ultimately generates cytotoxic reactive oxygen species (ROS). However, skin photosensitivity, due to the accumulation of PSs in skin cells, has hampered, among other elements, its clinical development and application. Therefore, these is an increasing interest in the use of (metal-based) PSs that are more specific to tumor cells. This may increase efficacy and corollary decrease side-effects. To this end, metal-containing nanoparticles with photosensitizing properties have recently been developed. In addition, several studies have reported that the use of immunogenic/immunomodulatory metal-based nanoparticles increases the antitumor efficacy of immune-checkpoint inhibitor-based immunotherapy mediated by anti-PD-(L)1 or CTLA-4 antibodies. In this review, we discuss the main metal complexes used as PDT PSs. Lastly, we review the preclinical studies associated with metal-based PDT PSs and immunotherapies. This therapeutic association could stimulate PDT. Full article
(This article belongs to the Special Issue Metallodrugs for Targeted Cancer Therapy)
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