A dual-targeting ruthenium nanodrug that inhibits primary tumor growth and lung metastasis
      via the PARP/ATM pathway

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Abstract

Background

Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis.

Results

Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo , 2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells.

Conclusions

Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

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Most cited references 57

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To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

F Danhier (2016)

Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.

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The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs.

Timothy Johnstone, Kogularamanan Suntharalingam, Stephen Lippard (2016)

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.

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The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials.

Leli Zeng, Pranav Gupta, Yanglu Chen … (2017)

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.

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Author and article information

Contributors

Yuji Wang:

ORCID: http://orcid.org/0000-0003-3842-7627

wangyuji@ccmu.edu.cn

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 23 April 2021

Publication date PMC-release: 23 April 2021

Publication date Collection: 2021

Volume: 19

Electronic Location Identifier: 115

Affiliations

[1 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Department of Medicinal Chemistry, , College of Pharmaceutical Sciences of Capital Medical University, ; 10 Xi Tou Tiao, You An Men, Beijing, 100069 People’s Republic of China

[2 ]GRID grid.419897.a, ISNI 0000 0004 0369 313X, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, , Beijing Laboratory of Biomedical Materials, ; Beijing, 100069 People’s Republic of China

[3 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, , Chinese Academy of Medical Sciences, ; Beijing, 100730 People’s Republic of China

[4 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Beijing Institute of Hepatology, Beijing Youan Hospital, , Capital Medical University, ; Beijing, 100069 People’s Republic of China

[5 ]GRID grid.267301.1, ISNI 0000 0004 0386 9246, Medicinal Chemistry Core, , The University of Tennessee Health Science Center, ; 579 College of Pharmacy Building, 881 Madison Avenue, Memphis, TN 38163 USA

Author information

Yuji Wang http://orcid.org/0000-0003-3842-7627

Article

Publisher ID: 799

DOI: 10.1186/s12951-021-00799-3

PMC ID: 8063440

SO-VID: 9031fdf9-7149-4904-9620-d5c6f1604330

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 15 November 2020

Date accepted : 8 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100010826, CHINA/UNESCO - the Great Wall Fellowship;

Award ID: IT&TCD 20180332

Award Recipient : Yuji Wang

Custom metadata

ScienceOpen disciplines: Biotechnology

Keywords: ruthenium,self-assembly,cell cycle,apoptosis,antitumor,antimetastatic

Data availability:

ScienceOpen disciplines: Biotechnology

Keywords: ruthenium, self-assembly, cell cycle, apoptosis, antitumor, antimetastatic

A dual-targeting ruthenium nanodrug that inhibits primary tumor growth and lung metastasis via the PARP/ATM pathway

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Genome Engineering using CRISPR

Most cited references 57

To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs.

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials.

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