Martin R. Gill

• PhD Chemistry
• Senior Lecturer at Swansea University

Super-resolution microscopy (SRM) has transformed biological imaging by overcoming the diffraction limit, offering nanoscale visualization of cellular structures and processes. However, the widespread use of organic fluorescent probes is often hindered by limitations such as photobleaching, short photostability, and inadequate performance in deep-t...

Ruthenium(II) polypyridyl complexes (RPCs) that emit from triplet metal to ligand charge transfer (MLCT) states find a wide variety of uses ranging from luminophores to potential anti-cancer or anti-bacterial therapeutics....

Triple negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis and median survival rate. Targeting PARP1/2 with PARP inhibitors (PARPi) and achieving synthetic lethality is an effective strategy for TNBCs with BRCA1/2 mutations, however, the majority of TNBCs are BRCA1/2 wild type. Synergistic drug combinations wi...

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a "micro-library" comprising a mix of commercially available drugs and DNA-binding ruthenium(I...

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer...

Ruthenium(II) polypyridyl complexes (RPCs) that emit from metal-to-ligand charge transfer (MLCT) states have been developed as DNA probes and are being examined as potential anticancer agents. Here, we report that MLCT-emissive RPCs that bind DNA undergo Förster resonance energy transfer (FRET) with Cy5.5-labeled DNA, forming mega-Stokes shift FRET...

The dinuclear RuII complex [(Ru(phen)2)2(tpphz)]⁴⁺ (phen=1,10‐phenanthroline, tpphz=tetrapyridophenazine) “RuRuPhen” blocks the transformation of G‐actin monomers to F‐actin filaments with no disassembly of pre‐formed F‐actin. Molecular docking studies indicate multiple RuRuPhen molecules bind to the surface of G‐actin but not the binding pockets o...

The dinuclear Ru(II) complex [(Ru(phen) 2 ) 2 (tpphz)] 4+ (phen = 1,10‐phenanthroline, tpphz = tetrapyridophenazine) “RuRuPhen” blocks the transformation of G‐actin to F‐actin filaments with no disassembly of pre‐formed F‐actin. Molecular docking studies indicate multiple RuRuPhen molecules bind to the surface of G‐actin but not the binding pockets...

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. “matc...

The ruthenium polypyridyl complex [Ru(dppz)2PIP]2+ (dppz: dipyridophenazine, PIP: (2-(phenyl)-imidazo[4,5-f ][1,10]phenanthroline), or Ru-PIP, is a potential anticancer drug that acts by inhibiting DNA replication. Due to the poor dissolution of Ru-PIP in aqueous media, a drug delivery agent would be a useful approach to overcome its limited bioava...

Cancer treatment and therapy have made significant leaps and bounds in these past decades. However, there are still cases where surgical removal is impossible, metastases are challenging, and chemotherapy and radiotherapy pose severe side effects. Therefore, a need to find more effective and specific treatments still exists. One way is through the...

Platinum drugs are heavily used first‐line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA‐binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer...

Theranostic radionuclides that emit Auger electrons (AE) can generate highly localised DNA damage and the accompanying gamma ray emission can be used for single-photon emission computed tomography (SPECT) imaging. Mismatched DNA base pairs (mismatches) are DNA lesions that are abundant in cells deficient in MMR (mismatch mediated repair) proteins....

The purpose of this exploratory study was to investigate the combination of a radiopharmaceutical, nanoparticles and ultrasound (US) enhanced delivery to develop a clinically viable therapeutic strategy for tumours overexpressing the epidermal growth factor receptor (EGFR). Molecularly targeted radionuclides have great potential for cancer therapy...

There is a need to improve and extend the use of clinically-approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallo-intercalators can rapidly stall DNA replication fork progression provides the rationale...

Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit o...

Targeted radionuclide therapy (TRT) combines the specificity of molecular targeting with the potent cytotoxicity of ionising radiation. An emerging question is how to most effectively integrate TRT with radiosensitizing small molecules [1]. Auger electron-emitting radionuclides such as ¹¹¹In are well-suited as the therapeutic radionuclide as their...

Targeted radionuclide therapy (TRT) combines the specificity of molecular targeting with the potent cytotoxicity of ionising radiation. An emerging question is how to most effectively integrate TRT with radiosensitizing small molecules [1]. Auger electron-emitting radionuclides such as 111In are well-suited as the therapeutic radionuclide as their...

Medicinal leads that are also compatible with imaging technologies are attractive, as they facilitate the development of therapeutics through direct mechanistic observations at the molecular level. In this context, the uptake and antimicrobial activities of several luminescent dinuclear RuII complexes against E. coli were assessed and compared to r...

Platinum complexes have been used for anti-cancer propose for decades, however, their high side effects resulting from damage to healthy cells cannot be neglected and prevent further clinical utilisation. Here, we designed a cyclometalated platinum (II) complex that can bind the endogenous nuclear factor-B (NF-B) protein. Employing detailed colocal...

The concomitant administration of ionising radiation (IR) in the form of external beam radiotherapy or targeted radionuclide therapy (TRT) alongside radiosensitizing small molecules is a highly successful strategy for the treatment of cancer. The major clinical impact of the radiosensitizing platinum(ii) drug cisplatin has encouraged the design of...

The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), main...

Introduction Radiolabelled nuclear localising peptides are a promising cancer therapy. However, These peptides have unfavourable circulation kinetics and are highly susceptible to degradation and elimination by local enzymes. Liposome nanoparticles consist of a phospholipid bilayer structure which can encapsulate a therapeutic payload. Such encapsu...

Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal g...

Substitutionally inert ruthenium(II) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting mono-intercalator [Ru(phen)2(tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronou...

This chapter describes the development of kinetically inert ruthenium(II) polypyridyl complexes (RPCs) as cellular imaging agents and as potential therapeutics. By employing planar polypyridyl coordination ligands, these complexes may interact with DNA by a multitude of reversible binding mechanisms, often with distinctive photophysical changes upo...

Targeted radionuclide therapy (TRT) is a branch of cancer medicine concerned with the use of radioisotopes, radiolabelled molecules, nanoparticles, or microparticles that either naturally accumulate in or are designed to target tumours. TRT combines the specificity of molecular and sometimes physical targeting with the potent cytotoxicity of ionisi...

Scientific Reports 6 : Article number: 31973 10.1038/srep31973 ; published online: 25 August 2016 ; updated: 22 December 2016 This Article contains an error in Figure 2c, where the y-axis ‘μg [Ru]/mg [cell protein]’ is incorrectly labelled as ‘ng [Ru]/mg [cell protein]’.

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz) 2 (PIP)] 2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) i...

Although metal-ion-directed self-assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self-assembled structures. Herein we report the fir...

The DNA binding and cellular localization properties of a new luminescent heterobimetallic Ir(III) Ru(II) tetrapyridophenazine complex are reported. Surprisingly, in standard cell media, in which its tetracationic, isostructural Ru(II) Ru(II) analogue is localized in the nucleus, the new tricationic complex is poorly taken up by live cells and demo...

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear RuII-PtII complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]3+ (tpy=2,2′:6′,2′′-terpyridine and tpypma=4-([...

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear Ru(II) -Pt(II) complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)](3+) (tpy=2,2':6',2''-terpyridine and tpyp...

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear RuII–PtII complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]3+ (tpy=2,2’:6’,2’’-terpyridine and tpypma=4-([...

The synthesis of two new luminescent dinuclear IrIII–RuII complexes containing tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′′,3′′′-j]phenazine (tpphz) as the bridging ligand is reported. Unlike many other complexes incorporating cyclometalated IrIII moieties, these complexes display good water solubility, allowing the first cell-based study on IrIII–RuII...

Two dinuclear osmium polypyridyl complexes function as convenient, easy to handle TEM contrast agents and facilitate the high-resolution visualisation of intracellular structure, particularly sub-nuclear detail.

The first transition-metal complex-based two-photon absorbing luminescence lifetime probes for cellular DNA are presented. This allows cell imaging of DNA free from endogenous fluorophores and potentially facilitates deep tissue imaging. In this initial study, ruthenium(II) luminophores are used as phosphorescent lifetime imaging microscopy (PLIM)...

The first transition-metal complex-based two-photon absorbing luminescence lifetime probes for cellular DNA are presented. This allows cell imaging of DNA free from endogenous fluorophores and potentially facilitates deep tissue imaging. In this initial study, ruthenium(II) luminophores are used as phosphorescent lifetime imaging microscopy (PLIM)...

miscellaneous_information

The characterization and bioactivity of the dinuclear ruthenium(II) complex [(Ru(DIP)2)2(tpphz)]4+ (DIP = 4,7-diphenyl-1,10-phenanthroline and tpphz = tetrapyridophenazine) is reported. This new complex is found to be luminescent in acetonitrile, where excitation into MLCT (metal-to-ligand charge-transfer) bands in the visible area of the spectrum...

In the last few decades, coordination complexes based on d(6) metal centres and polypyridyl ligand architectures been developed as structure- and site-specific reversible DNA binding agents. Due to their attractive photophysical properties, much of this research has focused on complexes based on ruthenium(II) centres and, more recently, attention h...

Dead or alive: We report the successful cellular uptake of two ruthenium polypyridyl DNA light switch complexes that function as multifunctional cellular DNA imaging agents and display potent cytotoxicity against cancer cells. The cytotoxic properties of one complex are of great interest as it offers a potential lead for the development of a new cl...

Mitochondria in live cells can be imaged with a ruthenium(II) complex that usually binds and images nuclear DNA. The cellular uptake mechanism of this probe was changed by using a biocompatible pH-sensitive polymersome vector. This change in delivery route, determines the final cellular location of the probe and thus modulates its imaging propertie...

Unique biphasic binding to calf-thymus DNA and to the polynucleotides poly(dA–dT)2, poly(dG–dC)2, poly(dA)–poly(dT), and poly(dG)–poly(dC) has been observed for RuII–polypyridyl complexes with a pendant catechol functionality. The RuII–polypyridyl complexes preferentially bind to more flexible, alternating purine–pyrimidine sequences, particularly...

The duplex-DNA binding properties of a nonintercalating polypyridyl ruthenium(II) complex that incorporates a linear extended ligand with a catechol moiety has been probed with a variety of photo- and biophysical techniques. These studies reveal that the complex groove binds to DNA sequences biphasically, and displays binding constants equivalent t...

We report the synthesis of three new complexes related to the achiral [Ru(tpm)(dppz)py](2+) cation (tpm=tripyridazole methane, dppz=dipyrido[3,2-a:2',3'-c]phenazine, py=pyridine) that contain an additional single functional group on the monodentate ancillary pyridyl ligand. Computational calculations indicate that the coordinated pyridyl rings are...

In the search for new biological imaging agents, metal coordination compounds able to emit from triplet metal-to-ligand charge transfer (MLCT) states offer many advantages as luminescent probes of DNA structure. However, poor cellular uptake restricts their use in live cells. Here, we present a dinuclear ruthenium(II) polypyridyl system that works...

The salts [NEt4][Ru(CN)(CO)2L(o-O2C6Cl4)] {L=PPh3 or P(OPh)3}, which undergo one-electron oxidation at the catecholate ligand to give neutral semiquinone complexes [Ru(CN)(CO)2L(o-O2C6Cl4)], react with the dimers [{Ru(CO)2L(micro-o-O2C6Cl4)}2] {L=PPh3 or P(OPh)3} to give [NEt4][(o-O2C6Cl4)L(OC)2Ru(micro-CN)Ru(CO)2L'(o-O2C6Cl4)] {L or L'=PPh3 or P(O...

A DNA Swiss-army knife: Photo- and biophysical studies on the hetero-dinuclear complex [{Ru(tpm)(dppz)}(μ-dpp[5]){fac-(CO) 3Re(dppz)}]3+ (see structure; tpm = tris(1-pyrazolyl) methane; dppz = dipyrido[3,2-a:2′,3′-c]phenazine; dpp[5] = 4,4′-dipyridylpentane) reveal that it is both a DNA light switch and a direct cleaving agent. (Chemical Equation P...