Synthesis and cellular uptake of neutral rhenium(I) morpholine complexes.

Morpholine motifs have been used extensively as targeting moieties for lysosomes, primarily in fluorescence imaging agents. Traditionally these imaging agents are based on organic molecules which have several shortcomings including small Stokes shifts, short emission lifetimes, and susceptibility to photobleaching. To explore alternative lysosome targeting imaging agents we have used a rhenium based phosphorescent platform which has been previously demonstrated to have an improved Stokes shift, a long lifetime emission, and is highly photostable.

Surface Functionalised Optical Fibre for Detection of Hydrogen Sulphide.

Dysregulated production of hydrogen sulphide in the human body has been associated with various diseases including cancer, underlining the importance of accurate detection of this molecule. Here, we report the detection of hydrogen sulphide using fluorescence-emission enhancement of two 1,8-naphthalimide fluorescent probes with an azide moiety in position 4. One probe, serving as a control, featured a methoxyethyl moiety through the imide to evaluate its effectiveness for hydrogen sulphide detection, while the other probe was modified with (3-aminopropyl)triethoxysilane (APTES) to enable direct covalent attachment to an optical fibre tip.

Rhenium(I) conjugates as tools for tracking cholesterol in cells.

Cholesterol is vital to control membrane integrity and fluidity, but is also a precursor to produce steroid hormones, bile acids, and vitamin D. Consequently, altered cholesterol biology has been linked to many diseases, including metabolic syndromes and cancer. Defining the intracellular pools of cholesterol and its trafficking within cells is essential to understand both normal cell physiology and mechanisms of pathogenesis.

Development of an optical fiber-based redox monitoring system for tissue metabolism.

An optical redox ratio can potentially be used to report on the dynamics of cell and tissue metabolism and define altered metabolic conditions for different pathologies. While there are methods to measure the optical redox ratio, they are not particularly suited to real-time in situ or in vivo analysis. Here, we have developed a fiber-optic system to measure redox ratios in cells and tissues and two mathematical models to enable real-time, in vivo redox measurements.

Redox ratio in the left ventricle of the growth restricted fetus is positively correlated with cardiac output.

Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long-term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart.

Neutral Re(I) Complex Platform for Live Intracellular Imaging.

Luminescent metal complexes are a valuable platform for the generation of cell imaging agents. However, many metal complexes are cationic, a factor that can dominate the intracellular accumulation to specific organelles. Neutral Re(I) complexes offer a more attractive platform for the development of bioconjugated imaging agents, where charge cannot influence their intracellular distribution.

Spectroscopic and Molecular Docking Study of the Interaction between Neutral Re(I) Tetrazolate Complexes and Bovine Serum Albumin.

Re(I) complexes have potential in biomedical sciences as imaging agents, diagnostics and therapeutics. Thus, it is crucial to understand how Re(I) complexes interact with carrier proteins, like serum albumins. Here, two neutral Re(I) complexes were used (fac-[Re(CO) (1,10-phenanthroline)L], in which L is either 4-cyanophenyltetrazolate (1) or 4-methoxycarbonylphenyltetrazole ester (2), to study the interactions with bovine serum albumin (BSA).

Concept Design, Development and Preliminary Physical and Chemical Characterization of Tamoxifen-Guided-Mesoporous Silica Nanoparticles.

Conventional chemotherapies used for breast cancer (BC) treatment are non-selective, attacking both healthy and cancerous cells. Therefore, new technologies that enhance drug efficacy and ameliorate the off-target toxic effects exhibited by currently used anticancer drugs are urgently needed. Here we report the design and synthesis of novel mesoporous silica nanoparticles (MSNs) equipped with the hormonal drug tamoxifen (TAM) to facilitate guidance towards estrogen receptors (ERs) which are upregulated in breast tumours.

In utero substrate restriction by placental insufficiency or maternal undernutrition decreases optical redox ratio in foetal perirenal fat.

Intrauterine growth restriction (IUGR) can result from reduced delivery of substrates, including oxygen and glucose, during pregnancy and may be caused by either placental insufficiency or maternal undernutrition. As a consequence of IUGR, there is altered programming of adipose tissue and this can be associated with metabolic diseases later in life. We have utilised two sheep models of IUGR, placental restriction and late gestation undernutrition, to determine the metabolic effects of growth restriction on foetal perirenal adipose tissue (PAT).

Cross-Coupling of Amide and Amide Derivatives to Umbelliferone Nonaflates: Synthesis of Coumarin Derivatives and Fluorescent Materials.

The Buchwald-Hartwig cross-coupling reaction between 4-methylumbelliferone-derived nonaflates with amides, carbamates, and sulfonamides is described. A wide variety of -substituted 7-amino coumarin analogues was prepared in good to excellent yields. The photophysical properties of aqueous-soluble derivatives were determined, and they displayed auxochrome-based variations.

Novel Tamoxifen Nanoformulations for Improving Breast Cancer Treatment: Old Wine in New Bottles.

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications.

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues.

The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two-photon microscopy.

Lipid profiles of prostate cancer cells.

Lipids are important cellular components which can be significantly altered in a range of disease states including prostate cancer. Here, a unique systematic approach has been used to define lipid profiles of prostate cancer cell lines, using quantitative mass spectrometry (LC-ESI-MS/MS), FTIR spectroscopy and fluorescent microscopy. All three approaches identified significant difference in the lipid profiles of the three prostate cancer cell lines (DU145, LNCaP and 22RV1) and one non-malignant cell line (PNT1a).

Norbornane-based cationic antimicrobial peptidomimetics targeting the bacterial membrane.

The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MIC = 0.25 μg/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion.

Luminescent protein staining with Re(i) tetrazolato complexes.

Within the general framework of our past and current studies dealing with the investigation of the photophysical properties and the biological behavior of the family of tetrazolato and tetrazole Re(i) complexes, we have endeavored to investigate their potential in the luminescent staining of proteins purified by acrylamide gel electrophoresis. With the aim to provide the first examples of luminescent Re(i) complexes to be exploited for this specific purpose, we have designed and prepared four new Re(i)-based species with the general formula fac-[Re(CO)3(N^N)(Tph)]2-/0, where Tph is the 5-(phenyl)tetrazolato anion and N^N is in turn represented by bathophenanthroline disulfonate (BPS), bathocuproine disulfonate (BCS) or by the SO3- free bathocuproine (BC). In this latter case, the neutral complex fac-[Re(CO)3(BC)(Tph)] served as a model species for the characterization of the former disulfonate complexes.

Mitochondrial imaging in live or fixed tissues using a luminescent iridium complex.

Mitochondrial morphology is important for the function of this critical organelle and, accordingly, altered mitochondrial structure is exhibited in many pathologies. Imaging of mitochondria can therefore provide important information about disease presence and progression. However, mitochondrial imaging is currently limited by the availability of agents that have the capacity to image mitochondrial morphology in both live and fixed samples.

Novel Gd-Loaded Silicon Nanohybrid: A Potential Epidermal Growth Factor Receptor Expressing Cancer Cell Targeting Magnetic Resonance Imaging Contrast Agent.

Continuing our research efforts in developing mesoporous silicon nanoparticle-based biomaterials for cancer therapy, we employed here porous silicon nanoparticles as a nanocarrier to deliver contrast agents to diseased cells. Nanoconfinement of small molecule Gd-chelates (L1-Gd) enhanced the T contrast dramatically compared to distinct Gd-chelate (L1-Gd) by virtue of its slow tumbling rate, increased number of bound water molecules, and their occupancy time. The newly synthesized Gd-chelate (L1-Gd) was covalently grafted on silicon nanostructures and conjugated to an antibody specific for epidermal growth factor receptor (EGFR) via a hydrazone linkage.

Label-free imaging of redox status and collagen deposition showing metabolic differences in the heart.

The heart has high metabolic demand to maintain function. The primary source of energy supply to support correct contractile muscle function differs between a fetus and an adult. In fetal life, ATP is primarily generated by glycolysis and lactate oxidation, whereas following birth, there is a shift towards a reliance on mitochondrial metabolism and fatty acid oxidation.

Synthesis, photophysical and cellular characterisation of folate and methotrexate labelled luminescent lanthanide complexes.

In this work we have developed a series of highly emissive europium(III) and terbium(III) complexes tethered to either folic acid (FA) or methotrexate (MTX), with the aim of developing visual probes that enable the imaging of folate receptors in cancer cells. The synthesis, photophysical properties and cellular behaviour are reported for four new lanthanide Ln(III) complexes, where either FA or MTX are tethered to 1,4,7-tris(carbonylmethyl)-10-(4'-quinolineacetic acid, (7'-acetamido)-1',2'-dihydro-2'-oxo)-1,4,7,10-tetraazacyclododecane Ln(III) complex, and Ln(III)=Eu(III) or Tb(III); herein referred to as Eu-FA, Eu-MTX, Tb-FA or Tb-MTX. All four complexes were found to be sensitive to the presence of the folate receptor in a range of cell lines.

Investigating Intracellular Localisation and Cytotoxicity Trends for Neutral and Cationic Iridium Tetrazolato Complexes in Live Cells.

A family of five neutral cyclometalated iridium(III) tetrazolato complexes and their methylated cationic analogues have been synthesised and characterised. The complexes are distinguished by variations of the substituents or degree of π conjugation on either the phenylpyridine or tetrazolato ligands. The photophysical properties of these species have been evaluated in organic and aqueous media, revealing predominantly a solvatochromic emission originating from mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity.

Crosslinked shells for nano-assembled capsules: a new encapsulation method for smaller Gd-loaded capsules with exceedingly high relaxivities.

Nano-assembled capsules can incorporate large payloads of high relaxivity Gd, permitting the development of highly detectable molecular imaging agents for MRI. A new encapsulating shell, based upon cross-linked peptides, is found to afford smaller capsules (127 nm average diameter) with exceptionally high per-Gd relaxivities (70.7 s mmolal).

Label-free imaging of healthy and infarcted fetal sheep hearts by two-photon microscopy.

Coronary heart disease is one of the largest causes of death worldwide, making this a significant health care issue. A critical problem for the adult human heart is that it does not undergo effective repair in response to damage, leaving patients with a poor prognosis. Unlike the adult, fetal hearts have the ability to repair after myocardial damage.

Singlet Oxygen Detection on a Nanostructured Porous Silicon Thin Film via Photonic Luminescence Enhancements.

Because reactive oxygen species are involved in a range of pathologies, developing analytical tools for this group of molecules opens new vistas for biomedical diagnostics. Herein, we fabricate a porous silicon microcavity (pSiMC) functionalized with luminescent singlet oxygen (O) probe EuA ((Eu(III)-2,2',2″-(10-(2-((4-(2-((4-(2-((anthracen-9-ylmethyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydroquinolin-7-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) as proof of concept of an optical sensor for reactive oxygen species. We characterize each surface modification step of the pSiMC by means of FTIR and X-ray photoelectron spectroscopy as well as by determining the optical shifts of the resonance wavelength of the pSiMC.

A Molecular Probe for the Detection of Polar Lipids in Live Cells.

Lipids have an important role in many aspects of cell biology, including membrane architecture/compartment formation, intracellular traffic, signalling, hormone regulation, inflammation, energy storage and metabolism. Lipid biology is therefore integrally involved in major human diseases, including metabolic disorders, neurodegenerative diseases, obesity, heart disease, immune disorders and cancers, which commonly display altered lipid transport and metabolism. However, the investigation of these important cellular processes has been limited by the availability of specific tools to visualise lipids in live cells.