Synthesis and surface modification of silver and gold nanoparticles. Nanomedicine applications against Glioblastoma Multiforme.

In the last decades noble metal nanoparticles (NPs) arose as one of the most powerful tools for applications in nanomedicine field and cancer treatment. Glioblastoma multiforme (GBM), in particular, is one of the most aggressive malignant brain tumors that nowadays still presents a dramatic scenario concerning median survival. Gold nanorods (GNRs) and silver nanoparticles (AgNPs) could find applications such as diagnostic imaging, hyperthermia and glioblastoma therapy. During these three years, both GNRs and AgNPs were synthesized with the “salt reduction” method and, through a novel double phase transfer process, using specifically designed thiol-based ligands, lipophilic GNRs and AgNPs were obtained and separately entrapped into biocompatible and biodegradable PEG-based polymeric nanoparticles (PNPs) suitable for drug delivery within the body. Moreover, a synergistic effect of AgNPs with the Alisertib drug, were investigated thanks to the simultaneous entrapment of these two moieties into PNPs. In addition, Chlorotoxin (Cltx), a peptide that specifically recognize brain cancer cells, was conjugated onto the external surface of PNPs. The so-obtained novel nanosystems were evaluated for in vitro and in vivo applications against glioblastoma multiforme. In particular, for GNRs-PNPs, their safety, their suitability as optoacoustic contrast agents, their selective laser-induced cells death and finally, a high tumor retention were all demonstrated. Concerning AgNPs-PNPs, promising tumor toxicity and a strong synergistic effect with Alisertib was observed (IC50 10 nM), as well as good in vivo biodistribution, high tumor uptake and significative tumor reduction in tumor bearing mice. Finally, the two nanostructures were linked together, through an organic framework, exploiting the click chemistry azido-alkyne Huisgen cycloaddition, between two ligands previously attached to the NPs surface; this multifunctional complex nanosystem was successfully entrapped into PNPs with nanoparticles’ properties maintenance, obtaining in this way a powerful and promising tool for cancer fight and defeat.

Near-field mediated enhancement effects on plasmonic nanostructures

In dieser Arbeit wird eine detaillierte Untersuchung und Charakterisierung der Zwei-Photonen-induzierten Fluoreszenzverstärkung von organischen Farbstoffen auf plasmonischen Nanostrukturen vorgestellt. Diese Fluoreszenzverstärkung ist insbesondere für hochaufgelöste Fluoreszenzmikroskopie und Einzelmolekülspektroskopie von großer Bedeutung. Durch die Zwei-Photonen-Anregung resultiert eine Begrenzung des Absorptionsprozesses auf das fokale Volumen. In Kombination mit dem elektrischen Nahfeld der Nanostrukturen als Anregungsquelle entsteht eine noch stärkere Verringerung des Anregungsvolumens auf eine Größe unterhalb der Beugungsgrenze. Dies erlaubt die selektive Messung ausgewählter Farbstoffe. Durch die Herstellung der Nanopartikel mittels Kolloidlithografie wird eine definierte, reproduzierbare Geometrie erhalten. Polymermultischichten dienen als Abstandshalter, um die Farbstoffe an einer exakten Distanz zum Metall zu positionieren. Durch die kovalente Anbindung des Farbstoffs an die oberste Schicht wird eine gleichmäßige Verteilung des Farbstoffs in geringer Konzentration erhalten. rnEs wird eine Verstärkung der Fluoreszenz um den Faktor 30 für Farbstoffe auf Goldellipsen detektiert, verglichen mit Farbstoffen außerhalb des Nahfelds. Sichelförmige Nanostrukturen erzeugen eine Verstärkung von 120. Dies belegt, dass das Ausmaß der Fluoreszenzverstärkung entscheidend von der Stärke des elektrischen Nahfelds der Nanostruktur abhängt. Auch das Material der Nanostruktur ist hierbei von Bedeutung. So erzeugen Silberellipsen eine 1,5-fach höhere Fluoreszenzverstärkung als identische Goldellipsen. Distanzabhängige Fluoreszenzmessungen zeigen, dass die Zwei-Photonen-angeregte Fluoreszenzverstärkung an strukturspezifischen Abständen zum Metall maximiert wird. Elliptische Strukturen zeigen ein Maximum bei einem Abstand von 8 nm zum Metall, wohingegen bei sichelförmigen Nanostrukturen die höchste Fluoreszenzintensität bei 12 nm gemessen wird. Bei kleineren Abständen unterliegt der Farbstoff einem starken Löschprozess, sogenanntes Quenching. Dieses konkurriert mit dem Verstärkungsprozess, wodurch es zu einer geringen Nettoverstärkung kommt. Hat die untersuchte Struktur Dimensionen größer als das Auflösungsvermögen des Mikroskops, ist eine direkte Visualisierung des elektrischen Nahfelds der Nanostruktur möglich. rnrnEin weiterer Fokus dieser Arbeit lag auf der Herstellung neuartiger Nanostrukturen durch kolloidlithografische Methoden. Gestapelte Dimere sichelförmiger Nanostrukturen mit exakter vertikaler Ausrichtung und einem Separationsabstand von etwa 10 nm wurden hergestellt. Die räumliche Nähe der beiden Strukturen führt zu einem Kopplungsprozess, der neue optische Resonanzen hervorruft. Diese können als Superpositionen der Plasmonenmoden der einzelnen Sicheln beschrieben werden. Ein Hybridisierungsmodell wird angewandt, um die spektralen Unterschiede zu erklären. Computersimulationen belegen die zugrunde liegende Theorie und erweitern das Modell um experimentell nicht aufgelöste Resonanzen. rnWeiterhin wird ein neuer Herstellungsprozess für sichelförmige Nanostrukturen vorgestellt, der eine präzise Formanpassung ermöglicht. Hierdurch kann die Lage der Plasmonenresonanz exakt justiert werden. Korrelationen der geometrischen Daten mit den Resonanzwellenlängen tragen zum grundlegenden Verständnis der Plasmonenresonanzen bei. Die vorgestellten Resultate wurden mittels Computersimulationen verifiziert. Der Fabrikationsprozess erlaubt die Herstellung von Dimeren sichelförmiger Nanostrukturen in einer Ebene. Durch die räumliche Nähe überlappen die elektrischen Nahfelder, wodurch es zu kopplungs-induzierten Shifts der Plasmonenresonanzen kommt. Der Unterschied zu theoretisch berechneten ungekoppelten Nanosicheln kann auch bei den gegenüberliegenden sichelförmigen Nanostrukturen mit Hilfe des Plasmonenhybridisierungsmodells erklärt werden.

Synthesis of novel cobalt and iron complexes for sustainable catalytic hydrogenations

Aim of the present work of thesis is to synthesize new non-noble metal based complexes to be employ in redox reactions by a metal-ligand cooperative mechanism. The need of replacing toxic and expensive precious metal complexes with more available and benign metals, has led to the development of new compounds based on cobalt and iron, which are the metals investigated in this study. A carbonyl-tetrahydroborato-bis[(2-diisopropylphosphino)ethyl]amine-cobalt complex bearing a PNP-type ligand is synthesized by a three-step route. Optimization attempt of reaction route were assessed in order to lowering reaction times and solvent waste. New cobalt complex has been tested in esters hydrogenation as well as in acceptorless dehydrogenative coupling of ethanol. Other varieties of substrates were also tested in order to evaluate any possible applications. Concerning iron complex, dicarbonyl-(η4-3,4-bis(4-methoxyphenyl)-2,5-diphenylcyclopenta-2,4-dienone)(1,3-dimethyl-ilidene)iron is synthesized by a three steps route, involving transmetallation of a silver complex, derived from an imidazolium salt, to iron complex. In order to avoid solvent waste, optimization is assessed. Studies were performed to assess activity of triscarbonyl iron precursor toward imidazolium salt and silver complexes.

Selective photo-oxidation of glucose

Biomass transformation into high-value chemicals has attracted attention according to the “green chemistry” principles. Low price and high availability make biomass one of the most interesting renewable resources as it provides the means to create sustainable alternatives to the oil-derived building blocks of the chemical industry In recent year, the need for alternative environmentally friendly routes to drive chemical reactions has in photocatalytic processes an interesting way to obtain valuable chemicals from various sources using the solar light as energy source. The purpose of this work was to use supported noble metal nanoparticles in the selective photo-oxidation of glucose through using visible light. Glucose was chosen as model molecule because it is the cheapest and the most common monosaccharide. Few studies about glucose photo oxidation have been conducted so far, and reaction mechanism is still not totally explained. The aim of this work was to systematically analyze and assess the impact of several parameters (eg. catalyst/substrate ratio, reaction time, effect of the solvent and light source) on the reaction pathway and to monitor the product distribution in order to draw a general reaction scheme for the photo oxidation of glucose under visible light. This study regards the reaction mechanism and the influence of several parameters, such as solvent, light power and substrate concentration. Furthermore, the work focuses on the influence of gold and silver nanoparticles and on the influence of metal loading. The glucose oxidation was monitored through the mass balance and the products selectivity. Reactions were evaluated in terms of glucose conversion, mass balance and selectivities towards arabinose and gluconic acid. In conclusion, this study is able to demonstrate that the photo oxidation of glucose under visible light is feasible; the full identification of the main products allows, for the first time, a comprehensive reaction mechanism scheme.

Core-crosslinked compartmentalized cylinders

We present a detailed study on the preparation of compartmentalized cylindrical nanoparticles via a templated approach: the polybutadiene part of a linear polybutadiene-block-poly(2-vinyl pyridine)-block-poly(tert-butyl methacrylate) block terpolymer, B420V280T790, having a bulk microstructure with PB cylinders covered by a P2VP double helix and embedded in a PtBMA matrix was selectively crosslinked. Subsequent sonication-assisted dissolution and chemical modifications such as quaternization (P2VP to P2VPq) and ester hydrolysis (PtBMA to poly(sodium methacrylate), PMANa) resulted in core-crosslinked cylinders soluble in organic and aqueous media. Different amounts of crosslinker and the influence of the sonication treatment on size and shape of the cylindrical aggregates were investigated. The cylinders always exhibit a compartmentalized corona. Under certain conditions, in particular quaternization of P2VP in mixtures of THF and MeOH, the helical arrangement of the P2VPq shell could be preserved even in solution, whereas in most other cases randomly distributed P2VP/P2VPq patches were observed. In aqueous solution at high pH, intramicellar interpolyelectrolyte complex (im-IPEC) formation occurred between the positively charged P2VPq shell and the negatively charged PMANa corona. We further show that different noble metal nanoparticles can be generated either selectively within the im-IPEC compartments (Pd) or randomly distributed among shell and corona of the cylinders (Au and Pt).

Soft Lewis acid catalyzed cycloisomerization of oxo-alkynes and enynes

In the literature, some transition metal salts have been used as soft Lewis acids to activate alkynes toward nucleophilic attack. For example, Pt(II), Au(I) and Pd(II) catalysts can catalyze cycloisomerization reactions of alkynyl compounds to give a variety of cyclic products. In order to expand the scope of these reactions, in chapter 2 of this dissertation, several alkynyl epoxides were isomerized to cyclic allyl vinyl ethers using PtCl2 as the catalyst. Three of these allyl vinyl ethers were hydrolyzed to 2-hydroxymorpholine derivatives and two were converted to piperidine derivatives by thermal Claisen rearrangement. In order to find more benign and inexpensive catalysts for these types of reactions, in chapter 3 of this dissertation, BiCl3 was used to catalyze the isomerization of eight enynes to pyrrolidine derivatives. This reaction was normally catalyzed by expensive noble metal catalysts, such as Pd(II), Pt(II) and Au(I). All the cyclic products are valuable intermediates in the synthesis of bioactive molecules, these soft Lewis acid catalyzed cycloisomerization may find applications in the synthesis of bioactive molecules.

The Electrodeposition of Iron-Manganese Alloys

Although the alteration of properties resulting from the alloying of metals in their usual commercial forms has been extensively investigated, the field of electrodeposition of alloys is believed generally not to have received the atten­tion that it merits.

Radiochemical determination of 129I and 36Cl in MEGAPIE, a proton irradiated lead-bismuth eutectic spallation target

The concentrations of the long-lived nuclear reaction products 129I and 36Cl have been measured in samples from the MEGAPIE liquid metal spallation target. Samples from the bulk target material (lead-bismuth eutectic, LBE), from the interface of the metal free surface with the cover gas, from LBE/steel interfaces and from noble metal absorber foils installed in the cover gas system were analysed using Accelerator Mass Spectrometry at the Laboratory of Ion beam Physics at ETH Zürich. The major part of 129I and 36Cl was found accumulated on the interfaces, particularly at the interface of LBE and the steel walls of the target container, while bulk LBE samples contain only a minor fraction of these nuclides. Both nuclides were also detected on the absorber foils to a certain extent (≪ 1% of the total amount). The latter number is negligible concerning the radio-hazard of the irradiated target material; however it indicates a certain affinity of the absorber foils for halogens, thus proving the principle of using noble metal foils for catching these volatile radionuclides. The total amounts of 129I and 36Cl in the target were estimated from the analytical data by averaging within the different groups of samples and summing up these averages over the total target. This estimation could account for about half of the amount of 129I and 36Cl predicted to be produced using nuclear physics modelling codes for both nuclides. The significance of the results and the associated uncertainties are discussed.

(Table 1) Platinum group element abundanves in ODP Leg 135 samples

Ocean Drilling Program Leg 135 backarc basin lavas are characterized by anomalously high Au contents (1.0-11.4 ppb) and strongly fractionated relative platinum group element (PGE) abundances (Pd/Ir ratio, approximately 100). The Rh and Ir contents are very low, ranging from below detection (approximately 0.02 ppb) to 0.08 ppb. The Pd and Pt contents range from <0.3 to 4 ppb. Rh, Pd, and Pt values are consistently and significantly higher in Site 836 and 839 samples relative to those from Sites 834 and 835. Major, trace, and rare earth element (REE) data suggest Sites 836 and 839 have a more pronounced arc signature than Sites 834 and 835. No correlation exists between noble metal abundance and indices of alteration or fractionation (e.g., loss on ignition (LOI), Mg#, and Cr or Ni contents), suggesting that measured values and ratios are primary and reflect characteristics of the mantle source. The evaluation of Leg 135 noble metal data with respect to potential mantle-source components is hindered by the lack of data on magmas derived from such sources. However, analyses of the limited available data for the different magma types suggest that the characteristic enrichment of Leg 135 lavas in Au, relative to Pd and Cu, cannot be derived solely from simple MORB-type or ocean-island-type mantle, or mantle depleted by a previous melt extraction event. The Au-enriched signature of the Lau basin lavas could, however, be produced through the addition of a sedimentary component from the downgoing slab. Separation of Au from the PGE occurs within oceanic hydrothermal systems and gold values of the resultant precipitates are 2-3 orders of magnitude higher than other oceanic crustal components. Even small additions of this component from the downgoing oceanic crust to a supra-subduction zone mantle melt could account for the high mean Au/Pd ratios of the Leg 135 samples (Sites 834 and 835, Au/Pd = 5.04; Sites 836 and 839, Au/Pd = 2.26).

Geochemistry data from the Toupugol volcanogenic complex

A large fragment of a paleovolcano of Silurian to Early Devonian age was discovered in the Voikar volcanic belt suggesting an ensimatic island are as its geodynamic environment. Formationally, the rocks under study are comparable to Pleistocene island arc volcanites and their paleo-analogues. The volcanites of the Toupugol complex underwent strong hydrothermal-metasomatic alteration: propylites, acid metasomatic rocks and quartz-carbonate veins, which must have resulted from hydrothermal-metasomatic alteration of andesitoids. Both volcanites and apovolcanic hydrothermal rocks in Toupugol were found to host noble metal mineralisation. It is found in close association with sulphides, particularly pyrite. Free gold was discovered in all investigated volcanites and hydrothermal rocks and is characterised by low mercury content and an unusual set of microimpurities (Pt, Pd, Cu, Fe, S) suggesting its links to the mantle substrate.

Research lines in Hyperthermia at the Bioinstrumentation Laboratory of the Centre for Biomedical Technology

The Bioinstrumentation Laboratory belongs to the Centre for Biomedical Technology (CTB) of the Technical University of Madrid and its main objective is to provide the scientific community with devices and techniques for the characterization of micro and nanostructures and consequently finding their best biomedical applications. Hyperthermia (greek word for “overheating”) is defined as the phenomenon that occurs when a body is exposed to an energy generating source that can produce a rise in temperature (42-45ºC) for a given time [1]. Specifically, the aim of the hyperthermia methods used in The Bioinstrumentation Laboratory is the development of thermal therapies, some of these using different kinds of nanoparticles, to kill cancer cells and reduce the damage on healthy tissues. The optical hyperthermia is based on noble metal nanoparticles and laser irradiation. This kind of nanoparticles has an immense potential associated to the development of therapies for cancer on account of their Surface Plasmon Resonance (SPR) enhanced light scattering and absorption. In a short period of time, the absorbed light is converted into localized heat, so we can take advantage of these characteristics to heat up tumor cells in order to obtain the cellular death [2]. In this case, the laboratory has an optical hyperthermia device based on a continuous wave laser used to kill glioblastoma cell lines (1321N1) in the presence of gold nanorods (Figure 1a). The wavelength of the laser light is 808 nm because the penetration of the light in the tissue is deeper in the Near Infrared Region. The first optical hyperthermia results show that the laser irradiation produces cellular death in the experimental samples of glioblastoma cell lines using gold nanorods but is not able to decrease the cellular viability of cancer cells in samples without the suitable nanorods (Figure 1b) [3]. The generation of magnetic hyperthermia is performed through changes of the magnetic induction in magnetic nanoparticles (MNPs) that are embedded in viscous medium. The Figure 2 shows a schematic design of the AC induction hyperthermia device in magnetic fluids. The equipment has been manufactured at The Bioinstrumentation Laboratory. The first block implies two steps: the signal selection with frequency manipulation option from 9 KHz to 2MHz, and a linear output up to 1500W. The second block is where magnetic field is generated ( 5mm, 10 turns). Finally, the third block is a software control where the user can establish initial parameters, and also shows the temperature response of MNPs due to the magnetic field applied [4-8]. The Bioinstrumentation Laboratory in collaboration with the Mexican company MRI-DT have recently implemented a new research line on Nuclear Magnetic Resonance Hyperthermia, which is sustained on the patent US 7,423,429B2 owned by this company. This investigation is based on the use of clinical MRI equipment not only for diagnosis but for therapy [9]. This idea consists of two main facts: Magnetic Resonance Imaging can cause focal heating [10], and the differentiation in resonant frequency between healthy and cancer cells [11]. To produce only heating in cancer cells when the whole body is irradiated, it is necessary to determine the specific resonant frequency of the target, using the information contained in the spectra of the area of interest. Then, special RF pulse sequence is applied to produce fast excitation and relaxation mechanism that generates temperature increase of the tumor, causing cellular death or metabolism malfunction that stops cellular division

Contribución al estudio de sistemas de hipertermia óptica y su aplicación en muestras biológicas

Las nanopartículas de metales nobles (especialmente las de oro) tienen un gran potencial asociado al desarrollo de sistemas de terapia contra el cáncer debido principalmente a sus propiedades ópticas, ya que cuando son irradiadas con un haz de luz sintonizado en longitud de onda con su máximo de Resonancia de Plasmón Superficial, absorben de manera muy eficiente dicha luz y la disipan rápidamente al medio en forma de calor localizado. Esta característica por tanto, puede ser aprovechada para conseguir elevar la temperatura de células tumorales hasta sobrepasar umbrales a partir de los cuales se produciría la muerte celular. Partiendo de estos principios, esta tesis se centra en el desarrollo y la caracterización de una serie de prototipos de hipertermia óptica basados en la irradiación de nanopartículas de oro con un haz de luz adecuado, así como en la aplicación in vitro de la terapia sobre células cancerígenas. Además, el trabajo se orienta a identificar y comprender los procesos mecánicos y térmicos asociados a este tipo de hipertermia, y a desarrollar modelos que los describan, estudiando y planteando nuevas formas de irradiación, para, en última instancia, poder optimizar los procesos descritos y hacerlos más efectivos. Los resultados obtenidos indican que, el uso de nanopartículas de oro, y más concretamente de nanorods de oro, para llevar a cabo terapias de hipertermia óptica, permite desarrollar terapias muy efectivas para inducir muerte en células cancerígenas, especialmente en tumores superficiales, o como complemento quirúrgico en tumores internos. Sin embargo, los efectos de la toxicidad de las nanopartículas de oro, aún deben ser detalladamente estudiados, ya que este tipo de terapias sólo será viable si se consigue una completa biocompatibilidad. Por otro lado, el estudio exhaustivo de los procesos térmicos que tienen lugar durante la irradiación de las nanopartículas ha dado lugar a una serie de modelos que permiten determinar la efectividad fototérmica de las nanopartículas y además, visualizar la evolución de la temperatura tanto a escala nanométrica como a escala macrométrica, en función de los parámetros ópticos y térmicos del sistema. El planteamiento de nuevas formas de irradiación y el desarrollo de dispositivos orientados a estudiar los fenómenos mecánicos que tienen lugar durante la irradiación pulsada de baja frecuencia y baja potencia de nanopartículas de oro, ha dado lugar a la detección de ondas de presión asociadas a procesos de expansión termoelástica, abriendo la puerta al desarrollo de terapias de hipertermia que combinen la muerte celular producida por calentamiento con la muerte derivada de los fenómenos mecánicos descritos.VII Noble metal nanoparticles (especially gold ones), have a huge potential in the development of therapy systems against cancer mainly due to their optical properties, so that, when these particles are irradiated with a light that is syntonized in wavelength with their maximum of Surface Plasmon Resonance, they effectively absorb and dissipate the light to the surrounding medium as localized heat. We can take advantage of this characteristic for rising the temperature of cancer cells above the threshold at which cellular death would occur. From these principles, this thesis is oriented to the development and characterization of a series of optical hyperthermia prototypes based on the irradiation of gold nanoparticles using the suitable light, and on the in vitro application of this therapy over cancer cells, to understand the mechanical and thermal processes associated with this kind of hyperthermia, developing descriptive models, and to study and to approach new ways of irradiation in order to, ultimately, optimize the described processes and make them more effective. The obtained results show that, the use of gold nanoparticles, and more specifically, of gold nanorods, to carry out optical hyperthermia therapies, allows the development of very effective therapies in order to induce death in VIII cancer cells, especially in superficial tumors, or like surgical complement in more internal tumors. However, the toxicity effects of the gold nanoparticles still need to be studied more detail, because this kind of therapies will be feasible only if a complete biocompatibility is achieved. On the other hand, the exhaustive study of the thermal processes that take place during the irradiation of the nanoparticles resulted in a series of models that allow the determination of the photothermal efficiency of the nanoparticles and also the visualization of the temperature evolution, both at nanoscale and at macroscale, as a function of the optical and thermal parameters of the system. The proposal of new ways of irradiation and the development of devices oriented to study the mechanical effects that take place during the low frequency and low power pulsing irradiation of gold nanoparticles has led to the detection of pressure waves associated to thermoelastic expansion processes, opening the door to the development of hyperthermia therapies that combine the cellular death due to the heating with the death derived from the described mechanical phenomena.

Three-way catalysts: past, present and future

In this article, the past and the state-of-the-art in Three-Way Catalyst (TWC) technology are reviewed. The main chemical reactions occurring in a gasoline engine are discussed and also the main reactions taking place in a TWC placed in the tailpipe, namely CO and hydrocarbons oxidation and nitrogen oxides reduction to molecular nitrogen. The main components of a TWC (substrates, noble metals and cerium oxides) and their role in the different chemical reactions occurring in a TWC are described. Finally, the problem of diesel vehicles gas aftertratment is described, and the current state-of-the art in catalytic converters for these vehicles are commented.

On the Dynamics of Mining Operations in Open Pit Mines

In this paper, mining dynamics is defined as the relationship between the mining rate and movement of mining operations conducted on the benches of a surface mine. This relationship describes the intensity of the pit development in space, in order to meet ore demand at the mill over time. Meeting the mill ore demand is a key factor in optimizing production scheduling in surface mines. Displacement velocity of mining operations within cutbacks, or independent pit units, is introduced in the context of long-term mine planning. Displacement velocity allows the place and time of transition of the mining operations from one independent pit unit to another to be determined as the condition for meeting the mill ore demand. An application using data from Mt Keith Nickel Operations in Western Australia is used to elaborate on the methods presented.

Blast fragmentation modelling for a green field open cut gold deposit

This paper outlines the methodology of blast fragmentation modeling undertaken for a green field feasibility study at the Riska gold deposit in Indonesia. The favoured milling process for the feasibility study was dump leaching,with no crushing of the ore material extracted from the pit. For this reason,blast fragmentation was a critical issue to be addressed by the study. A range of blast designs were considered with bench heights and blasthole diameters ranging from 4 m to 7 m and 76 mm to 102 mm respectively. Rock mass data was obtained from 19 diamond drill cores across the deposit (total drill length approximately 2200 m). Intact rock strength was estimated from qualitative strength descriptors,while the in situ block size distribution of the rock mass was estimated from the Rock Quality Designation (RQD) of the core.