Organometallic Chemistry Volume 38

A Review of the Recent Literature

By Ian J. S. Fairlamb, Jason M. Lynam

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-376-2

Contents

Preface Ian J. S. Fairlamb and Jason M. Lynam, v,
New developments in the biomedical chemistry of metal complexes: from small molecules to nanotheranostic design Rory L. Arrowsmith, Sofia I. Pascu and Hubert Smugowski, 1,
Air-stable chiral primary phosphines part (ii) predicting the air-stability of phosphines Beverly Stewart, Anthony Harriman and Lee J. Higham, 36,
Organometallics aspects of C–H bond activation/functionalization Anant R. Kapdi, 48,
Organo-transition metal cluster complexes Mark G. Humphrey and Marie P. Cifuentes, 75,
Alkali/coinage metals – organolithium, organocuprate chemistry Philip J. Harford and Andrew E. H. Wheatley, 91,
Group 2 (Be–Ba) and group 12 (Zn–Hg) Sarah B. J. Dane, Timothy C. King and Dominic S. Wright, 112,

CHAPTER 1

New developments in the biomedical chemistry of metal complexes: from small molecules to nanotheranostic design

Rory L. Arrowsmith, Sofia I. Pascu and Hubert Smugowski

DOI: 10.1039/9781849734868-00001

Introduction

Molecular imaging is a key area for development worldwide. In 2007, this was defined by the Society of Nuclear Medicine as a new interdisciplinary research field, which is at the interface between clinical and preclinical research. This is highlighted by the increasing demand for new imaging probes for specific biological targets. By the end of 2010 more than 3.2 million positron emission tomography (PET) studies have been carried out worldwide. It is widely recognised that optimal disease management is achieved by monitoring patient status before, during and after therapy. PET agents offer high resolution, noninvasive imaging with provision of invaluable diagnosis of biological function at agent concentrations below the pharmacological threshold. There is currently intense interest in the development of new PET agents for imaging a wide range of disease states, and of new drugs for targeted radiotherapy. Drugs containing a radio-nuclide are known as radiopharmaceuticals and can be used for diagnosis and/or therapy. Radiopharmaceuticals chosen for the purpose of diagnosis are usually positron emitters (PET) or gamma emitters (SPECT), whereas therapeutic radiopharmaceuticals usually rely upon β- emission and the Auger effect causing cell death. The choice of radioisotope is also made according to an optimum half-life, which at the same time minimises radiation doses whilst giving sufficient time for synthesis and accumulation. The first pilot trial of PET imaging with 64Cu labeled trastuzumab (Herceptin™, a monoclonal antibody therapeutic) in metastatic breast cancer has been completed in USA in 2010. The choice of radionuclide is dependent on availability, half-life and pharmacokinetics. The isotope 18F (t1/2 109.8 min) is most widely used for imaging applications, especially as 18Fluorodeoxyglucose (18FDG) where there are no limitations owing to the availability of a cyclotron typically needed for radionuclide generation. 18FDG, the “gold standard” for PET imaging tumours/ischaemic myocardium in clinical practice, lacks selectivity and is not universally applicable for imaging all tumours: for example does not image hypoxic tumors per se. Common cyclotron-produced positron emitters such as 11C (t1/2 20.4 min) and 18F (t1/2 109.8 min) have relatively short lives in the context of following relatively slow biological processes such as the accumulation of a labeled monoclonal antibody at a target site in vivo. The most commonly used positron emitting isotopes are 18F, 11C, 13N, 15O, however there is growing interest in use of metal radioisotopes such as 60Cu, 64Cu, 68Ga and 89Zr. The relatively long half-life of 64Cu (t1/2 12.7h) as well as the availability of 68Ga (t1/2 1.13 h) from commercial, portable, generators makes these attractive radioisotopes for PET imaging as these may be used at a site remote from a cyclotron. Imaging with readily available metallic radioisotopes for Single Photon Emission Computed Tomography (SPECT) such as 99mTc(t1/2 6 h) and 111In(t1/2 2.8 days) are by far the most widely used in nuclear medicine on a global scale. The first tomographic device, SPECT, was developed by Kuhl and Edwards in 1963. In this technique detection of the gamma emissions from the radionuclide enable a 3D image to be produced.

Compared with SPECT, PET imaging has the crucial advantage in terms of sensitivity and resolution. Such metallic radionuclides ultimately undergo uptake within cells and while the distribution of these complexes can be determined in vivo at the 1–2 mm range of resolution, little is known of their fate once they are in the intercellular environment. This often hampers the rational design of new diagnostics and therapeutics and ultimately the accurate diagnosis of cancer. There is growing interest in molecular imaging as a non-invasive, highly sensitive methods capable of both early diagnosis and enhancing the understanding of the molecular basis of the disease.

Molecular imaging also combines understanding of molecular function with in vivo imaging. As a result it can report upon disease mechanisms at a cellular and sub-cellular level, as well as the effectiveness and selectivity towards target cells of a specific therapy. Optical imaging, therefore, can be used to follow the uptake of luminescent complexes in both cells and multicellular organisms. In vitro studies not only function as a platform for assessing the suitability of in vivo work and as a drug discovery tool, but also reveal uptake of small molecules into components of the cell via colocalisation studies, which in turn gives an indication of the likely activity that an investigated compound may show in vivo. This in turn enhances the mechanistic understanding of pharmacological processes involved. Recent publications of luminescent metal complexes for which their properties were explored in biological systems, will be highlighted with a strong emphasis on organometallic compounds. Furthermore, in vivo optical imaging can enable detection of tumours on the basis of the selectivity of the imaging probe, with high sensitivity yet without exposure to ionising radiation.

This review will discuss recent advancements of metal complexes for imaging at a cellular level using optical imaging and at an organism level with a focus on multimodality imaging probe design – including those applicable for Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Near Infra-Red (NIR).

Radiopharmaceuticals and multimodality probe design considerations

Radiopharmaceuticals are designed to answer a specific medical need and are based on the knowledge of molecular biology. The first generation of radiopharmaceuticals involved radioactive isotopes aimed at mimicking normal biological processes, such as 2-[18F]-fluoro-2-deoxy-D-glucose and [99mTcO4]2- , which take advantage of higher glucose uptake by cancer cells and mimic iodine uptake by the thyroid, respectively. There is a current trend towards ‘second generation’ radiopharmaceuticals that use a biologically active molecule (BAM), such as a peptide or antibody for specific targeting. Much of the work utilises the labeling of standard chelating agents such as 1,4,7,10-tetraazacyclododecane-N,N’,N”,N”’,-tetraacetic acid (DOTA), triethylenetetramine (TETA) or 1,4,8,11-tetra-azacyclododecane-1,4,8,11-tetraacetic acid (TETA), (Fig. 1) conjugated to a biomolecule (BAM) via a linker and a chelator.

Developments such as the scintillation detector and improved detection technology aided the advancement of PET and SPECT. Despite the scintillation detector remaining virtually the same as the original designed by Anger in 1958, the recent development of the dual-headed gamma camera has had a significant positive effect on PET. Multiple detector systems also achieved better sensitivity and efficiency to enable simultaneous scanning of multiple sections. Combining modalities such as SPECT/ CT, PET/X-ray, PET/MRI, or most frequently PET/CT, allows for better image quality, shorter scanning time and reduced costs. This results in more efficient use of radiopharmaceuticals and more facile recognition of abnormalities. The synergistic combination of PET and MRI holds promise for a successful next generation of dual-modality scanners in medical imaging. These instruments will provide accurate diagnoses thanks to the sensitive and quantifiable signal of PET and the high soft-tissue resolution of MRI. Furthermore, patients will receive reduced radiation doses. However, these new tools require a new class of imaging probes. Therefore, there has recently been increasing interest in the development of dual-modality PET–MRI agents. A standard dual-modal PET-MRI imaging agent was based on a PET isotope and gadolinium. The second generation of dual/ multimodal contrast agents are synthesised using MNPs, having a proven record of biocompatibility and a track record of extensive use in the clinic as MRI contrast agents.

A combination with optical imaging enables both greater understanding of the probe both in cells and in an organism as well as enabling the identification of a tumour; the advantages of the high sensitivity of PET and SPECT, which are not limited by tissue penetration as is optical imaging and presents itself as a very interesting marriage of modalities with potential to improve both scientific knowledge and patient diagnosis and therapy. There are only very few examples in the literature described as dual/multi-modality hybrid nanomaterial used for PET/MRI or PET/MRI/NIRF. The development of PET radiopharmaceuticals labeled with generator-produced PET radionuclides has facilitated greater use of this imaging method in clinical nuclear medicine. For example, the 68Ge/68Ga parent and daughter radionuclides are ideal for this: the half life of 68Ga isotope (68 min) is long enough to achieve the synthesis of a wide variety of radiopharmaceuticals and allow for long data acquisitions, thus enhancing the images quality (vide infra).

There is significant research effort carried out that focuses on finding new theranostic targets, of which is beyond the scope of this review (see Ref. 13 for further information). It can be envisaged that diagnostic radiometals, such as 64Cu, 67Ga, 68Ga, 99mTc for example may be used as future diagnostic agents which are simultaneously amenable for coupling with radio-therapeutic agents such as 177Lu, 90Y, 111In or 212Pb: this could even allow for follow-up treatments provided the chemical properties of the complex are not altered significantly by the change in metal. A diagnostic agent and a therapeutic agent make a ‘theranostic pair’. However, intrinsically cytotoxic agents could also be radiolabelled with another approach being to utilise nanoparticles filled with a drug targeted with a BAM.

Nanomedicines design in imaging applications

Drug delivery methods involving nanomedicines to deliver chemotherapeutics selectively to tumours have been developed in recent years. Succesful examples reported were based on designs that involved coupling drugs to receptor-specific ligands and/or protection of the drug by wrap- ping in a polymer or lyposome with enhanced kinetic stability in vitro. The precise way in which such nanomedicines act within cells remains unknown.

Currently, it is believed that using fluorescence microscopy techniques to image radiolabelled nanomedicines within cells (nanotheranostics) could provide valuable information on the cell behaviour and generate the next generation of contrast agents. Molecular imaging probes can act as diagnostic therapeutics, allowing prediction of response to treatment, dosimetry to be calculated on an individual basis as well as opening the possibility of simultaneous diagnosis and therapy – these theranostics remain a holy grail.

Nanoparticles, such as core-shell silica coated magnetic nanoparticles, gold nanoparticles or quantum dots have become very attractive for biological and medical applications because of the progressions in methods for their synthesis, coatings and analysis. There are various fields within the biosciences where nanoparticles can be very useful, such as tissue engineering; drug, radionuclide and gene delivery; magnetic resonance imaging contrast enhancement; hyperthermia; detoxification of biological fluids; cell separation; tissue repair and magnetofection.

In this review, several examples for the use of nanoparticles involving transition metal or gallium or indium complexes for biomedical applications will be discussed. The major disadvantage of most medical treatments is that they are non-specific. The damaging side effects of therapeutic remedies are caused by their administration: they are not targetted specifically, but employ general distribution systems. This makes direct drug delivery the most promising application of magnetic nanoparticles. Nanoparticles are capable of carrying pharmaceuticals on their surface, and by applying an external magnetic field, the drugs could be directed to the target organ for accurate release. With only 1 in 10,000 immuno-targeted therapies reaching their target, encapsulation within nanoparticles is an attractive form of drug delivery for release into tumours.

Magnetic nanoparticles (MNPs) are of particular interest due to their potential firstly to enable imaging that unlike gadolinium chelates do not rapidly accumulate in the liver, secondly to act as a drug targeting system and thirdly that they can be covered with biocompatible coatings preventing the body’s innate immune system from attacking the drug carriers. Additionally, with the use of an external magnetic field and gradient, it is possible to confine the particles to a designated tissue area. Their use in MRI is still under consideration, however, thanks to new methods of particle synthesis, functionalisation, coatings and analysis, MNPs are even more attractive for all kinds of medical applications in the future. For a recent review on magnetic nanoparticles in theranostics see Ref. 21.

This review emphasises recent developments of luminescent metal complexes (including the gallium, indium and the transition elements) for imaging in vitro and/or in vivo, whilst highlighting multimodal imaging, theranostics (combined ‘all-in-one’ diagnostics and therapeutics) and selected examples from coordination chemistry and nanotechnology covering molecular imaging probe design and testing.

Transition metal-based imaging and therapy probes

Iridium. Iridium(III) complexes are of great interest due to their high phosphorescence, which is as a result of the rapid intersystem crossing from a singlet state to a triplet state due to the 5d electronic configuration. Thanks to the largely ligand-based phosphorescence origin of Ir(III) complexes, the emission wavelength is tuneable, leading to a large array of applications in addition to those in bioimaging. Iridium complexes display large Stokes shifts, long lifetimes and limited photobleaching when com- pared to organic fluorophores. Despite this until recently few iridium(III) complexes were reported to enter cells.

Yu et al. developed two cationic iridium polypyridine complexes in 2008 for cytoplasmic imaging, with low cytotoxicity and with emission in green and red respectively, both displaying internalisation in the cell. Subsequently iridium(III) polypyridine indole complexes showing high cytotoxicity and uptake in cells was demonstrated by Lo et al. in 2009. From 2010 onwards there have been an growing number of iridium(III) complexes developed and entering cells, with increasingly interesting properties and potential within this field. Li et al. developed cationic iridium(III) complexes displaying low cytotoxicity as phosphorescent cytoplasm imaging agents, possessing variable emission properties by way of varying the ligand structure. It was possible to achieve colours from blue to red purely by modifying the pyridine coordinate, with further modifications carried out to attain a NIR probe. The large Stokes shifts, exclusive cytoplasmic uptake and insignificant cytotoxicity bring excellent potential to enhance colocalisation studies; since the tunable properties ensure the choice of a probe with non-overlapping emission. Furthermore, Williams et al. reported an iridium complex, 1 distinguishable from standard organic dyes using a 10 ns delay in laser pulse and acquisition (see Fig. 2). An iridium(III) complex developed by Li et al., could luminesce upon entry to the nucleus by way of a molecular transporter via a reaction-based mechanism. This allows selective and rapid nuclear imaging of live cells with very low cytotoxicity at the concentration required for imaging. Notably, zwitterionic iridium(III) complexes have also been developed and displayed uptake in cells. Furthermore, photoswitchable iridium complexes were designed that can reversibly switch between an open and a closed from when irradiated with light.

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