The application of nanomaterials (NMs) in biomedicine is increasing rapidly and offers excellent prospects for the development of new non-invasive strategies for the diagnosis and treatment of cancer. In this review, we provide a brief description of cancer pathology and the characteristics that are important for tumor-targeted NM design, followed by an overview of the different types of NMs explored to date, covering synthetic aspects and approaches explored for their application in unimodal and multimodal imaging, diagnosis and therapy. Significant synthetic advances now allow for the preparation of NMs with highly controlled geometry, surface charge, physicochemical properties, and the decoration of their surfaces with polymers and bioactive molecules in order to improve biocompatibility and to achieve active targeting. This is stimulating the development of a diverse range of nanometer-sized objects that can recognize cancer tissue, enabling visualization of tumors, delivery of anti-cancer drugs and/or the destruction of tumors by different therapeutic techniques.

Keywords: Cluster compounds / Polyoxometalates / Metalloprotein mimics / Enzymes / Inhibitors / Bioinorganic chemistryPolyoxometalates (POMs) are inorganic cluster compounds that have been shown to possess a number of pharmacological properties, including antidiabetic, antibacterial, antiprotozoal, antiviral and anticancer activities. Their molecular mechanism of action is largely unknown. However, several studies indicate that many of their activities may be due to the inhibition of enzymes, in particular, of those enzymes that are accessible from the extracellular space and do not require the penetration of cell membranes. In this review, we describe the recent progress in the preparation and optimiza-[a] Institute

The three new dioxo-tetraazamacrocyclic ligands with a fused, very rigid bispidine (3,7-diazabicyclo[3.3.1]nonane) group connecting the two tertiary amine donors, and ethyl, propyl, or benzene groups connecting the two amide donors are highly preorganized and lead to very stable, uncharged Cu(II) complexes. Solution spectroscopy and solid state structures indicate that these are square pyramidal with a solvent molecule occupying the apical position. Cyclic voltammetry defines a reversible Cu(III/II) couple and a strongly negative irreversible Cu(II/I) couple (ca. -2 V vs Fc/Fc(+)), indicating that the Cu(II) complexes are very stable in solution. This is supported by superoxide dismutase (SOD) and human serum challenge experiments as well as the biodistribution, which all show that the benzene-based ligand has the highest in vitro and in vivo stability and that this was expected on the basis of the macrocycle ring size and shape and the highest degree of preorganization. This ligand is easy to functionalize for a possible coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging).

The development of novel radiopharmaceuticals for imaging and therapy requires rapid and reproducible in vitro assays to estimate their in vivo stability and dissociation behaviour. In general, these assays should allow an assessment of dissociation of the radiometal from the radiopharmaceuticals. In the past, a series of chemical challenges has been widely used to estimate complex stability under non-physiological and non-radiotracer conditions providing limited information on the potential in vivo stability. In contrast, we herein present two independent in vitro methods to measure the stability of radiocopper complexes under physiologically relevant conditions. To quantify and compare the dissociation behaviour of six wellestablished 64 Cu chelates (TETA, DOTA, NOTA, Cyclam, diamSar and EDTA), we combine a protein challenge experiment considering the stability of the chelates in the presence of human superoxide dismutase with a serum assay measuring the stability of the radiometal complexes against human serum. Unlike HPLC-and TLC-based analytical techniques, we describe the stability assessments by standard gel electrophoretic procedures, which allow a timesaving workflow as well as simultaneous processing and comparative analysis of a variety of copper-containing chelates and conjugates thereof. [ 64 Cu]Cu-diamSar is the most kinetically stable ligand, whereas the acyclic chelate [ 64 Cu]Cu-EDTA underwent an almost complete complex dissociation. Furthermore, kinetic stability studies in human serum carried out for [ 64 Cu]Cu-diamSar revealed no substantial time-dependent influence under commonly used labelling conditions. Both described assays, the protein challenge experiment as well as the serum stability assay, are not restricted to radiocopper, but may be adopted for other radiometal containing chelates.

1,4,7‐Triazacyclononane (TACN)‐based mono‐ and poly‐nuclear metal complexes have found extensive use as biological mimics for understanding the structural and operational aspects of complex natural systems. Their coordination flexibility has also provided researchers access to a vast library of radiometal‐binding motifs that display excellent thermodynamic stability and kinetic inertness upon metal complexation. Synthetic modification of the TACN backbone has yielded ligands that can form metal complexes with coordination geometries well suited for these applications. In particular, Leone Spiccia's research has played a significant role in accelerating the progress in these two fields. With a focus on his contributions to the topics of biomimicry and radiopharmaceuticals, this Minireview uses relevant examples to put in perspective the utility of macrocyclic coordination chemistry for biological inorganic chemistry applications.

[44/47Sc]­Sc3+, [68Ga]­Ga3+, and [111In]­In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H3glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc­(glyox)­(H2O)] and [In­(glyox)­(H2O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10–5 M) and indium-111 (RCY > 99%, [L] = 10–8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [44Sc]­ScCl3 (RCY > 99%, [L] = 10–6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [68Ga]­Ga­(glyox) and [111In]­In­(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H3glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc­(glyox) in addition to the in-batch UV–vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc­(glyox) and Ga­(glyox), confirming the viability of the cells. These initial investigations suggest H3glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.

The Cu(II) complex of H(4)TETP (H(4)TETP = 1,4,8,11-tetraazatetradecane-1,4,8,11-tetrapropionic acid) is five-coordinate with a distorted square-pyramidal structure (τ = 0.45; i.e. the geometry is nearly half-way between square-pyramidal and trigonal-bipyramidal) and a relatively long Cu-N and a short Cu-O bond; the comparison between powder and solution electronic spectroscopy, the frozen solution EPR spectrum and ligand-field-based calculations (angular overlap model, AOM) indicate that the solution and solid state structures are very similar, i.e. the complex has a relatively low "in-plane" and a significant axial ligand field with a d(x(2)-y(2)) ground state. The ligand-enforced structure is therefore shown to lead to a partially quenched Jahn-Teller distortion and to a relatively low complex stability, lower than with the corresponding acetate-derived ligand H(4)TETA. This is confirmed by potentiometric titration and by the biodistribution with (64)Cu-labeled ligands which show that the uptake in the liver is significantly increased with the H(4)TETP-based system.

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.