Applications of “Hot” and “Cold” Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging

Abstract

The applications of coordination chemistry to molecular imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in molecular imaging have mainly been focused on compounds with aliphatic backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomography) using (64) CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compound entered clinical trials in the US and the UK during the first decade of the 21(st) century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to aromatic groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliphatic ATSM complexes, allows the stabilization of a number of imaging probes, with special interest in "cold" and "hot" Cu(II) and Ga(III) derivatives for PET applications and (111) In(III) derivatives for SPECT (single-photon emission computed tomography) applications, whilst Zn(II) derivatives display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.

Synthesis, Radiolabelling and In Vitro Imaging of Multifunctional Nanoceramics

“…The radioactive tracers [ 64 Cu]Cu(OAc) 2 and [ 64 Cu]Cu[ATSM]/A display appreciable hypoxia selectivity versus normoxia, and can be used for the delineation of tumour cells deprived of oxygen, as well as ischemic and hypoxic myocardium . The metal complex was first used in clinical trials in 2000 as an imaging agent for tumor hypoxia . Ga[ATSM]/A is a new system that so far has not shown sufficient kinetic stability in the radiolabelled form ,,.…”

“…[48] The metal complex was first used in clinical trials in 2000 as an imaging agent for tumor hypoxia. [49] Ga[ATSM]/A is a new system that so far has not shown sufficient kinetic stability in the radiolabelled form. [50,51,52] We and others [31] have also designed and developed new methods to incorporate radioisotopes to chelator-free nanoparticles, and characterised emerging nanomedicines in vitro and in vivo.…”

Behavior of Supramolecular Assemblies of Radiometal-Filled and Fluorescent Carbon Nanocapsules In Vitro and In Vivo

“…Any loss of copper will lead to the biodistribution being dominated by biological copper metabolic pathways. 3,4 Ligands such as cross-bridged cyclams 5 and cryptands 6 are, to date, the most promising. Here, we report the potential of modified single-walled nanotubes (SWNTs) to both contain and deliver radiocopper in an aqueous environment as a superior alternative to chelators.…”

Radio- and nano-chemistry of aqueous Ga(iii) ions anchored onto graphene oxide-modified complexes

“…29 Interestingly, complex 3 shows a stronger fluorescence emission intensity under hypoxic conditions (ESI †) consistent with previous findings on the hypoxia selectivity of this family of gallium compounds supported on rigid N/S ligand frameworks. 29,30 Cellular cytotoxicity investigations performed on the non-radiolabelled compounds in PC-3 and EMT-6 cancer cell lines (ESI †) confirmed the low toxicity of the synthesised graphene oxide nanocomposites in these particular cell lines, being suitable candidates as synthetic scaffolds for anchoring imaging agents. Crystal violet assays were carried out in the PC-3 and EMT-6 cancer cell lines.…”

“…1 and ESI, † was selected for the potential enhancement of the GO-based radionanocomposite properties as related/similar compounds have shown inherent hypoxia selectivity. 29,30 In this case, a free amino group incorporated in the ligand framework at the exocyclic N(H) in 2 opens the way for future straightforward bioconjugations. The synthesis of gallium bis(thiosemicarbazonato) complex was additionally carried out: the non-radiolabelled and radiolabelled gallium(III) complexes (3 and [ 68 Ga]-3) were prepared via an optimised, transmetallation protocol from the corresponding zinc complex precursor (2) allowing for a reduction in reaction times and increased reaction yields (Tables S3 and S4, ESI †).…”