Maria Paula Cabral Campello

Bisphosphonates as radionuclide carriers for imaging or systemic therapy

Bisphosphonates (BPs), biologically stable analogs of naturally occurring pyrophosphates, became the treatment of choice for pathologic conditions characterized by increased osteoclast-mediated bone resorption, namely Pagets disease, osteoporosis and tumor bone disease. Moreover, the clinical success of BPs is also associated with their use in (99m)Tc-based radiopharmaceuticals for bone imaging. In addition to the successful delivery of (99m)Tc (γ-emitter) to bone, BPs have also been used to deliver β(-)-particle emitting radiometals (e.g.(153)Sm, (186/188)Re) for bone-pain palliation. The main goal of this Review is to update the most recent research efforts toward the synthesis, characterization and biological evaluation of novel BP-containing radiometal complexes and radiohalogenated compounds for diagnostic or therapeutic purposes. The structure and in vivo properties of those compounds will be discussed and compared to the clinically available ones, namely in terms of image quality and therapeutic effect. We will also mention briefly the use of BPs as carriers of multimodal nuclear and optical imaging probes.

URANIUM COMPLEXES WITH HYDROTRIS(PYRAZOLYL) BORATE

Abstract Uranium tetraiodide, prepared by a high temperature method, reacts with two equivalents of KHBpz 3 in CH 2 Cl 2 giving the orange compound [UI 2 (HBpz 3 ) 2 ( 1 ) in 62% yield. The same reaction in THF provides the compound [UI{O(CH 2 ) 4 I}(HBpz 3 ) 2 ] ( 2 ) in 66% isolated yield and arising from ring opening of THF by the uranium tetraiodide. The solid state structure of compound 2 has been determined by X-ray crystallography. Compound 1 reacts with NaOC 2 H 5 in the molar ratio 1 : 1 giving the monoalkoxide [UI(OC 2 H 5 )(HBpz 3 ) 2 ] ( 3 ), which crystallizes in the monoclinic space group P 2 1 / n . X-ray crystallographic analysis shows that in complexes 2 and 3 the uranium is 8-coordinate with the two tridentate HBpz 3 ligands, iodide, and alkoxide displaying square antiprismatic geometry. The solid state structure of the analogous monomeric compound [UCl(OC 2 H 5 )HBpz 3 ) 2 ] ( 4 ) is also described and compared with those of compounds 2 and 3 .

Radiochemical and biological behaviour of 153Sm and 166Ho complexes anchored by a novel bis(methylphosphonate) tetraazamacrocycle

The novel bis(methylphosphonate) 2,2′-[4,10-bis(phosphonomethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl] diacetic acid, trans-H6DO2A2P, has been synthesized and characterized by multinuclear NMR spectroscopy (1H, 13C and 31P). 153Sm and 166Ho complexes with trans-H6DO2A2P have been prepared in high yield using a 1:2 metal to ligand molar ratio at 70 °C, pH 8−9. These complexes are hydrophilic, negatively charged and stable in vitro under physiological solutions, up to 48 h. They present a low plasmatic protein binding and some in vitro hydroxyapatite adsorption, mainly for 166Ho-trans-DO2A2P. Both complexes are stable in vivo, have a fast tissue clearance from most organs and a rapid total excretion from whole animal body. Moderate bone uptake was also observed but the accumulated radioactivity rapidly decreases with time.

Radiolabeled Mannosylated Dextran Derivatives Bearing an NIR-Fluorophore for Sentinel Lymph Node Imaging

Current methods for sentinel lymph node (SLN) mapping involve the use of radioactivity detection with technetium-99m sulfur colloid and/or visually guided identification using a blue dye. To overcome the kinetic variations of two individual imaging agents through the lymphatic system, we report herein on two multifunctional macromolecules, 5a and 6a, that contain a radionuclide ((99m)Tc or (68)Ga) and a near-infrared (NIR) reporter for pre- and/or intraoperative SLN mapping by nuclear and NIR optical imaging techniques. Both bimodal probes are dextran-based polymers (10 kDa) functionalized with pyrazole-diamine (Pz) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating units for labeling with fac-[(99m)Tc(CO)3](+) or (68)Ga(III), respectively, mannose units for receptor targeting, and NIR fluorophore units for optical imaging. The probes allowed a clear visualization of the popliteal node by single-photon emission computed tomography (SPECT/CT) or positron emission tomography (PET/CT), as well as real-time optically guided excision. Biodistribution studies confirmed that both macromolecules present a significant accumulation in the popliteal node (5a: 3.87 ± 0.63% IA/organ; 6a: 1.04 ± 0.26% IA/organ), with minimal spread to other organs. The multifunctional nanoplatforms display a popliteal extraction efficiency >90%, highlighting their potential to be further explored as dual imaging agents.

Novel Heterobimetallic Radiotheranostic: Preparation, Activity, and Biodistribution

A novel RuII(arene) theranostic complex is presented. It is based on a 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid macrocycle bearing a triarylphosphine and can be tracked in vivo by using the γ emission of 153Sm atoms. Notably, the heteroditopic ligand can be selectively metalated with ruthenium at the phosphorus atom despite the presence of other functionalities that are prone to metal coordination. Subsequent labeling with radionuclides such as 153Sm can then be performed easily. The resulting heterobimetallic complex exhibits favorable solubility and stability properties in biologically relevant media. It also shows in vitro cytotoxicity in line with that expected for this type of metallodrug, and is nontoxic to the organism as a whole. As a proof of concept, initial studies in healthy mice were performed to obtain information about the uptake, biodistribution, and excretion of the radiolabeled complex.

Interrogating the Role of Receptor-Mediated Mechanisms: Biological Fate of Peptide-Functionalized Radiolabeled Gold Nanoparticles in Tumor Mice

To get a better insight on the transport mechanism of peptide-conjugated nanoparticles to tumors, we performed in vivo biological studies of bombesin (BBN) peptide functionalized gold nanoparticles (AuNPs) in human prostate tumor bearing mice. Initially, we sought to compare AuNPs with thiol derivatives of acyclic and macrocyclic chelators of DTPA and DOTA types. The DTPA derivatives were unable to provide a stable coordination of (67)Ga, and therefore, the functionalization with the BBN analogues was pursued for the DOTA-containing AuNPs. The DOTA-coated AuNPs were functionalized with BBN[7-14] using a unidentate cysteine group or a bidentate thioctic group to attach the peptide. AuNPs functionalized with thioctic-BBN displayed the highest in vitro cellular internalization (≈ 25%, 15 min) in gastrin releasing peptide (GRP) receptor expressing cancer cells. However, these results fail to translate to in vivo tumor uptake. Biodistribution studies following intravenous (IV) and intraperitoneal (IP) administration of nanoconjugates in tumor bearing mice indicated that the presence of BBN influences to some degree the biological profile of the nanoconstructs. For IV administration, the receptor-mediated pathway appears to be outweighed by the EPR effect. By contrast, in IP administration, it is reasoned that the GRPr-mediated mechanism plays a role in pancreas uptake.

Biophysical characterization and antineoplastic activity of new bis(thiosemicarbazonato) Cu(II) complexes

Aiming to explore alternative mechanisms of cellular uptake and cytotoxicity, we have studied a new family of copper(II) complexes (CuL1-CuL4) with bis(thiosemicarbazone) (BTSC) ligands containing pendant protonable cyclic amines (morpholine and piperidine). Herein, we report on the synthesis and characterization of these new complexes, as well as on their biological performance (cytotoxic activity, cellular uptake, protein and DNA binding), in comparison with the parental CuIIATSM (ATSM=diacetyl-bis(N4-methylthiosemicarbazonate) complex without pendant cyclic amines. The new compounds have been characterized by a range of analytical techniques including ESI-MS, IR spectroscopy, cyclic voltammetry, reverse-phase HPLC and X-ray spectroscopy. In vitro cytotoxicity studies revealed that the copper complexes are cytotoxic, unlike the corresponding ligands, with a similar potency to that of CuATSM. Unlike CuATSM, the new complexes were able to circumvent cisplatin cross-resistance. The presence of the protonable cyclic amines did not lead to an enhancement of the interaction of the complexes with human serum albumin or calf thymus DNA. However, CuL1-CuL4 showed a remarkably augmented cellular uptake compared with CuATSM, as proved by uptake, internalization and externalization studies that were performed using the radioactive congeners 64CuL1-64CuL4. The enhanced cellular uptake of CuL1-CuL4 indicates that this new family of CuIIBTSC complexes deserves to be further evaluated in the design of metallodrugs for cancer theranostics.

Ultrastructural features of cells following incubation with metal complexes using phenanthroline-based ligands: The influence of the metal center

To cite this article: Fernanda Marques, António Pedro Matos, Cristina P. Matos, Isabel Correia, João Costa Pessoa & Maria Paula Campello (2017) Ultrastructural features of cells following incubation with metal complexes using phenanthroline-based ligands: The influence of the metal center, Ultrastructural Pathology, 41:1, 128-129, DOI: 10.1080/01913123.2016.1274124 To link to this article: http://dx.doi.org/10.1080/01913123.2016.1274124