In Vitro and In Vivo Comparison of Random versus Site-Specific Conjugation of Bifunctional Chelating Agents to the CD33-Binding Antibody for Use in Alpha- and Beta-Radioimmunotherapy.

Radiometal chelator conjugation is a cornerstone of radioimmunotherapy (RIT). Continued interest in selective placement of chelators remains an active topic of discussion in the field. With several simple site-specific methods being recently reported, it was of interest to investigate the benefits and potential drawbacks of the site-specific method with a full comparison to a more typical random conjugation method that is currently utilized in clinical applications.

Theranostic Potential of the iPSMA-Bombesin Radioligand in Patients with Metastatic Prostate Cancer: A Pilot Study.

Prostate cancer (PC) represents the second most diagnosed form of cancer in men on a global scale. Despite the theranostic efficacy of prostate-specific membrane antigen (PSMA) radioligands, there is a spectrum of PC disease in which PSMA expression is low or absent. The gastrin-releasing peptide receptor (GRPR), also known as the bombesin type 2 receptor, has been identified as a target in both the early and advanced stages of PC.

Tb production by cyclotrons: what level of Gd enrichment allows clinical applications?

Background: Tb represents a potentially useful radionuclide for diagnostic medical applications, but its production remains a challenging problem, in spite of the fact that many production routes have been already investigated and tested. A recent experimental campaign, conducted with low-energy proton beams impinging on a Gd target with 91.9% enrichment, demonstrated a significant co-production of Tb, a contaminant of great concern since its half-life is comparable to that of Tb and its high-energy γ emissions severely impact on the dose released and on the quality of the SPECT images.

Molecularly Targeted Lanthanide Nanoparticles for Cancer Theranostic Applications.

Injectable colloidal solutions of lanthanide oxides (nanoparticles between 10 and 100 nm in size) have demonstrated high biocompatibility and no toxicity when the nanoparticulate units are functionalized with specific biomolecules that molecularly target various proteins in the tumor microenvironment. Among the proteins successfully targeted by functionalized lanthanide nanoparticles are folic receptors, fibroblast activation protein (FAP), gastrin-releasing peptide receptor (GRP-R), prostate-specific membrane antigen (PSMA), and integrins associated with tumor neovasculature. Lutetium, samarium, europium, holmium, and terbium, either as lanthanide oxide nanoparticles or as nanoparticles doped with lanthanide ions, have demonstrated their theranostic potential through their ability to generate molecular images by magnetic resonance, nuclear, optical, or computed tomography imaging.

Nuclear Cross-Section of Proton-Induced Reactions on Enriched Ti Targets for the Production of Theranostic Sc Radionuclide, Sc, Sc, Sc, Sc, and V.

The cross-sections of the Ti(p,x)Sc, Sc, Sc, Sc, Sc, and V nuclear reactions were measured from 18 to 70 MeV, with particular attention to Sc production. Enriched Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility.

Development and Characterization of Tc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer.

Previously, we demonstrated that the Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) cell uptake and tumor radiation doses compared to Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a Tc-/Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel Tc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified.

The innovative Mn for positron emission tomography (PET) imaging: Production cross section modeling and dosimetric evaluation.

Background: Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn can be neurotoxic. Mn may be a valid alternative as positron emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn , thus reducing its toxicity.

IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for Drug Delivery.

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000's, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled ' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals.

A Review on the Current State and Future Perspectives of [Tc]Tc-Housed PSMA-i in Prostate Cancer.

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.

Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations.

: The [Tc][Tc(N)(PNP)] system, where PNP is a bisphosphinoamine, is an interesting platform for the development of tumor '' agents. Here, we compared the reactivity and impact of three [Tc(N)(PNP)] frameworks on the stability, receptor targeting properties, biodistribution, and metabolism of the corresponding [Tc][Tc(N)(PNP)]-tagged cRGDfK peptide to determine the best performing agent and to select the framework useful for the preparation of [Tc][Tc(N)(PNP)]-housing molecular targeting agents. cRGDfK pentapeptide was conjugated to Cys and labeled with each [Tc(N)(PNP)] framework.

Ac-rHDL Nanoparticles: A Potential Agent for Targeted Alpha-Particle Therapy of Tumors Overexpressing SR-BI Proteins.

Actinium-225 and other alpha-particle-emitting radionuclides have shown high potential for cancer treatment. Reconstituted high-density lipoproteins (rHDL) specifically recognize the scavenger receptor B type I (SR-BI) overexpressed in several types of cancer cells. Furthermore, after rHDL-SR-BI recognition, the rHDL content is injected into the cell cytoplasm.

A feasibility study of the therapeutic application of a mixture of Cu radioisotopes produced by cyclotrons with proton irradiation.

Purpose: Cu and Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of Cu is already well established. However, the production of Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular Cu.

Design, Synthesis and Preclinical Assessment of Tc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging.

Fibroblast activation protein (FAP) is expressed in the microenvironment of most human epithelial tumors. Ga-labeled FAP inhibitors based on the cyanopyrrolidine structure (FAPI) are currently used for the detection of the tumor microenvironment by PET imaging. This research aimed to design, synthesize and preclinically evaluate a new FAP inhibitor radiopharmaceutical based on the Tc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (Tc-iFAP) structure for SPECT imaging.

Preclinical dosimetric studies of Lu-scFvD2B and comparison with Lu-PSMA-617 and Lu-iPSMA endoradiotherapeutic agents.

Purpose: Internal dosimetry has become a very important tool to evaluate the risks and benefits of new endoradiotherapeutic agents. Nowadays, some of the most successful targeted radionuclide therapy (TRT) agents are Lu-DOTA conjugates based on low molecular weight (LMW) Glu-ureido PSMA inhibitors. It has, however, been demonstrated that the DOTA chelating moiety reduces the internalization of the LMW-PSMA agent and its radiation dose to the tumor.

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives.

The zinc dithiocarbamates functionalized with folic acid and were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (). Zinc complexes and show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes or and the cation -[Tc(HO)(CO)], in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes -[Tc(CO)(SS)(P)] bioconjugated to folic acid ( and ).

Bioconjugated technetium carbonyls by transmetalation reaction with zinc derivatives.

The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[Tc(HO)(CO)] has been studied as a new strategy to bind biomolecules to this radionuclide for preparing radiopharmaceuticals with high molar activity. All complexes were obtained in high yields by heating at moderate temperatures and without subsequent purification. The chemical identity was ascertained by HPLC comparison with the homologous rhenium complexes.

Drug Delivery Systems-Based Dendrimers and Polymer Micelles for Nuclear Diagnosis and Therapy.

Polymeric nanoparticles encompass micelles and dendrimers. They are used for improving or controlling the action of the loaded therapy or imaging agent, including radionuclides. Some radionuclides possess properties appropriate for simultaneous imaging and therapy of a disease and are therefore called theranostic.

Development of Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen.

The clinical translation of theranostic Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a Lu-labelled agent with a better pharmacokinetic profile than those previously reported.

Radiolabeled Protein-inhibitor Peptides with Rapid Clinical Translation towards Imaging and Therapy.

Protein interactions are the basis for the biological functioning of human beings. However, many of these interactions are also responsible for diseases, including cancer. Synthetic inhibitors of protein interactions based on small molecules are widely investigated in medicinal chemistry.

Lu-Bombesin-PLGA (paclitaxel): A targeted controlled-release nanomedicine for bimodal therapy of breast cancer.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in >75% of breast cancers. Lu-Bombesin (Lu-BN) has demonstrated the ability to target GRPr and facilitate efficient delivery of therapeutic radiation doses to malignant cells. Poly(d,l‑lactide‑co‑glycolide) acid (PLGA) nanoparticles can work as smart drug controlled-release systems activated through pH changes.

Radiation effective dose assessment of [Mn]- and [Mn]-chloride.

In order to establish the potential of [Mn]Cl as safe PET brain tracers, the radiation effective dose (ED) of [Mn]- and [Mn]-chloride has been assessed by using biokinetic models in anthropomorphic phantoms. Results showed that [Mn]-chloride releases one hundred thirty times more radiation dose (ED = 1.35 mSv/MBq) than [Mn]-chloride (ED = 1.

Internal radiation dose assessment of radiopharmaceuticals prepared with cyclotron-produced Tc.

Purpose: Technetium-99m ( Tc) is the radioisotope most widely used in diagnostic nuclear medicine. It is readily available from Mo/ Tc generators as the β decay product of the Mo (T  = 66 h) parent nuclide. This latter is obtained as a fission product in nuclear reactors by neutron-induced reactions on highly enriched uranium.

[Tc][Tc(N)(DASD)(PNP n)] (DASD = 1,4-Dioxa-8-azaspiro[4,5]decandithiocarbamate, PNP n = Bisphosphinoamine) for Myocardial Imaging: Synthesis, Pharmacological and Pharmacokinetic Studies.

[Tc][TcN-DBODC(5) is the lead candidate of a class of cationic complexes proposed as myocardial imaging agents (MPIAs). Phase I clinical studies showed that its clinical properties were comparable to those of the commercially available agents. Thus, modification of [Tc]TcN-DBODC(5), directed to obtain an ideal myocardial imaging without interference from the adjacent organ activities, is desirable.