155Tb production by cyclotrons: what level of 155Gd enrichment allows clinical applications?

BACKGROUND: 155Tb 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 155Gd target with 91.9% enrichment, demonstrated a significant co-production of 156gTb, a contaminant of great concern since its half-life is comparable to that of 155Tb and its high-energy γ emissions severely impact on the dose released and on the quality of the SPECT images. In the present investigation, the isotopic purity of the enriched 155Gd target necessary to minimize the co-production of contaminant radioisotopes, in particular 156gTb, was explored using various computational simulations. RESULTS: Starting from the recent experimental data obtained with a 91.9% 155Gd-enriched target, the co-production of other Tb radioisotopes besides 155Tb has been theoretically evaluated using the Talys code. It was found that 156Gd, with an isotopic content of 5.87%, was the principal contributor to the co-production of 156gTb. The analysis also demonstrated that the maximum amount of 156Gd admissible for 155Tb production with a radionuclidic purity higher than 99% was 1%. A less stringent condition was obtained through computational dosimetry analysis, suggesting that a 2% content of 156Gd in the target can be tolerated to limit the dose increase to the patient below the 10% limit. Moreover, it has been demonstrated that the imaging properties of the produced 155Tb are not severely affected by this level of impurity in the target. CONCLUSIONS: 155Tb can be produced with a quality suitable for medical applications using low-energy proton beams and 155Gd-enriched targets, if the 156Gd impurity content does not exceed 2%. Under these conditions, the dose increase due to the presence of contaminant radioisotopes remains below the 10% limit and good quality images, comparable to those of 111In, are guaranteed.

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. Likewise, photodynamic therapy, targeted radiotherapy (neutron-activated nanoparticles), drug delivery guidance, and image-guided tumor therapy are some examples of their potential therapeutic applications. This review provides an overview of cancer theranostics based on lanthanide nanoparticles coated with specific peptides, ligands, and proteins targeting the tumor microenvironment.

The innovative 52g 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 Mn2 + can be neurotoxic. 52g 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 Mn2 + , thus reducing its toxicity. Recently, the reaction n a t $^{nat}$ V(α,x)52g Mn has been proposed as a possible alternative to the standard n a t $^{nat}$ Cr(p,x)52g Mn one, but improvements in the modeling were needed to better compare the two production routes. PURPOSE: This work focuses on the development of precise simulations and models to compare the 52g Mn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co-produced radioactive contaminants, versus pure 52g MnCl2 . METHODS: The nuclear code Talys has been employed to optimize the n a t $^{nat}$ V(α,x)52g Mn cross section by tuning the parameters of the microscopic level densities. Thick-target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of [ x x $^{xx}$ Mn]Cl2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52g MnCl2 in normal mice. At the end, the yield of x x $^{xx}$ Mn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation. RESULTS: Good agreement was obtained between cross-section calculations and measurements. The comparison of the two reaction channels suggests that n a t $^{nat}$ V(α,x)52g Mn leads to higher yield and higher purity, resulting in more favorable radiation dosimetry for patients. CONCLUSIONS: Both n a t $^{nat}$ V(α,x) and n a t $^{nat}$ Cr(p,x) production routes provide clinically acceptable 52g MnCl2 for PET imaging. However, the n a t $^{nat}$ V(α,x)52g Mn reaction provides a DI systematically lower than the one obtainable with n a t $^{nat}$ Cr(p,x)52g Mn and a longer time window in which it can be used clinically (RNP ≥ 99%).

Development and Characterization of 99mTc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer.

Previously, we demonstrated that the 177Lu-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 177Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a 99mTc-/177Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel 99mTc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified. Then, two HYNIC derivatives, HYNIC-Gly-Gly-Cys-NH2 (HYNIC-GGC) and succinimidyl-HYNIC (S-HYNIC), were used to conjugate the scFvD2B-Tag and scFvD2B isoforms, respectively. Subsequently, chemical characterization, immunoreactivity tests (affinity and specificity), radiochemical purity tests, stability tests in human serum, cellular uptake and internalization in LNCaP(+), PC3-PIP(++) or PC3(-) PCa cells of the resulting unlabeled HYNIC-scFvD2B conjugates (HscFv) and 99mTc-HscFv agents were performed. The results showed that incorporating HYNIC as a chelator did not affect the affinity, specificity or stability of scFvD2B. After purification, the radiochemical purity of 99mTc-HscFv radiotracers was greater than 95%. A two-sample t-test of 99mTc-HscFv1 and 99mTc-HscFv1 uptake in PC3-PIP vs. PC3 showed a p-value < 0.001, indicating that the PSMA receptor interaction of 99mTc-HscFv agents was statistically significantly higher in PSMA-positive cells than in the negative controls. In conclusion, the results of this research warrant further preclinical studies to determine whether the in vivo pharmacokinetics and tumor uptake of 99mTc-HscFv still offer sufficient advantages over HYNIC-conjugated peptides to be considered for SPECT/PSMA imaging.

Nuclear Cross-Section of Proton-Induced Reactions on Enriched 48Ti Targets for the Production of Theranostic 47Sc Radionuclide, 46cSc, 44mSc, 44gSc, 43Sc, and 48V.

The cross-sections of the 48Ti(p,x)47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V nuclear reactions were measured from 18 to 70 MeV, with particular attention to 47Sc production. Enriched 48Ti 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. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: 47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V. 47Sc production was also discussed, considering yield and radionuclidic purity, for different 47Sc production scenarios.

A Review on the Current State and Future Perspectives of [99mTc]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.g., 68Ga, 64Cu, 177Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, 99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on 99mTc outscores that of PET agents and 99mTc-PSMA SPECT/CT may be a cost-effective alternative for 68Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [99mTc]Tc-tagged PSMA agents with particular attention to [99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [68Ga]Ga-PSMA11.

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 'Nanosized delivery systems for radiopharmaceuticals' 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. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor.

225Ac-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. This research aimed to prepare a targeted 225Ac-delivering nanosystem by encapsulating the radionuclide into rHDL nanoparticles. The synthesis of rHDL was performed in two steps using the microfluidic synthesis method for the subsequent encapsulation of 225Ac, previously complexed to a lipophilic molecule (225Ac-DOTA-benzene-p-SCN, CLog P = 3.42). The nanosystem (13 nm particle size) showed a radiochemical purity higher than 99% and stability in human serum. In vitro studies in HEP-G2 and PC-3 cancer cells (SR-BI positive) demonstrated that 225Ac was successfully internalized into the cytoplasm of cells, delivering high radiation doses to cell nuclei (107 Gy to PC-3 and 161 Gy to HEP-G2 nuclei at 24 h), resulting in a significant decrease in cell viability down to 3.22 ± 0.72% for the PC-3 and to 1.79 ± 0.23% for HEP-G2 at 192 h after 225Ac-rHDL treatment. After intratumoral 225Ac-rHDL administration in mice bearing HEP-G2 tumors, the biokinetic profile showed significant retention of radioactivity in the tumor masses (90.16 ± 2.52% of the injected activity), which generated ablative radiation doses (649 Gy/MBq). The results demonstrated adequate properties of rHDL as a stable carrier for selective deposition of 225Ac within cancer cells overexpressing SR-BI. The results obtained in this research justify further preclinical studies, designed to evaluate the therapeutic efficacy of the 225Ac-rHDL system for targeted alpha-particle therapy of tumors that overexpress the SR-BI receptor.

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

Background: The [99mTc][Tc(N)(PNP)] system, where PNP is a bisphosphinoamine, is an interesting platform for the development of tumor 'receptor-specific' 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 [99mTc][Tc(N)(PNP)]-tagged cRGDfK peptide to determine the best performing agent and to select the framework useful for the preparation of [99mTc][Tc(N)(PNP)]-housing molecular targeting agents. Methods: cRGDfK pentapeptide was conjugated to Cys and labeled with each [Tc(N)(PNP)] framework. Radioconjugates were assessed for their lipophilicity, stability, in vitro and in vivo targeting properties, and performance. Results: All compounds were equally synthetically accessible and easy to purify (RCY ≥ 95%). The main influences of the synthon on the targeting peptide were observed in in vitro cell binding and in vivo. Conclusions: The variation in the substituents on the phosphorus atoms of the PNP enables a fine tuning of the biological features of the radioconjugates. ws[99mTc][Tc(N)(PNP3OH)]- and [99mTc][Tc(N)(PNP3)]- are better performing synthons in terms of labeling efficiency and in vivo performance than the [99mTc][Tc(N)(PNP43)] framework and are therefore more suitable for further radiopharmaceutical purposes. Furthermore, the good labeling properties of the ws[99mTc][Tc(N)(PNP3OH)]- framework can be exploited to extend this technology to the labeling of temperature-sensitive biomolecules suitable for SPECT imaging.

A feasibility study of the therapeutic application of a mixture of 67/64 Cu radioisotopes produced by cyclotrons with proton irradiation.

PURPOSE: 64 Cu and 67 Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64 Cu is already well established. However, the production of 67 Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular 64 Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64 Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem. METHODS: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) 70 Zn in the energy range 70-45 MeV; (ii) 68 Zn in the energy range 70-35 MeV; (iii) a combination of 70 Zn (70-55 MeV) and 68 Zn (55-35 MeV). The contribution of each copper radioisotope to the human-absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64 CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed 67/64 Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by 67 Cu and 64 Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity. RESULTS: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67 CuCl2 are higher than those of 64 CuCl2 . Absorbed dose values per unit of administered activity of 67/64 CuCl2 mixture increase with time after the EOB because the amount of 67 Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67 Cu is greater than that of 64 Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64 Cu administered activity must be about five times higher than that of 67 Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the 64 CuCl2 -absorbed dose to healthy organs will reach higher values than those of 67 CuCl2 . The supplemental activity of the 67/64 CuCl2 mixture, required to get the same tumor-absorbed dose produced by 67 CuCl2 , triggers a dose increment (DI) in healthy organs. The waiting time post-EOB necessary to keep this DI below 10% (t10% ) depends on the irradiation methods employed for the production of the 67/64 CuCl2 mixture. CONCLUSIONS: A mixture of cyclotron produced 67/64 Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with pure 67 Cu. Irradiation of a 70 Zn+68 Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t10% (10 h), and less than 1% of 61 Cu and 60 Cu impurities.

Design, Synthesis and Preclinical Assessment of 99mTc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging.

Fibroblast activation protein (FAP) is expressed in the microenvironment of most human epithelial tumors. 68Ga-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 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-iFAP) structure for SPECT imaging. Molecular docking for affinity calculations was performed using the AutoDock software. The chemical synthesis was based on a series of coupling reactions of 6-hidrazinylnicotinic acid (HYNIC) and D-alanine to a boronic acid derivative. The iFAP was prepared as a lyophilized formulation based on EDDA/SnCl2 for labeling with 99mTc. The radiochemical purity (R.P.) was verified via ITLC-SG and reversed-phase radio-HPLC. The stability in human serum was evaluated by size-exclusion HPLC. In vitro cell uptake was assessed using N30 stromal endometrial cells (FAP positive) and human fibroblasts (FAP negative). Biodistribution and tumor uptake were determined in Hep-G2 tumor-bearing nude mice, from which images were acquired using a micro-SPECT/CT. The iFAP ligand (Ki = 0.536 nm, AutoDock affinity), characterized by UV-Vis, FT-IR, 1H-NMR and UPLC-mass spectroscopies, was synthesized with a chemical purity of 92%. The 99mTc-iFAP was obtained with a R.P. >98%. In vitro and in vivo studies indicated high radiotracer stability in human serum (>95% at 24 h), specific recognition for FAP, high tumor uptake (7.05 ± 1.13% ID/g at 30 min) and fast kidney elimination. The results found in this research justify additional dosimetric and clinical studies to establish the sensitivity and specificity of the 99mTc-iFAP.

Preclinical dosimetric studies of 177 Lu-scFvD2B and comparison with 177 Lu-PSMA-617 and 177 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 177 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. Previously, we reported that 177 Lu-scFvD2B, an antibody-based construct, demonstrated statistically significant higher cell uptake and internalization in LNCaP prostate cancer (PCa) cells (PSMA-positive) when compared to the LMW-PSMA agents, 177 Lu-PSMA-617 and 177 Lu-iPSMA, two of the endoradiotherapeutic agents which currently are the most used in PCa therapy. The aim of this study is to estimate the preclinical 177 Lu-scFvD2B organ and tumor-absorbed doses, and to compare the values with those of 177 Lu-PSMA-617 and 177 Lu-iPSMA. METHODS: 177 Lu-scFvD2B, 177 Lu-PSMA-617, and 177 Lu-iPSMA were prepared and their radiochemical purity determined. Biodistribution studies of each radiopharmaceutical were then carried out in healthy mice to define the main source organs (SO) and to calculate the number of disintegrations in each source organs per unit of administered activity (NSO ). Absorbed dose in the main organs were then calculated for each 177 Lu-conjugate by means of OLINDA/EXM 2.1.1 software, using the calculated NSO for both the adult male and the mouse phantoms as program inputs. Images of mice bearing micropulmonary tumors injected with 177 Lu-conjugates were also obtained. Tumor standardized uptake values (SUV) for the different conjugates, obtained from the 3D SPECT image reconstruction of these mice, were used as the number of disintegrations in a tumor site per unit of administered activity (NT ). The tumor-absorbed dose was calculated using the published electron dose S-values for sphere models with diameters ranging from 10 µm to 10 mm and considering a uniform activity distribution and tumor density equivalent to water density. RESULTS: All 177 Lu-labeled agents were obtained in high yield (98%). Dosimetric studies carried out using mouse phantoms demonstrated that organ absorbed doses of 177 Lu-scFvD2B were from 1.4 to 2.3 times higher than those for 177 Lu-iPSMA and from 1.5 to 2.6 times higher than those for 177 Lu-PSMA-617. However, the 177 Lu-scFvD2B values of tumor-absorbed doses for all investigated tumor sizes were from 2.8 to 3.0 times greater than those calculated for 177 Lu-iPSMA and 177 Lu-PSMA-617, respectively. Moreover, 177 Lu-scFvD2B showed the highest tumor/kidney ratio when compared to those reported for 177 Lu-albumin conjugates. CONCLUSIONS: In this preclinical study, we demonstrated the potential of 177 Lu-scFvD2B as a therapeutic agent for PSMA-expressing tumors, due to its higher tumor-absorbed dose when compared with 177 Lu-LMW agents.

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

The zinc dithiocarbamates functionalized with folic acid 2Zn and 3Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1Zn). Zinc complexes 2Zn and 3Zn 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 2Zn or 3Zn and the cation fac-[99mTc(H2O)3(CO)3]+, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[99mTc(CO)3(SS)(P)] bioconjugated to folic acid (2Tc and 3Tc). In spite of the low solubility of 2Zn and 3Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2Re and 3Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2Tc and 3Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2Tc and 3Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.

Hyaluronan is a natural and effective immunological adjuvant for protein-based vaccines.

One of the main goals of vaccine research is the development of adjuvants that can enhance immune responses and are both safe and biocompatible. We explored the application of the natural polymer hyaluronan (HA) as a promising immunological adjuvant for protein-based vaccines. Chemical conjugation of HA to antigens strongly increased their immunogenicity, reduced booster requirements, and allowed antigen dose sparing. HA-based bioconjugates stimulated robust and long-lasting humoral responses without the addition of other immunostimulatory compounds and proved highly efficient when compared to other adjuvants. Due to its intrinsic biocompatibility, HA allowed the exploitation of different injection routes and did not induce inflammation at the inoculation site. This polymer promoted rapid translocation of the antigen to draining lymph nodes, thus facilitating encounters with antigen-presenting cells. Overall, HA can be regarded as an effective and biocompatible adjuvant to be exploited for the design of a wide variety of vaccines.

Bioconjugated technetium carbonyls by transmetalation reaction with zinc derivatives.

The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[99mTc(H2O)3(CO)3]+ 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. Stability studies in cysteine solution and serum have shown a good stability of the coordination set fac-[99mTc(CO)3(SS)(P)]. Preliminary biological studies of the radiocomplex functionalized with D-(+)-glucosamine with carcinoma cells have been performed.

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. The diversity in core materials and surface modification, as well as radiolabeling strategies, offers multiples possibilities for preparing polymeric nanoparticles using radionuclides. The present review describes different strategies in the preparation of such nanoparticles and their applications in nuclear nanomedicine.

Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen.

The clinical translation of theranostic 177Lu-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 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidneys. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy.

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. The development of radiolabeled protein-inhibitor peptides for molecular imaging and targeted therapy with quickstep towards clinical translation is an interesting and active research field in the radiopharmaceutical sciences. In this article, recent achievements concerning the design, translational research and theranostic applications of structurally-modified small radiopeptides, such as prostate-specific membrane antigen (PSMA) inhibitors, fibroblast activation protein (FAP) inhibitors and antagonists of chemokine-4 receptor ligands (CXCR-4-L), with high affinity for cancer-associated target proteins, are reviewed and discussed.

177Lu-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. 177Lu-Bombesin (177Lu-BN) has demonstrated the ability to target GRPr and facilitate efficient delivery of therapeutic radiation doses to malignant cells. Poly(d,l­lactide­co­glycolide) acid (PLGA) nanoparticles can work as smart drug controlled-release systems activated through pH changes. Considering that paclitaxel (PTX) is a first-line drug for cancer treatment, this work aimed to synthesize and chemically characterize a novel polymeric PTX-loaded nanosystem with grafted 177Lu-BN and to evaluate its performance as a targeted controlled-release nanomedicine for concomitant radiotherapy and chemotherapy of breast cancer. PLGA(PTX) nanoparticles were synthesized using the single emulsification-solvent evaporation method with PVA as a stabilizer in the presence of PTX. Thereafter, the activation of PLGA carboxylic groups for BN attachment through the Lys1-amine group was performed. Results of the chemical characterization by FT-IR, DLS, HPLC and SEM/TEM demonstrated the successful synthesis of BN-PLGA(PTX) with a hydrodynamic diameter of 163.54 ±â€¯33.25 nm. The entrapment efficiency of paclitaxel was 92.8 ±â€¯3.6%. The nanosystem showed an adequate controlled release of the anticancer drug, which increased significantly due to the pH change from neutral (pH = 7.4) to acidic conditions (pH = 5.3). After labeling with 177Lu and purification by ultrafiltration, 177Lu-BN-PLGA(PTX) was obtained with a radiochemical purity of 99 ±â€¯1%. In vitro and in vivo studies using MDA-MB-231 breast cancer cells (GRPr-positive) demonstrated a 177Lu-BN-PLGA(PTX) specific uptake and a significantly higher cytotoxic effect for the radiolabeled nanosystem than the unlabeled BN-PLGA(PTX) nanoparticles. Using a pulmonary micrometastasis MDA-MB-231 model, the added value of 177Lu-BN-PLGA(PTX) for tumor imaging was confirmed. The 177Lu-BN-PLGA(PTX) nanomedicine is suitable as a targeted paclitaxel delivery system with concomitant radiotherapeutic effect for the treatment of GRPr-positive breast cancer.

Radiation effective dose assessment of [51Mn]- and [52Mn]-chloride.

In order to establish the potential of [51/52Mn]Cl2 as safe PET brain tracers, the radiation effective dose (ED) of [51Mn]- and [52Mn]-chloride has been assessed by using biokinetic models in anthropomorphic phantoms. Results showed that [52Mn]-chloride releases one hundred thirty times more radiation dose (ED = 1.35 mSv/MBq) than [51Mn]-chloride (ED = 1.02E-02 mSv/MBq). Although the maximum positron energy of 52Mn allows a PET image resolution similar to that of 18F, activities below 15 MBq should be administered.