The International Atomic Energy Agency organized a technical meeting at its headquarters in Vienna, Austria, in 2022 that included 17 experts representing 12 countries, whose research spanned the ...development and use of radiolabeled agents for imaging infection. The meeting focused largely on bacterial pathogens. The group discussed and evaluated the advantages and disadvantages of several radiopharmaceuticals, as well as the science driving various imaging approaches. The main objective was to understand why few infection-targeted radiotracers are used in clinical practice despite the urgent need to better characterize bacterial infections. This article summarizes the resulting consensus, at least among the included scientists and countries, on the current status of radiopharmaceutical development for infection imaging. Also included are opinions and recommendations regarding current research standards in this area. This and future International Atomic Energy Agency-sponsored collaborations will advance the goal of providing the medical community with innovative, practical tools for the specific image-based diagnosis of infection.
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 tumour. Previously, we reported that
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
Lu-PSMA-617 and
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
Lu-scFvD2B organ and tumor-absorbed doses and to compare the values with those of
Lu-PSMA-617 and
Lu-iPSMA.
Lu-scFvD2B,
Lu-PSMA-617 and
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 (N
). Absorbed dose in the main organs were then calculated for each
Lu-conjugate by means of OLINDA/EXM 2.1.1 software, using the calculated N
for both the adult male and the mouse phantoms as program inputs. Images of mice bearing micro-pulmonary tumors injected with
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 (N
). 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.
All
Lu-labelled agents were obtained in high yield (98%). Dosimetric studies carried out using mouse phantoms demonstrated that organ absorbed doses of
Lu-scFvD2B were from 1.4 to 2.3 times higher than those for
Lu-iPSMA and from 1.5 to 2.6 times higher than those for
Lu-PSMA-617. However, the
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
Lu-iPSMA and
Lu-PSMA-617, respectively. Moreover,
Lu-scFvD2B showed the highest tumor/kidney ratio when compared to those reported for
Lu-albumin conjugates.
In this preclinical study, we demonstrated the potential of
Lu-scFvD2B as a therapeutic agent for PSMA-expressing tumors, due to its higher tumor-absorbed dose when compared with
Lu-LMW agents.
To characterize quantitatively a single-photon emission computed tomography/computed tomography (SPECT/CT) system through experiments carried out on three-dimensional (3D) printed phantoms with ...bioinspired anatomic geometries.
The sensitivity factor of the SPECT/CT system was obtained after correcting the image quality degrading effects. Photon attenuation correction was carried out through CT attenuation maps. Scattering was corrected by 2 methods. The first method introduces a compensation factor based on photopeak and scatter window widths, which corrects the 3D image during iterative reconstruction algorithm. The second estimates scatter within a photopeak window, which is applied projection by projection before the 3D reconstruction. Partial volume effect was corrected using a calibration method based on spheres of different sizes. A liver-like and a multisphere phantom were designed and 3D printed. SPECT/CT images of the designed phantoms filled with different activities were acquired and quantified. A correlation coefficient based on linear regression was calculated with the aim of comparing proposed methods.
The quantitative SPECT methodology allowed quantification with percentage errors between 1.01-8.96%. The activity measurements validated the 99mTc quantitative performance of the SPECT/CT system. The statistical analysis showed correlation coefficients of 1.00 for the first method and 0.99 for the second one.
The implementation of two alternative methodologies for the calculation of sensitivity factors, allowed to correct image quality degrading effects, satisfying all the suggested stages in imaging quantification. The designed phantoms allowed to assess the characterization of a SPECT/CT system. This study demonstrates the effectiveness of 3D printing to develop bioinspired phantoms for the quantitative assessment of 99mTc imaging.
•A single-photon emission computed tomography was characterized quantitatively .•Three-dimensional printed phantoms with bioinspired geometries were developed .•SPECT images were corrected for attenuation, scattering and partial volume effect .•99mTc was assessed quantitatively with experiments which used 3D printed phantoms .•The followed methodology quantified SPECT images with errors less than 8.96% .
The aim of this study was to characterize the in vivo volumetric distribution of three folate-based biosensors by different imaging modalities (X-ray, fluorescence, Cerenkov luminescence, and ...radioisotopic imaging) through the development of a tridimensional image reconstruction algorithm. The preclinical and multimodal Xtreme imaging system, with a Multimodal Animal Rotation System (MARS), was used to acquire bidimensional images, which were processed to obtain the tridimensional reconstruction. Images of mice at different times (biosensor distribution) were simultaneously obtained from the four imaging modalities. The filtered back projection and inverse Radon transformation were used as main image-processing techniques. The algorithm developed in Matlab was able to calculate the volumetric profiles of
99m
Tc-Folate-Bombesin (radioisotopic image),
177
Lu-Folate-Bombesin (Cerenkov image), and FolateRSense™ 680 (fluorescence image) in tumors and kidneys of mice, and no significant differences were detected in the volumetric quantifications among measurement techniques. The imaging tridimensional reconstruction algorithm can be easily extrapolated to different 2D acquisition-type images. This characteristic flexibility of the algorithm developed in this study is a remarkable advantage in comparison to similar reconstruction methods.
Recently, it was demonstrated that doxorubicin (Dox.HCl), a chemotherapeutic agent, could be photoactivated by Cerenkov radiation (CR). The objective of the present work was to develop a multimodal ...chemotherapy-radiotherapy-photodynamic therapeutic system based on reconstituted high-density lipoprotein (rHDL) loaded with Dox.HCl and
Lu-DOTA.
Lu acts as a therapeutic radionuclide and CR source. The system can be visualized by nuclear imaging. Fluorescence microscopy showed that rHDL-Dox specifically recognized cancer cells (T47D) that are positive for SR-B1 receptors. Encapsulated Dox.HCl was released into the cells and produced reactive oxygen species when irradiated with a 450-nm laser (photodynamic effect). The same effect occurred when Dox.HCl was irradiated by
Lu CR. Through
experiments, it was confirmed that the addition of
Lu-DOTA to the rHDL-Dox nanosystem did not affect the specific recognition of SR-B1 receptors expressed in cells, or the cellular internalization of
Lu-DOTA. The toxicity induced by the rHDL-Dox/
Lu nanosystem in cell lines with high (T47D and PC3), poor (H9C2) and almost-zero (human fibroblasts (FB)) expression of SR-B1 was evaluated
and confirmed the synergy of the combined chemotherapy-radiotherapy-photodynamic therapeutic effect; this induced toxicity was proportional to the expression of the SR-B1 receptor on the surface of the cells used. The HDL-Dox/
Lu nanosystem experienced uptake by tumor cells and the liver-both tissues with high expression of SR-B1 receptors-but not by the heart.
Lu CR offered the possibility of imparting photodynamic therapy where laser light could not reach.
C6 rat glioma cells are one of the most aggressive carcinogenic tumors, due to its high mortality rate in human beings and animals. The current treatment for this illness includes surgery, radio and ...chemotherapy, showing relapse in patients treated with those therapies. Since the ozone was found to be an effective bioreactive to inhibit growth of several carcinoma cells in vitro and in vivo. In this research, therapeutic peritoneum insufflation of ozone/oxygen dissolved in the physiological solution of NaCl 0.9% was dosed for fifteen days on different female mice groups in an advanced stage of C6 tumor (n=6). The first of them was the control group which had no treatment, the second group was dosage with oxygen every second day, the third group was dosed with ozone every second day, and finally the fourth group was dosed with ozone dissolved every fifth day. The size of the tumor was higher in both groups dosage by ozone, nevertheless tumor activity measured by microPET was 98% less in the fourth group compared with the control group. That result proves that ozone provokes an increase in the tumor volume even though the decrease of the cell activity. Those results were confirmed by the quantification of hydroperoxides, total cholesterol and total triglycerides.
•Serum VEGF was significantly elevated in calcitriol-treated mice.•Calcitriol reduced thrombospondin-1 mRNA expression and protein in breast cancer.•Calcitriol stimulated VEGF mRNA expression and ...protein secretion in breast cancer.•Calcitriol reduced tumor growth in mice xenografted with breast cancer cells.•Calcitriol increased necrosis in tumors of breast cancer bearing mice.
Calcitriol, a potent antineoplastic vitamin D metabolite, inhibits proliferation, induces apoptosis and slows the growth of tumors. Calcitriol also may exert either antiangiogenic or proangiogenic effects depending on the tissue. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (Tsp-1) are key factors involved in promoting and inhibiting angiogenesis, respectively. The effects of calcitriol on Tsp-1 have not been studied in the mammary gland, while VEGF regulation is not clear, since opposite outcomes have been demonstrated. Therefore, the present study was undertaken to investigate the effects of calcitriol on VEGF and Tsp-1 expression in primary breast tumor-derived cells and a panel of established breast cancer cell lines. In vivo studies in athymic mice were also performed in order to gain further insight into the biological effects of calcitriol on angiogenesis.
Real time-PCR and ELISA analyses showed that calcitriol stimulated VEGF mRNA expression and protein secretion while elicited the opposite effect on Tsp-1 in 7 out of 8 cell lines studied, independently of the cell phenotype (P<0.05 in n=5). In vivo, calcitriol significantly inhibited the relative tumoral volume after 4 weeks of treatment; however, serum VEGF was higher in calcitriol-treated animals compared to controls (P<0.05). The integrated fluorescence intensity analysis of CD31, a vessel marker, showed that xenografted breast cancer cells developed tumors with similar vascular density regardless of the treatment. Nevertheless, larger necrotic areas were observed in the tumors of calcitriol-treated mice compared to controls. Since the antineoplastic activity of calcitriol has been consistently demonstrated in several studies including this one, our results suggest that the antitumoral effect of calcitriol in vivo involve different mechanisms not necessarily related to the inhibition of tumor vascularization. Overall, our findings indicate that calcitriol can impact the angiogenic process in breast cancer by regulating VEGF and Tsp-1 expression.
This article is part of a Special Issue entitled ‘16th Vitamin D Workshop’.
•Rhodamines were encapsulated in reconstituted high-density lipoprotein nanoparticles and released inside the breast cancer cell overexpressing SR-B1 receptor.•Cell death was produced after rhodamine ...excitation with the Cerenkov radiation from 177Lu, a beta emitter radionuclide that reach cancer cells through radiopharmaceuticals.•The photodynamic - radiotherapeutic system has theragnostic properties due to imaging properties of 177Lu gamma emission.
Reconstituted high-density lipoprotein (rHDL) nanoparticles are excellent transporters of molecules and very useful for targeted therapy as they specifically recognize the scavenger receptor, class B1 (SR-B1) that is present on the surface of a wide range of tumor cells. However, they have rarely been employed to transport photosensitizers (PS) for photodynamic therapy (PDT). Rhodamine (R) compounds have been dismissed as useful PSs for PDT due to their low 1O2 production, excitation wavelengths with little tissue penetration, and poor selectivity for tumor cells. It was recently demonstrated that when irradiating at 532 nm or with Cerenkov radiation (CR) from a β-emitting radionuclide, R123, R6G, and RB undergo electron transfer reactions (type I reaction) with folic acid. R6G also produces type I reactions with O2. In this work, the photodynamic effects of the rHDL-R system were evaluated in vitro. rHDL nanoparticles loaded with R123, R6G, and RB were synthesized, and the PS was internalized into T47D tumor cells. When cells were irradiated with a 532-nm laser in the presence of an rHDL-R systems, a cytotoxic photodynamic effect was obtained in the order R6G > R123 > RB. In the presence of CR from a 177Lu source, cytotoxicity showed the order R6G > RB > R123. The higher cytotoxicity induced by R6G in both cases corresponds to higher cellular internalization and larger production of type I and II reactions. Thus, in this work, it is proposed that rHDL-R/177Lu system can be applied in theragnostics as a multimodal radiotherapy-PDT-imaging system (imaging by SPECT or Cerenkov) and in hypoxic solid tumors in which external radiation is not effective and 177Lu-CR acts as light source.
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Prostate-specific membrane antigens (PSMAs) are frequently overexpressed in both tumor stromal endothelial cells and malignant cells (stromal/tumor cells) of various cancers. The RGD (Arg-Gly-Asp) ...peptide sequence can specifically detect integrins involved in tumor angiogenesis. This study aimed to preclinically evaluate the cytotoxicity, biokinetics, dosimetry, and therapeutic efficacy of 225Ac-iPSMA-RGD to determine its potential as an improved radiopharmaceutical for alpha therapy compared with the 225Ac-iPSMA and 225Ac-RGD monomers. HEHA-HYNIC-iPSMA-RGD (iPSMA-RGD) was synthesized and characterized by FT-IR, UV-vis, and UPLC mass spectroscopy. The cytotoxicity of 225Ac-iPSMA-RGD was assessed in HCT116 colorectal cancer cells. Biodistribution, biokinetics, and therapeutic efficacy were evaluated in nude mice with induced HCT116 tumors. In vitro results showed increased DNA double-strand breaks through ROS generation, cell apoptosis, and death in HCT116 cells treated with 225Ac-iPSMA-RGD. The results also demonstrated in vivo cytotoxicity in cancer cells after treatment with 225Ac-iPSMA-RGD and biokinetic and dosimetric properties suitable for alpha therapy, delivering ablative radiation doses up to 237 Gy/3.7 kBq to HCT116 tumors in mice. Given the phenotype of HCT116 cancer cells, the results of this study warrant further dosimetric and clinical studies to determine the potential of 225Ac-iPSMA-RGD in the treatment of colorectal cancer.
Reconstituted high-density lipoproteins (rHDLs) can transport and specifically release drugs and imaging agents, mediated by the Scavenger Receptor Type B1 (SR-B1) present in a wide variety of tumor ...cells, providing convenient platforms for developing theranostic systems. Usually, phospholipids or Apo-A1 lipoproteins on the particle surfaces are the motifs used to conjugate molecules for the multifunctional purposes of the rHDL nanoparticles. Cholesterol has been less addressed as a region to bind molecules or functional groups to the rHDL surface. To maximize the efficacy and improve the radiolabeling of rHDL theranostic systems, we synthesized compounds with bifunctional agents covalently linked to cholesterol. This strategy means that the radionuclide was bound to the surface, while the therapeutic agent was encapsulated in the lipophilic core. In this research, HYNIC-S-(CH2)3-S-Cholesterol and DOTA-benzene-p-SC-NH-(CH2)2-NH-Cholesterol derivatives were synthesized to prepare nanoparticles (NPs) of HYNIC-rHDL and DOTA-rHDL, which can subsequently be linked to radionuclides for SPECT/PET imaging or targeted radiotherapy. HYNIC is used to complexing 99mTc and DOTA for labeling molecules with 111, 113mIn, 67, 68Ga, 177Lu, 161Tb, 225Ac, and 64Cu, among others. In vitro studies showed that the NPs of HYNIC-rHDL and DOTA-rHDL maintain specific recognition by SR-B1 and the ability to internalize and release, in the cytosol of cancer cells, the molecules carried in their core. The biodistribution in mice showed a similar behavior between rHDL (without surface modification) and HYNIC-rHDL, while DOTA-rHDL exhibited a different biodistribution pattern due to the significant reduction in the lipophilicity of the modified cholesterol molecule. Both systems demonstrated characteristics for the development of suitable theranostic platforms for personalized cancer treatment.
