Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 24 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Polycaprolactone Antimony Nanoparticles as Drug Delivery System for Leishmaniasis.

BACKGROUND: Leishmaniasis is a neglected disease endemic in tropical and subtropical areas, with an incidence about 1.6 million cases/year. The first-line treatment of this disease is pentavalent antimony, and the second-line are pentamidine and amphotericin B. All the treatments available cause severe side effects and often have difficulty in accessing parasites within infected cells. STUDY QUESTION: This study aimed to determine if the use of nanoparticles loaded with meglumine antimoniate could reach and targeting infected organs with leishmaniasis, reducing the dosage used and promoting less adverse effects. STUDY DESIGN: This study was performed comparing the meglumine nanoparticle in two experimental groups. The first one healthy mice and the second one inducted mice (leishmaniasis). MEASURES AND OUTCOMES: The nanoparticles loaded with meglumine antimoniate (nanoantimony) were prepared by double-emulsion solvent evaporation method and showed a size of about 150-200 nm. BALB/c mice infected or not with Leishmania amazonensis (cutaneous leishmaniasis model) or Leishmania infantum (visceral leishmaniasis model) was used to access the biodistribution of nanoantimony and meglumine antimoniate labeled with technetium-99m. RESULTS: The biodistribution profiles showed a preferential targeting of the nanoparticles to the liver, spleen, and lungs. Because these are the main organs infected, the nanoparticle may be used for this purpose. The results for cutaneous leishmaniasis showed a low uptake by the lesion (infected region). CONCLUSIONS: The results demonstrated the potential use of these nanoparticles to improve the efficacy of meglumine antimoniate in the treatment of visceral leishmaniasis, indicating their potential as an alternative therapeutic strategy for leishmaniasis infections.

Decorated Superparamagnetic Iron Oxide Nanoparticles with Monoclonal Antibody and Diethylene-Triamine-Pentaacetic Acid Labeled with Thechnetium-99m and Galium-68 for Breast Cancer Imaging.

PURPOSE: In this study we developed and tested an iron oxide nanoparticle conjugated with DTPA and Trastuzumab, which can efficiently be radiolabeled with 99m-Tc and Ga-68, generating a nanoradiopharmaceutical agent to be used for SPECT and PET imaging. METHODS: The production of iron oxide nanoparticle conjugated with DTPA and Trastuzumab was made using phosphorylethanolamine (PEA) surface modification. Both radiolabeling process was made by the direct radiolabeling of the nanoparticles. The in vivo assay was done in female Balb/c nude mice xenografted with breast cancer. Also a planar imaging using the radiolabeled nanoparticle was performed. RESULTS: No thrombus and immune response leading to unwanted interaction and incorporation of nanoparticles by endothelium and organs, except filtration by the kidneys, was observed. In fact, more than 80% of 99mTc-DTPA-TZMB@Fe3O4 nanoparticles seems to be cleared by the renal pathway but the implanted tumor whose seems to increase the expression of HER2 receptors enhancing the uptake by all other organs. CONCLUSION: However, even in this unfavorable situation the tumor bioconcentrated much larger amounts of the nano-agent than normal tissues giving clear enough contrast for breast cancer imaging for diagnostics purpose by both SPECT and PET technique. Graphical Abstract ᅟ.

New chalcone compound as a promising antileishmanial drug for an old neglected disease: Biological evaluation using radiolabelled biodistribution.

OBJECTIVES: Treatment of leishmaniasis remains a challenge, especially due to the need for multiple painful injections, the toxicity of current drugs against the disease, their lack of efficacy and, lately, drug resistance. The aim of this study was to demonstrate the biological behaviour of 3-nitro-2'-hydroxy-4',6'-dimethoxychalcone (CH8) in a murine model of cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). METHODS: To evaluate its biological behaviour, compound CH8 was radiolabelled with technetium-99m (99mTc) using the direct reaction. Groups of animals infected with ether Leishmania infantum (as a model for VL) or Leishmania amazonensis (as a model for CL) were administered CH8-99mTc orally or subcutaneously, respectively, and its biodistribution was evaluated. RESULTS: Oral administration of CH8-99mTc resulted in poor absorption. However, the absorbed drug was expressively taken up in the blood and liver, the main organ infected in VL. CH8-99mTc administered by the subcutaneous route showed a poor distribution and significant uptake in the left ear, suggesting a local effect in the skin. In addition, the VL and CL infection models did not considerably alter the biodistribution profile by the oral and subcutaneous routes, respectively. CONCLUSION: These results suggest that CH8 is a promising candidate for oral treatment of VL and for intralesional treatment of CL, showing a prominent local effect.

MUC1 aptamer-capped mesoporous silica nanoparticles for controlled drug delivery and radio-imaging applications.

Mucin 1 (MUC1) is a cell surface protein overexpressed in breast cancer. Mesoporous silica nanoparticles (MSNs) loaded with safranin O, functionalized with aminopropyl groups and gated with the negatively charged MUC1 aptamer have been prepared (S1-apMUC1) for specific targeting and cargo release in tumoral versus non-tumoral cells. Confocal microscopy studies showed that the S1-apMUC1 nanoparticles were internalized in MDA-MB-231 breast cancer cells that overexpress MUC1 receptor with subsequent pore opening and cargo release. Interestingly, the MCF-10-A non-tumorigenic breast epithelial cell line that do not overexpress MUC1, showed reduced (S1-apMUC1) internalization. Negligible internalization was also found for S1-ap nanoparticles that contained a scrambled DNA sequence as gatekeeper. S2-apMUC1 nanoparticles (similar to S1-apMUC1 but loaded with doxorubicin) internalized in MDA-MB-231 cells and induced a remarkable reduction in cell viability. Moreover, S1-apMUC1 nanoparticles radio-labeled with 99mTc (S1-apMUC1-Tc) showed a remarkable tumor targeting in in vivo studies with MDA-MB-231 tumor-bearing Balb/c mice.

A new approach for radiosynoviorthesis: A dose-optimized planning method based on Monte Carlo simulation and synovial measurement using 3D slicer and MRI.

PURPOSE: Recently, there has been a growing interest in a methodology for dose planning in radiosynoviorthesis to substitute fixed activity. Clinical practice based on fixed activity frequently does not embrace radiopharmaceutical dose optimization in patients. The aim of this paper is to propose and discuss a dose planning methodology considering the radiological findings of interest obtained by three-dimensional magnetic resonance imaging combined with Monte Carlo simulation in radiosynoviorthesis treatment applied to hemophilic arthropathy. METHOD: The parameters analyzed were: surface area of the synovial membrane (synovial size), synovial thickness and joint effusion obtained by 3D MRI of nine knees from nine patients on a SIEMENS AVANTO 1.5 T scanner using a knee coil. The 3D Slicer software performed both the semiautomatic segmentation and quantitation of these radiological findings. A Lucite phantom 3D MRI validated the quantitation methodology. The study used Monte Carlo N-Particle eXtended code version 2.6 for calculating the S-values required to set up the injected activity to deliver a 100 Gy absorbed dose at a determined synovial thickness. The radionuclides assessed were: 90Y, 32P, 188Re, 186Re, 153Sm, and 177Lu, and the present study shows their effective treatment ranges. RESULT: The quantitation methodology was successfully tested, with an error below 5% for different materials. S-values calculated could provide data on the activity to be injected into the joint, considering no extra-articular leakage from joint cavity. Calculation of effective treatment range could assist with the therapeutic decision, with an optimized protocol for dose prescription in RSO. CONCLUSION: Using 3D Slicer software, this study focused on segmentation and quantitation of radiological features such as joint effusion, synovial size, and thickness, all obtained by 3D MRI in patients' knees with hemophilic arthropathy. The combination of synovial size and thickness with the parameters obtained by Monte Carlo simulation such as effective treatment range and S-value, from which is calculated the injected activity, could be used for treatment planning in RSO. Data from this methodology could be a potential aid to clinical decision making by selecting the most suitable radionuclide; justifying the procedure, fractioning the dose, and the calculated injected activity for children and adolescents, considering both the synovial size and thickness.

Anti-MUC1 nano-aptamers for triple-negative breast cancer imaging by single-photon emission computed tomography in inducted animals: initial considerations.

The early and specific detection of tumors remains a barrier in oncology, especially in cases such as the triple-negative breast cancer (TNBC). To address this gap, aptamers have found an important application in the recognition of tumor biomarkers such as mucin 1 (MUC1). However, there are still some difficulties in the use of aptamer, as their rapid biological clearance makes their use as drugs limited. In this study, the anti-MUC1 aptamer was used as a drug delivery system (DDS) for a radioactive polymeric nanoparticle (NP) in the imaging of TNBCs. Thus, poly(lactic-co-glycolic acid) NPs loaded with the anti-MUC1 aptamer and labeled with technetium-99m were used for a biodistribution study and imaging of TNBC. The results confirmed that the NP was successfully obtained, with a mean size of 262 nm, according to the dynamic light scattering data. The biodistribution assay in induced animal models with TNBC showed that although there was a high capture by intestine (>30%), the DDS developed had a high tumor uptake (5%) and with great in vivo imaging properties, corroborating the possibility of use of this DDS as an imaging drug for TNBC.

Nano-Hydroxyapatite Doped with Ho-166 as Drug Delivery System for Bone Cancer Therapy and Diagnosis: Developing a Theragnostic Radiopharmaceuticals.

BACKGROUND: The use of nanobiomaterials is increasing each day. Among the immense variety of nanomaterials developed and studied the hydroxyapatite is one of the most ones. OBJECTIVE: In this study we developed and tested nano-hydroxyapatite dopped with Ho-166 for bone cancer. RESULTS: The results showed that the nano-hydroxyapatite dopped with Ho-166 has a great affinity for the bone. CONCLUSION: The pre-clinical studies support the use as a nano-radiopharmaceuticals for bone cancer treatment and diagnosis.

Nanoradiopharmaceuticals for breast cancer imaging: development, characterization, and imaging in inducted animals.

Monoclonal antibodies as polymeric nanoparticles are quite interesting and endow this new drug category with many advantages, especially by reducing the number of adverse reactions and, in the case of radiopharmaceuticals, also reducing the amount of radiation (dose) administered to the patient. In this study, a nanoradiopharmaceutical was developed using polylactic acid (PLA)/polyvinyl alcohol (PVA)/montmorillonite (MMT)/trastuzumab nanoparticles labeled with technetium-99m (99mTc) for breast cancer imaging. In order to confirm the nanoparticle formation, atomic force microscopy and dynamic light scattering were performed. Cytotoxicity of the nanoparticle and biodistribution with 99mTc in healthy and inducted animals were also measured. The results from atomic force microscopy showed that the nanoparticles were spherical, with a size range of ~200-500 nm. The dynamic light scattering analysis demonstrated that over 90% of the nanoparticles produced had a size of 287 nm with a zeta potential of -14,6 mV. The cytotoxicity results demonstrated that the nanoparticles were capable of reaching breast cancer cells. The biodistribution data demonstrated that the PLA/PVA/MMT/trastuzumab nanoparticles labeled with 99mTc have great renal clearance and also a high uptake by the lesion, as ~45% of the PLA/PVA/MMT/trastuzumab nanoparticles injected were taken up by the lesion. The data support PLA/PVA/MMT/trastuzumab labeled with 99mTc nanoparticles as nanoradiopharmaceuticals for breast cancer imaging.

Nanoradiopharmaceuticals for Bone Cancer Metastasis Imaging.

Drug delivery systems are under intense investigation all around the world, especially in oncology research. Indeed, in some cases, like bone metastasis, nanodrugs may represent the last and best choice for both treatment and imaging of early cancer foci. Nuclear medicine has been using MDP labelled with 99mTc as radiopharmaceuticals for many years; however, their use as nanoradiopharmaceuticals is very innovative and creates a new way to establish radiopharmacy in this new scenario offered by nanotechnology. In this study we developed and tested nano-MDP-labelled with 99mTc in rats induced with bone cancer metastasis and the results showed that it may work in patients. However, some further experiments are required in order to initiate protocols in humans.

In vivo studies: comparing the administration via and the impact on the biodistribution of radiopharmaceuticals.

The use of in vivo assay to determine the biodistribution and subsequent inter-comparison with human parameters has been used since the dawn of science. The use of this type of test admits the metabolic equity among animals for inter-comparison. Thus, the use of Wistar rats in particular is quite frequent. Regarding routes of administration, there are three ways to test priority: jugular vein, intraocular (eye plexus) and caudal; there is a consensus that these three pathways behave in the same way, or at least very similar. Biodistribution studies of drugs, especially radiopharmaceuticals, have been using randomly any of these pathways believed to be effective in their likeness without worrying about your real analytic equity. In this study, we performed in vivo assay in 8 Wistar rats using 99mTc -labeled Herceptin to review the route of administration on the biodistribution result. Thus, four mice were injected via the intraocular (eye plexus), and four were injected via tail (caudal plexus). The results were quite disparate and call the attention of the scientific community to reassess the protocols for animal experiments, in order to have uniformity and fairness between the data and may represent a test for human inter-comparison of more reliable and trustworthy way.

Development of novel nanoparticle for bone cancer.

Bone metastasis is responsible for up to 99% of bone tumors. As no cure has yet to be discovered, available treatments simply strive to improve quality of life. One of such treatments is the use of EDTMP (ethylenediamine-tetramethylenephosphonic acid) labeled with Samarium-153, which has been shown to improve survival in 70-80% of patients treated. A major disadvantage of this radiopharmaceutical is its superficial delivery, resulting in the need for multiple doses. The current work describes novel polymeric nanoparticles of EDTMP and evaluation of their biodistribution in vivo. Nanoparticles were prepared using a double emulsion-solvent evaporation method and characterized by AFM (atomic force microscopy). Nanoparticles (200-500 nm) were then labeled with Technetium-99m for biodistribution analysis in healthy Wistar rats. Polymeric nanoparticles of EDTMP were observed to accumulate at bone tissue for long periods of time (150 min), resulting in prolonged release of EDTMP at the target site. This finding suggests that this novel pharmaceutical formulation of EDTMP provides better targeted delivery than free EDTMP and may be a more optimal treatment for management of bone metastasis pain.

Radiolabelled nanohydroxyapatite with 99mTc: perspectives to nanoradiopharmaceuticals construction.

The use of nanoparticles is under intense investigation. The possible advantages proposed by these systems are very impressive and the results may be quite schemer. In this scenario, the association of nanoparticles with radioactive materials (radionuclide) may be the most important step since the discovery of radioactive for nuclear medicine and radiopharmacy, especially for cancer targeting and therapy. In this study, we developed radiolabelled nanoparticles of hydroxyapatite with technetium 99m for bone cancer imaging. The results demonstrated that it is possible to label nanoparticles of hydroxyapatite, and due to its physicochemical properties is possible to develop nano-radiopharmaceutical for bone imaging.

Monoclonal antibodies: application in radiopharmacy.

In this study was carried on a systematic review of the data was carried out in the topic of monoclonal antibodies in the last 40 years. All the data collected and summarized revealed that this new class of medicine may bring great advance in the field of radiopharmacy, oncology and imaging.

Residual C-peptide in patients with Type 1 diabetes and multiethnic backgrounds.

OBJECTIVE: To evaluate serum C-peptide in 88 patients from a multiethnic population with Type-1 diabetes and variable disease durations. METHOD: Eighty-eight patients with a mean disease duration of 8.1 +7.6 years were included and underwent C-peptide measurement before and after glucagon stimulation. Chi-squared and Mann Whitney U-tests were used to compare the variables between groups (all two-tailed, α = 0.05). Spearmans correlation coefficient was used to test the association between the continuous variables. Logistic regression was used for the multivariate analysis. Twenty-eight (31.8%) individuals had significantly detectable C-peptide levels after stimuli, particularly those with a shorter disease duration (p<0.001). RESULTS: Patients with detectable C-peptide levels required lower insulin doses (p<0.009) and had similar HbA1C results (p = 0.182) and fewer chronic complications (p = 0.029). CONCLUSION: C-peptide detection was common in Type-1 diabetics, particularly shortly after being diagnosed. This result may have clinical implications.

Biodistribution of nanoparticles: initial considerations.

Nanotechnology is attracting increasing attention worldwide. This study was made use of modern technology to decipher most of the intriguing biological aspects of nanoparticles. Labeling with technetium-99m ((99m)Tc) of six nanoparticles using different compositions and formulations, as well as complete biodistribution studies in mice was done. The results showed that the behaviors of nanoparticles were very different from each other. Mesoporous silica showed a high affinity for lung tissue, whereas polymeric nanoparticles were rapidly recognized and metabolized by the liver. The six nanoparticles showed different renal clearance times, suggesting that their area mechanisms of action were related to interaction and solubility. The labeling process in all samples showed similar results (all >99%). Biodistribution was demonstrated to be important for the study of nanoparticles, and could be used to predict the possible mechanism of action of nanoparticles.

Polymeric nanoparticles of FMISO: are nano-radiopharmaceuticals better than conventional ones?

Nanotechnology has been the last frontier in the diagnoses and treatment of many diseases, especially in oncology. The use of nanoparticles of radiopharmaceuticals may represent the future of Nuclear Medicine. In this study we developed, characterized and tested polymeric nanoparticles of FMISO (fluoromisonidazole) in a dynamic study of biodistribution. The results of the development as characterization showed that nanoparticles were well obtained with a size range of 300- 500 nm and a spherical shape.

Radiolabeling of cramoll 1,4: evaluation of the biodistribution.

The cramoll 1,4 is a well-studied lectin. However, few studies about its biodistribution have been done before. In this study, we radiolabeled the cramol 1,4 with Tc-99m and analyzed the biodistribution. The results showed that the cramol has an abnormal uptake by the bowel with reflections on its clearance mechanism.