Application Of 131I Research Articles

Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma

Sodium iodide symporter (NIS) gene transfer for active accumulation of iodide in tumor cells is a powerful theranostic strategy facilitating both diagnostic and therapeutic application of radioiodide. In glioblastoma (GBM), the blood-brain barrier (BBB) presents an additional delivery barrier for nucleic acid nanoparticles. In the present study, we designed dual-targeted NIS plasmid DNA complexes containing targeting ligands for the transferrin receptor (TfR) and the epidermal growth factor receptor (EGFR), thus providing the potential for active transport across the BBB followed by targeting of tumor cells. Invitro 125I transfection studies confirmed TfR- and EGFR-dependent transfection efficiency and NIS-specific iodide uptake of dual-targeted polyplexes. Invivo gene transfer in mice bearing orthotopic U87 GBM xenografts was assessed at 48h after intravenous polyplex injection by positron emission tomography (PET) imaging using 18F-labeled tetrafluoroborate (TFB) as tracer. The tumoral 18F-TFB uptake of mice treated with dual-targeted polyplexes (0.56%± 0.08% ID/mL) was significantly higher compared with mice treated with EGFR-mono-targeted (0.33%± 0.03% ID/mL) or TfR-mono-targeted (0.27%± 0.04% ID/mL) polyplexes. In therapy studies, application of 131I induced a superior therapeutic effect of the dual-targeted therapy, demonstrated by a significant delay in tumor growth and prolonged survival.

Selective sodium iodide symporter (NIS) gene therapy of glioblastoma mediated by EGFR-targeted lipopolyplexes

Lipo-oligomers, post-functionalized with ligands to enhance targeting, represent promising new vehicles for the tumor-specific delivery of therapeutic genes such as the sodium iodide symporter (NIS). Due to its iodide trapping activity, NIS is a powerful theranostic tool for diagnostic imaging and the application of therapeutic radionuclides. 124I PET imaging allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression, and application of 131I enables cytoreduction. In our experimental design, we used epidermal growth factor receptor (EGFR)-targeted polyplexes (GE11) initially characterized in vitro using 125I uptake assays. Mice bearing an orthotopic glioblastoma were treated subsequently with mono-dibenzocyclooctyne (DBCO)-PEG24-GE11/NIS or bisDBCO-PEG24-GE11/NIS, and 24–48 h later, 124I uptake was assessed by positron emission tomography (PET) imaging. The best-performing polyplex in the imaging studies was then selected for 131I therapy studies. The in vitro studies showed EGFR-dependent and NIS-specific transfection efficiency of the polyplexes. The injection of monoDBCO-PEG24-GE11/NIS polyplexes 48 h before 124I application was characterized to be the optimal regime in the imaging studies and was therefore used for an 131I therapy study, showing a significant decrease in tumor growth and a significant extension of survival in the therapy group. These studies demonstrate the potential of EGFR-targeted polyplex-mediated NIS gene therapy as a new strategy for the therapy of glioblastoma.

The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment.

Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past two decades, significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery towards promising new applications in disseminated disease, in particular through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

Taking Advantage of the TGFB1 Biology in Differentiated Thyroid Cancer to Stimulate Sodium Iodide Symporter (NIS)-Mediated Iodide Uptake in Engineered Mesenchymal Stem Cells

The sodium iodide symporter (NIS) mediates the active transport of iodide into thyroid follicular cells, providing the basis for the use of radioiodide for diagnostic imaging and therapy of differentiated thyroid cancer and also non-thyroidal tumors after tumor-selective NIS gene transfer. Based on their excellent tumor-homing capacity, mesenchymal stem cells (MSCs) can be employed as tumor-selective NIS gene delivery vehicles. Transgenic expression of NIS in genetically engineered MSCs allows noninvasive imaging of functional NIS expression as well as therapeutic application of 131I. The use of promoters activated by tumor micromilieu-derived signals to drive NIS expression enhances selectivity and effectiveness, while limiting potential off-target effects. In this study we aimed to exploit the central role of transforming growth factor B1 (TGFB1) in tumor milieu-associated signaling using a TGFB1-inducible synthetic SMAD-responsive promoter to selectively drive NIS-transgene expression in engineered MSCs (SMAD-NIS-MSC) in the context of differentiated thyroid cancer based on the critical role of TGFB1 in the pathogenesis of radioiodine refractory differentiated thyroid cancer. To evaluate the TGFB1 expression in thyroid cancer cell lines, the TGFB1 concentration in conditioned medium (CM) from an array of established human papillary thyroid cancer (PTC) cell lines (BCPAP and K1) was measured by ELISA. BCPAP-CM showed a higher concentration of TGFB1, while a lower concentration was measured in K1-CM. Stimulation of SMAD-NIS-MSCs with PTC-CM showed a significant increase of NIS-mediated radioiodide-125 uptake in these MSCs in vitro. In addition, iodide uptake in SMAD-NIS-MSCs was significantly stimulated by co-culture with thyroid cancer cells. Cell migration assay was performed to validate the effect of PTC-CM in MSC recruitment. MSCs subjected to a gradient between tumor CM and serum free medium showed a directed chemotaxis towards CM with increased forward migration index (FMI) and center of mass (CoM). In a next step, based on the in vitro studies, SMAD-NIS-MSCs will be systemically applied via the tail vein to mice harboring subcutaneous PTC tumors and tumoral iodide uptake will be monitored by 123I-scintigraphy. Taken together, these data indicate the feasibility of commandeering TGF-β/SMAD signaling in the TGFB1-rich tumor environments of radioiodine refractory differentiated thyroid carcinomas to re-establish functional NIS expression using engineered mesenchymal stem cells as therapy vehicles.

SUN-120 Regional Hyperthermia Enhances Selective Mesenchymal Stem Cell Migration Towards the Tumor Stroma

The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To enhance the actively recruitment of MSCs to growing tumor stroma and thereby trigger targeted delivery of the NIS gene to the tumor, we examined the combination with regional hyperthermia, as heat induces the secretion of immunomodulatory chemokines, cytokines and growth factors, well-known attractants of MSCs.Human hepatocellular carcinoma cells (HuH7) were heat-treated in a water bath at 41 °C for 1h, followed by incubation at 37 °C for 0-48h. mRNA and protein levels of chemokines involved in MSC migration was analyzed by RT-PCR and ELISA. Chemotaxis of MSCs in relation to a gradient of supernatants was tested in a 3D live cell tracking migration assay. In a subcutaneous HuH7 mouse xenograft tumor model, a single systemic injection of CMV-NIS-MSCs was applied 6h, 24h, 48h after or 24h, 48h before hyperthermia treatment and tumoral 123I accumulation was assessed by 123I-scintigraphy. Ex vivo NIS analysis of tumor sections was performed by RT-PCR and immunohistochemistry. The optimal imaging regime was then used for a 131I therapy study.Chemokine mRNA and protein analysis indicated a substantial increase in expression levels of chemokines and growth factors, involved in MSC tumor homing, after heat exposure. In addition, MSCs showed directed migration towards the supernatant of thermo-stimulated cancer cells. In vivo, with the optimal regime, we observed a significantly increased uptake of 123I in tumors of heat-treated animals (41 °C) when thermostimulated 24h after CMV-NIS-MSC injection compared to control animals (37 °C). Immunohistochemical staining of tumor sections showed strong tumoral NIS-specific immunoreactivity and RT-PCR an increased NIS mRNA expression in heat-treated tumors, thereby confirming tumor-selective, temperature-dependent MSC migration. CMV-NIS-MSC-mediated 131I therapy combined with regional hyperthermia resulted in a reduced tumor growth that was associated with prolonged survival of regional heat-treated animals compared to normothermic mice and to the saline control group.In summary, we have demonstrated a significantly increased, selective MSC migration towards the tumor stroma after regional hyperthermia in the 123I imaging study. The combination of MSC-mediated NIS gene therapy with mild regional hyperthermia resulting in stimulated therapeutic efficacy of NIS-mediated 131I therapy.

Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter (NIS) gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells.

Purpose: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the NIS gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs).Experimental Design: NIS induction in heat-treated HSP70B-NIS-MSCs was verified by 125I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by 123I-scintigraphy. The most effective uptake regime was then selected for 131I therapy.Results: The HSP70B promoter showed low basal activity in vitro and was significantly induced in response to heat. In vivo, the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated 131I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups.Conclusions: The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic NIS gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.

TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer.

Based on their excellent tumor-homing capacity, genetically engineered mesenchymal stem cells (MSCs) are under investigation as tumor-selective gene delivery vehicles. Transgenic expression of the sodium iodide symporter (NIS) in genetically engineered MSCs allows noninvasive tracking of MSC homing by imaging of functional NIS expression as well as therapeutic application of 131I. The use of tumor stroma-activated promoters can improve tumor-specific MSC-mediated transgene delivery. The essential role of transforming growth factor B1 (TGFB1) and the SMAD downstream target in the signaling between tumor and the surrounding stroma makes the biology of this pathway a potential option to better control NIS expression within the tumor milieu. Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by a synthetic SMAD-responsive promoter (SMAD-NIS-MSCs). Radioiodide uptake assays revealed a 4.9-fold increase in NIS-mediated perchlorate-sensitive iodide uptake in SMAD-NIS-MSCs after TGFB1 stimulation compared to unstimulated cells demonstrating the successful establishment of MSCs, which induce NIS expression in response to activation of TGFB1 signaling using a SMAD-responsive promoter. 123I-scintigraphy revealed significant tumor-specific radioiodide accumulation and thus NIS expression after systemic application of SMAD-NIS-MSCs into mice harboring subcutaneous tumors derived from the human hepatocellular carcinoma (HCC) cell line HuH7, which express TGFB1. 131I therapy in SMAD-NIS-MSCs-treated mice demonstrated a significant delay in tumor growth and prolonged survival. Making use of the tumoral TGFB1 signaling network in the context of MSC-mediated NIS gene delivery is a promising approach to foster tumor stroma-selectivity of NIS transgene expression and tailor NIS-based gene therapy to TGFB1-rich tumor environments.

EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases.

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases.The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I.For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131I resulted in marked delay in metastases spread, which was associated with improved animal survival.In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.

The success of 131I ablation in thyroid cancer patients is significantly reduced after a diagnostic activity of 40 MBq 131I

Dosimetry studies have shown that activities of 131I as small as 10-20 MBq may cause a stunning effect. A result of this stunning effect may be a lower success rate of the ablative 131I therapy for differentiated thyroid carcinoma (DTC). The aim of this study was to determine whether pre-therapeutic uptake measurement with 40 MBq 131I causes a lower success rate of ablation. retrospective chart review study. In two hospitals the ablation protocols differed in one respect only: in the one hospital no diagnostic 131I was applied before ablation (group 1, n = 48), whereas in the other hospital a 24-h uptake-measurement with 40 MBq 131I was performed (group 2, n = 51). Included were all DTC patients without distant metastases who had undergone 131I ablation between July 2002 and December 2005, and who had returned for 131I follow-up. Successful ablation was defined as absence of pathological 131I uptake on diagnostic whole-body scintigraphy and undetectable thyroglobulin-levels under TSH stimulation. Overall, ablation was successful in 31/48 patients (65%) in group 1 and in 17/51 patients (33%) in group 2 (p=0.002). Multivariate analysis showed that pre-therapeutic uptake measurement using 40 MBq 131I was an independent determinant for success of ablation (p = 0.002). After applying a diagnostic activity of 40 MBq 131I before ablation, the success rate of ablation is severely reduced. Consequently, the routine application of 131I for diagnostic scintigraphy or uptake measurement prior to 131I ablation is best avoided.

Diagnostic 123I and 131I activities and radioiodine therapy

Urinary iodine excretion (UIE) provides information about iodine supply and release. In the present study we investigated effects of the application of different radioiodine isotopes on UIE in patients with differentiated thyroid carcinoma (DTC). In 91 consecutive patients with DTC UIE, measured as iodine/creatinine ratio, was determined before and after application of 123I and 131I for diagnostic or therapeutic purposes. Additionally, remnant volume (V) was determined prior to therapy. Group A consisted of 33 patients with supposed successful ablation of DTC. These patients received 370 MBq 131I for diagnostic use and served as controls. 58 patients (group B) with remnants, relapses and metastases received 370 MBq 123I for diagnostics prior to therapy with 1.5-22.2 GBq 131I. Factors influencing individual changes in urinary iodine excretion (deltaUIE) were investigated by using non-parametric tests. In group A UIE did not change significantly after application of 131I. As well, UIE remained unchanged after diagnostic application of 123I in group B. In contrast, UIE increased significantly already 24 h after therapeutic application of 131I in this group. In patients with small remnants (V < 2.5 ml) a significant but only moderate increase of UIE could be observed (average increase: 47 microg I/g crea). In patients with larger remnants, with relapses or metastases increase of UIE values was significant and more pronounced. It was confirmed that UIE increased significantly during radioiodine therapy in patients with DTC and radioiodine-accumulating tissue. The increase of UIE after therapeutic administration of radioiodine can be explained by the disintegrated thyroid follicles in thyroid remnants. The radioiodine-induced iodine release may be one reason for thyroid "stunning" even after application of diagnostic amounts of 131I.

Doença nodular de tireóide

The thyroid gland is fairly homogeneous but nodules are frequent. Nodules greater than 1.0 cm are usually palpable, but non-palpable nodules, smaller than 1.0 cm are far more frequent. Thyroid nodular disease, the etiology of which is multifactorial, encompasses lesions, from the small incidentaloma to large multinodular intrathoracic goiter. The main diagnostic issues are related to the functional and morphological characterization using TSH measurements and image methods. Fine needle aspiration biopsy is the method of choice to rule out malignancy, the incidence of which is similar in single or multinodular goiter (MNG). MNG treatment can be surgical or radioactive iodine (131I) could be indicated if the 131I uptake is adequate. It is likely that the use of recombinant human TSH (rhTSH) will strongly change the application of 131I in MNG treatment. The benign single thyroid nodule, "cold" or "hot" at scintigraphy, can be treated with percutaneous ethanol injection. The "hot" nodule can also be treated by surgery or 131I.

Early change of thyroid hormone concentration after 131I treatment in patients with solitary toxic adenoma

In spite of extensive use of 131I for treatment of hyperthyroidism, the results of early outcome are variable. In our prospective clinical study we tested whether 131I induced necrosis causing clinical aggravation of hyperthyroidism and increasing the free thyroid hormone concentration in the serum of patients with solitary toxic adenoma not pretreated with antithyroid drugs. 30 consecutive patients were treated with 925 MBq 131I. Serum concentration of thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroglobulin (Tg), and interleukin-6 (IL-6) were measured before and after application of 131I. After application of 131I no clinical worsening was observed. FT4 and fT3 concentration did not change significantly within the first five days, whereas both of them significantly decreased after 12 days (p < 0.0001). Slight and clinically irrelevant increase in the level of the two thyroid hormones was observed in 9 patients. Furthermore, we observed a prolonged increase in Tg concentration and a transient increase in IL-6 concentration. Neither evidence of any clinical aggravation of hyperthyroidism nor any significant increase in thyroid hormone concentration by 131I induced necrosis of thyroid cells was found. Therefore, the application of 131I may be considered as a safe and effective treatment for patients with hyperthyroidism due to toxic adenoma.

Radioiodine treatment of feline hyperthyroidism in Germany

Establishment of radioiodine treatment of feline hyperthyroidism in veterinary routine in accordance with German radiation protection regulations. 35 cats with proven hyperthyroidism were treated with 131I in a special ward. Thyroid uptake and effective halflife were determined using gammacamera dosimetry. Patients were released when measured whole body activity was below the limit defined in the German "Strahlenschutzverordnung". 17/20 cats treated with 150 MBq radioiodine and 15/15 cats treated with 250 MBq had normal thyroid function after therapy, normal values for FT3 and FT4 were reached after two and normal TSH levels after three weeks. In 14 cats normal thyroid function was confirmed by controls 3-6 months later. Thyroidal iodine uptake was 24 +/- 10%, effective halflife 2.5 +/- 0.7 days. Whole body activity < 1 MBq was reached 13 +/- 4 days after application of 131I. Radiation exposure of cat owners was estimated as 1.97 microSv/MBq for adults. Radioiodine therapy of feline hyperthyroidism is highly effective and safe. It can easily be performed in accordance with German radiation protection regulations, although this requires hospitalisation for approximately two weeks. Practical considerations on radiation exposure of cat owners do not justify this long interval. Regulations for the veterinary use of radioactive substances similar to existing regulations for medical use in humans are highly desirable.

Disposal of therapeutic 131I waste using a multiple holding tank system.

Therapeutic application of 131I for the treatment of thyroid cancer generates a significant amount of liquid radioactive waste. Discharge of this waste into the public sewage system is governed by local regulations. In Canada, the permissible concentration is such that only a few patients can be treated in modern water-efficient buildings if this waste is discharged directly through the toilet to the public sewage system. If the toilet discharge is first collected into a holding tank for physical decay before it is released, a large patient load can be handled without exceeding the permissible concentration. In this paper, the principles of operation and the design parameters are discussed, and a multiple holding tank system installed in the Princess Margaret Hospital/Ontario Cancer Institute is described.

Erhöhte Sensitivität der Ganzkörperszintigraphie mit 131J für den Nachweis jodspeichernder Metastasen durch spätere Aufnahme-Zeitpunkte

In the follow-up of thyroid cancer patients we sometimes observed discrepancies between elevated thyroglobulin levels and negative results of post- therapeutic or diagnostic scans 48 h and 72 h after oral application of131I routinely. Consequently, delayed 131I scans (96 h and later) were performed in addition. In all cases, delayed 131I scans either showed a higher imaging quality or additional metastatic lesions. Thus, posttherapeutic (and diagnostic) scans should include late images (4 d and later).

Distribution of 14C-formaldehyde after pulpotomy with formocresol

Pulpotomies were performed on rhesus monkeys with use of formocresol to determine if there was uptake of 14C-formaldehyde into the systemic circulation after formocresol pulpotomies. Five-minute exposure of pulpal tissue to the 14C-formocresol resulted in the systemic absorption of approximately 1% of the dose. Two hours of exposure of pulp tissue to the 14C-formocresol did not increase the systemic absorption. Multiple sequential pulpotomies resulted in proportionately higher systemic absorption of 14C-formaldehyde. Application of 131I to pulpotomy sites indicated that formocresol compromises the microcirculation of the dental pulp. Autoradiography disclosed extensive concentrations of 14C-formaldehyde in the pulp, dentin, periodontal ligament, and bone.

Quantitative paper radiochromatography using tollens reagent—I: The application of 131I to radiometric estimation of monosaccharides and polyols

For the estimation of saccharides, a radiochromatographic quantitative method, based on the reaction with ammoniacal silver nitrate, has been developed. Conditions for the quantitative deposition of silver on the filter paper have been established. The silver deposit formed was transformed into Ag 131I. The radioactivity of 131I located in the spots is related to the amount of the substance determined. The method has been checked using six substances, representing aldoses, ketoses, hexitols and cyclitols. The relationships between integrated spot activity, maximal spot activity and radiometrically estimated spot length, and the amount of substance have been studied.