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1.
Radiat Environ Biophys ; 62(4): 483-495, 2023 11.
Article in English | MEDLINE | ID: mdl-37831188

ABSTRACT

A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard biokinetic models become inadequate for assessing radionuclide intake and estimating the resulting dose, as DTPA perturbs the regular biokinetics of the radionuclide. At present, most attempts existing in the literature are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. Recently, several approaches have been presented with the aim of developing a generic model, one of which reported the unperturbed biokinetics of plutonium (Pu), the chelation process and the behaviour of the chelated compound An-DTPA with a single model structure. The aim of the approach described in this present work is the development of a generic model that is able to describe the biokinetics of Am, DTPA and the chelate Am-DTPA simultaneously. Since accidental intakes in humans present many unknowns and large uncertainties, data from controlled studies in animals were used. In these studies, different amounts of DTPA were administered at different times after contamination with known quantities of Am. To account for the enhancement of faecal excretion and reduction in liver retention, DTPA is assumed to chelate Am not only in extracellular fluids, but also in hepatocytes. A good agreement was found between the predictions of the proposed model and the experimental results for urinary and faecal excretion and accumulation and retention in the liver. However, the decorporation from the skeletal compartment could not be reproduced satisfactorily under these simple assumptions.


Subject(s)
Pentetic Acid , Plutonium , Humans , Rats , Animals , Pentetic Acid/therapeutic use , Americium , Models, Biological , Chelating Agents/therapeutic use
2.
Biochem Biophys Res Commun ; 671: 192-199, 2023 09 03.
Article in English | MEDLINE | ID: mdl-37302294

ABSTRACT

The therapeutic effects and application of radiotherapy are restricted to some extent due to low radiosensitivity of tumor tissues and adverse effects by excess dosage. Current radiosensitizers are confronted with problems in clinical translation because of complicated manufacture technique and high cost. In this research, we have synthesized a radiosensitizer with advantages in low cost and mass production, which could be applied to CT imaging and enhanced radiotherapy in breast cancer, namely Bi-DTPA. It not only enhanced tumor CT imaging which resulted in better therapeutic accuracy, but also realized radiotherapy sensitization by producing massive ROS and inhibit tumor proliferation, providing a sound perspective in the clinical translation of the radiosensitizer.


Subject(s)
Neoplasms , Radiation-Sensitizing Agents , Humans , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/therapeutic use , Radiation Tolerance , Neoplasms/drug therapy , Pentetic Acid/pharmacology , Pentetic Acid/therapeutic use , Tomography, X-Ray Computed/methods
3.
Chem Biol Interact ; 378: 110488, 2023 Jun 01.
Article in English | MEDLINE | ID: mdl-37054935

ABSTRACT

Internal exposure to plutonium can occur through inhalation for the nuclear worker, but also for the public if the radionuclide was released into the atmosphere in the context of a nuclear accident or terrorist attack. DieThylenetriaminePentaAcetic acid (DTPA) is currently still the only authorized chelator that can be used to decorporate internalized plutonium. The Linear HydrOxyPyridinOne-based ligand named 3,4,3-Li(1,2-HOPO) remains the most promising drug candidate to replace it in the hopes of improving chelating treatment. This study aimed to assess the efficacy of 3,4,3-Li(1,2-HOPO) in removing plutonium from rats exposed to the lungs, depending on the timing and route of treatment, and almost always compared to DTPA at a ten-fold higher dose used as a reference chelator. First, early intravenous injection or inhalation of 3,4,3-Li(1,2-HOPO) demonstrated superior efficacy over DTPA in preventing plutonium accumulation in liver and bone in rats exposed by injection or lung intubation. However, this superiority of 3,4,3-Li(1,2-HOPO) was much less pronounced with delayed treatment. In rats given plutonium in the lungs, the experiments also showed that 3,4,3-Li-HOPO reduced pulmonary retention of plutonium more effectively than DTPA only when the chelators were injected early but not at delayed times, while it was always the better of the two chelators when they were inhaled. Under our experimental conditions, the rapid oral administration of 3,4,3-Li(1,2-HOPO) was successful in preventing systemic accumulation of plutonium, but not in decreasing lung retention. Thus, after exposure to plutonium by inhalation, the best emergency treatment would be the rapid inhalation of a 3,4,3-Li(1,2-HOPO) aerosol to limit pulmonary retention of plutonium and prevent extrapulmonary deposition of plutonium in target systemic tissues.


Subject(s)
Plutonium , Rats , Animals , Plutonium/analysis , Plutonium/pharmacology , Chelation Therapy , Chelating Agents/pharmacology , Chelating Agents/therapeutic use , Pentetic Acid/pharmacology , Pentetic Acid/therapeutic use , Lung , Lithium/pharmacology
4.
Biomed Pharmacother ; 155: 113668, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36088858

ABSTRACT

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and has poor prognosis. Theranostic agents are the current trend in drug development, but are lacking in EOC. YKL40 is predominantly expressed and involved in tumorigenesis in EOC. In this study, we developed a companion theranostic agent targeting YKL40. We measured YKL40 expression levels in ascites using ELISA and correlated them with the clinical outcomes of patients with EOC. We developed radionuclide labeled In-111/Lu-177-DTPA-YKL40 neutralizing antibodies and investigated their radiochemical purity, SPECT/CT imaging, bio-distribution, and therapeutic responses in ovarian cancer xenograft mice. We demonstrated that YKL40 expression levels in ascites were significantly higher in EOC patients with serous histological type, high tumor grade, advanced stage, tumor recurrence, chemoresistance, and tumor-related death. The radiochemical purity of In-111/Lu-177-DTPA-YKL40 neutralizing antibodies reached more than 90% after 24 h of labeling. SPECT/CT imaging showed significant accumulation of In-111-DTPA-YKL40 and Lu-177-DTPA-YKL40 antibodies at the tumor site of ovarian cancer xenograft mice 24 h after administration. Lu-177-DTPA-YKL40 antibodies significantly inhibited tumor growth in ovarian cancer xenograft mice. Our study indicated that In-111/Lu-177-DTPA-YKL40 neutralizing antibodies could be potential companion theranostic agents for patients with EOC.


Subject(s)
Ovarian Neoplasms , Radiopharmaceuticals , Female , Humans , Animals , Mice , Carcinoma, Ovarian Epithelial/pathology , Chitinase-3-Like Protein 1 , Ascites , Precision Medicine , Neoplasm Recurrence, Local , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Radioisotopes , Pentetic Acid/therapeutic use , Antibodies, Neutralizing/therapeutic use , Cell Line, Tumor
5.
Health Phys ; 123(3): 197-207, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35613373

ABSTRACT

ABSTRACT: An individual underwent an extensive diethylenetriaminepentaacetate (DTPA) chelation therapy that started several months after plutonium incorporation, most likely by inhalation of a soluble compound. After receiving multiple intravenous infusions of DTPA, the patient continued the treatment by pulmonary delivery of aerosolized DTPA. The purpose of the present work is to provide and discuss the bioassay data obtained during the DTPA aerosol therapy and compare them with those under the DTPA infusion therapy that have been largely interpreted elsewhere. As with DTPA given intravenously, each delayed DTPA inhalation increased the clearance of plutonium not only in urine but also in feces, thus demonstrating the ability to remove plutonium retained by extrapulmonary tissues. Also, the slow decline of increased plutonium urinary elimination together with enhanced fecal excretion are two features coherent with the contribution of intracellular chelation to overall decorporation. The therapeutic benefit of DTPA inhalation appeared lower than with DTPA infusion, most likely due to a lower amount of DTPA reaching the systemic compartments where plutonium chelation predominates. The results suggest that DTPA administration through aerosol could be an alternative to the invasive procedure using a needle, i.e., intravenous injection/infusion, when protracted decorporation therapy is needed following transuranic internalization. Indeed, the patient may be more inclined to undergo a chelation treatment for a longer period because taking DTPA by inhalation may make it less cumbersome and painful.


Subject(s)
Plutonium , Aerosols , Chelating Agents/therapeutic use , Chelation Therapy , Humans , Pentetic Acid/therapeutic use
6.
Health Phys ; 121(5): 494-505, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34591820

ABSTRACT

ABSTRACT: In a worker who had internalized plutonium, most likely through inhalation of a somewhat soluble compound, an extensive diethylenetriaminepentaacetate (DTPA) treatment regimen was initiated several months after contamination. Numerous radiotoxicological analyses were performed in both fecal and urinary specimens collected, sometimes for three consecutive days after DTPA administration. Activity measurements showed the continued effectiveness of DTPA intravenous infusions in removing plutonium from tissues of retention even if the treatment regimen started very belatedly after contamination. In the present case, the activity excreted through urine within the first 24-h after a DTPA infusion contributed only about half of that activity excreted within the first three days (i.e., the cumulative activity of the first three 24-h urine collections). In addition, the careful study of the data revealed that DTPA-induced excretion of plutonium via fecal pathway significantly contributed to the overall decorporation. The intracellular chelation of plutonium may be responsible for this enhanced excretion of activity in feces as well as for the delayed and sustained increased clearance of activity in urine. The authors would suggest that the occupational physicians offer to individuals who internalized moderately soluble or soluble plutonium compounds undergo a long-term DTPA treatment, especially when it is not initiated promptly after intake. Under this scenario, measurements of plutonium in successive urine and fecal collections after treatment should be required to get a better estimate of the therapeutic benefit. Also, intracellular chelation and fecal route should be taken into account for better interpretation of radiotoxicological data and modeling of plutonium kinetics under delayed DTPA treatment.


Subject(s)
Plutonium , Chelating Agents/therapeutic use , Feces/chemistry , Humans , Kinetics , Pentetic Acid/therapeutic use , Plutonium/analysis
7.
Health Phys ; 119(6): 715-732, 2020 12.
Article in English | MEDLINE | ID: mdl-33196524

ABSTRACT

The administration of chelation therapy to treat significant intakes of actinides, such as plutonium, affects the actinide's normal biokinetics. In particular, it enhances the actinide's rate of excretion, such that the standard biokinetic models cannot be applied directly to the chelation-affected bioassay data in order to estimate the intake and assess the radiation dose. The present study proposes a new chelation model that can be applied to the chelation-affected bioassay data after plutonium intake via wound and treatment with DTPA. In the proposed model, chelation is assumed to occur in the blood, liver, and parts of the skeleton. Ten datasets, consisting of measurements of C-DTPA, Pu, and Pu involving humans given radiolabeled DTPA and humans occupationally exposed to plutonium via wound and treated with chelation therapy, were used for model development. The combined dataset consisted of daily and cumulative excretion (urine and feces), wound counts, measurements of excised tissue, blood, and post-mortem tissue analyses of liver and skeleton. The combined data were simultaneously fit using the chelation model linked with a plutonium systemic model, which was linked to an ad hoc wound model. The proposed chelation model was used for dose assessment of the wound cases used in this study.


Subject(s)
Biological Assay/methods , Chelating Agents/therapeutic use , Occupational Exposure/analysis , Pentetic Acid/therapeutic use , Plutonium/analysis , Radiation Injuries/prevention & control , Wounds, Penetrating/drug therapy , Bone and Bones/metabolism , Chelation Therapy/methods , Data Interpretation, Statistical , Feces/chemistry , Humans , Liver/metabolism , Male , Models, Biological , Occupational Exposure/adverse effects , Plutonium/adverse effects , Radiation Dosage , Radiation Injuries/diagnosis , Radiation Injuries/urine , Urinalysis , Wounds, Penetrating/etiology
8.
Radiat Environ Biophys ; 58(2): 227-235, 2019 05.
Article in English | MEDLINE | ID: mdl-30627772

ABSTRACT

A recently proposed system of models for plutonium decorporation (SPD) was developed using data from an individual occupationally exposed to plutonium via a wound [from United States Transuranium and Uranium Registries (USTUR) Case 0212]. The present study evaluated the SPD using chelation treatment data, urine measurements, and post-mortem plutonium activities in the skeleton and liver from USTUR Case 0269. This individual was occupationally exposed to moderately soluble plutonium via inhalation and extensively treated with chelating agents. The SPD was linked to the International Commission on Radiological Protection (ICRP) Publication 66 Human Respiratory Tract Model (HRTM) and the ICRP Publication 30 Gastrointestinal Tract model to evaluate the goodness-of-fit to the urinary excretion data and the predictions of post-mortem plutonium retention in the skeleton and liver. The goodness-of-fit was also evaluated when the SPD was linked to the ICRP Publication 130 HRTM and the ICRP Publication 100 Human Alimentary Tract Model. The present study showed that the proposed SPD was useful for fitting the entire, chelation-affected and non-affected, urine bioassay data, and for predicting the post-mortem plutonium retention in the skeleton and liver at time of death, 38.5 years after the accident. The results of this work are consistent with the conclusion that Ca-EDTA is less effective than Ca-DTPA for enhancing urinary excretion of plutonium.


Subject(s)
Air Pollutants, Radioactive/urine , Chelating Agents/therapeutic use , Edetic Acid/therapeutic use , Inhalation Exposure , Models, Biological , Pentetic Acid/therapeutic use , Plutonium/urine , Radiation Injuries/prevention & control , Air Pollutants, Radioactive/pharmacokinetics , Bone and Bones/metabolism , Gastrointestinal Tract/metabolism , Humans , Liver/metabolism , Occupational Exposure , Plutonium/pharmacokinetics , Respiratory System/metabolism
9.
Mil Med Res ; 5(1): 27, 2018 08 06.
Article in English | MEDLINE | ID: mdl-30086798

ABSTRACT

A wide spectrum of scenarios may lead to radiation incidents and the liberation of radioactive material. In the case of a terrorist attack by a "dirty bomb", there is a risk of mechanical and thermal trauma, external irradiation, superficial contamination and incorporation of radioactive material. The first treatment priority must be given to the care of trauma patients with life-threatening injuries, as the health effects of radiation occur with latency. Radionuclide incorporation will lead to a longer-lasting irradiation from inside the body, associated with a higher risk of stochastic radiation effects (e.g., occurrence of tumors) in the long run. It must be expected that victims with potentially incorporated radionuclides will far outnumber trauma patients. The elimination of radionuclides can be enhanced by the administration of decorporation agents such as (Ca) Diethylenetriaminepentaacetic acid (DTPA) or Prussian blue, reducing the radiological burden of the body. There is still no consensus whether decorporation treatment should be started immediately based only on a suspicion of radionuclide incorporation ("urgent approach") or if the results of internal dosimetry confirming the necessity of a treatment should be awaited, accepting the delay caused by the measurements and computations ("precautionary approach"). As the therapeutic effectiveness may be substantially decreased if treatment initiation is delayed only by several days, depending on the radionuclide, the physicochemical properties of the compounds involved and the route of absorption, we favor an "urgent approach" from a medical point of view. In doubt, it seems justified to treat victims by precaution, as the adverse effects of the medication seem minimal. However, in the case of a high number of victims, an "urgent treatment approach" may require a large number of daily doses of antidotes, and therefore, adequate investments in preparedness and antidote stockpiling are necessary.


Subject(s)
Decontamination/methods , Nuclear Weapons , Radiation Injuries/therapy , Radiation-Protective Agents/therapeutic use , Radioactive Hazard Release , Animals , Antidotes/therapeutic use , Civil Defense , Disaster Medicine , Ferrocyanides/therapeutic use , Humans , Pentetic Acid/therapeutic use , Radioisotopes/chemistry , Radiometry , Terrorism
10.
Invest Radiol ; 53(6): 373-379, 2018 06.
Article in English | MEDLINE | ID: mdl-29419708

ABSTRACT

OBJECTIVES: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). MATERIALS AND METHODS: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. RESULTS: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. CONCLUSIONS: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.


Subject(s)
Antidotes/therapeutic use , Contrast Media/adverse effects , Gadolinium/adverse effects , Pentetic Acid/therapeutic use , Administration, Intravenous , Adult , Aged , Antidotes/administration & dosage , Contrast Media/metabolism , Female , Gadolinium/urine , Humans , Male , Middle Aged , Pentetic Acid/administration & dosage , Treatment Outcome
11.
Radiat Prot Dosimetry ; 178(2): 160-169, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-28985407

ABSTRACT

The National Council of Radiation Protection and Measurements' (NCRP) wound model was applied to the bioassay data from a United States Transuranium and Uranium Registries' whole-body tissue donor, Case 0212. This individual was exposed to plutonium nitrate as a result of an occupational wound injury and he underwent extensive chelation treatment with Ca-DTPA. All major soft tissues and bones were collected post-mortem and radiochemically analyzed for 238Pu, 239,240Pu and 241Am. The 239,240Pu activity in the total body was estimated to be 232.0 Bq, with 80.3 Bq retained in the liver, 115.1 Bq in the skeleton and 14.3 Bq in the wound. The maximum likelihood method was used to simultaneously fit the 'post-treatment' urinary excretion and post-mortem liver and skeleton retention data. It was demonstrated that the deposited material was predominantly a strongly retained soluble compound (nitrate) with a 22% fraction of plutonium particles. The residual intake, the amount of plutonium deposited in the wound that was not removed from the system by Ca-DTPA, was estimated to be 288 Bq. The resulting committed effective dose was 134 mSv. Accounting for plutonium eliminated in the urine during chelation therapy, the actual 'untreated' intake was 1204 Bq, and the projected committed effective dose was 567 mSv. Hence, DTPA treatment reduced the dose by a factor of 4.


Subject(s)
Finger Injuries/therapy , Nitrates/analysis , Nitrates/poisoning , Occupational Exposure/analysis , Plutonium/analysis , Plutonium/poisoning , Radiation Injuries/therapy , Chelating Agents/therapeutic use , Combined Modality Therapy , Fatal Outcome , Humans , Male , Middle Aged , Pentetic Acid/therapeutic use , Whole-Body Counting
12.
Health Phys ; 113(1): 30-40, 2017 07.
Article in English | MEDLINE | ID: mdl-28542009

ABSTRACT

After a chelation treatment, assessment of intake and doses is the primary concern of an internal dosimetrist. Using the urinary excretion data from two actual wound cases encountered at Los Alamos National Laboratory (LANL), this paper discusses several methods that can be used to interpret intakes from the urinary data collected after one or multiple chelation treatments. One of the methods uses only the data assumed to be unaffected by chelation (data collected beyond 100 d after the last treatment). This method, used by many facilities for official dose records, was implemented by employing maximum likelihood analysis and Bayesian analysis methods. The impacts of an improper assumption about the physicochemical behavior of a radioactive material and the importance of the use of a facility-specific biokinetic model when available have also been demonstrated. Another method analyzed both the affected and unaffected urinary data using an empirical urinary excretion model. This method, although case-specific, was useful in determining the actual intakes and the doses averted or the reduction in body burdens due to chelation treatments. This approach was important in determining the enhancement factors, the behavior of the chelate, and other observations that may be pertinent to several DTPA compartmental modeling approaches being conducted by the health physics community.


Subject(s)
Models, Biological , Pentetic Acid/therapeutic use , Plutonium/urine , Radiation Injuries/prevention & control , Radiation Injuries/urine , Urination , Chelation Therapy/methods , Computer Simulation , Humans , Male , Metabolic Clearance Rate , Plutonium/pharmacokinetics , Radiation Dosage , Radiation Monitoring/methods , Treatment Outcome , Wounds, Penetrating/metabolism , Wounds, Penetrating/therapy
13.
J Control Release ; 259: 168-175, 2017 08 10.
Article in English | MEDLINE | ID: mdl-28007514

ABSTRACT

Sodium dodecyl sulfate (SDS) is generally regarded as a potent permeability enhancer in oral formulations; however, one concern related to the use of any permeation enhancer is its possible absorption of unwanted toxins during the period of epithelial permeability enhancement. In this work, the safety and efficacy of an SDS-containing bubble carrier system that is developed from an orally administered enteric-coated capsule are evaluated. The bubble carriers comprise diethylene triamine pentaacetic acid (DTPA) dianhydride, sodium bicarbonate (SBC), SDS, and insulin. Upon exposure to the intestinal fluid, DTPA dianhydride hydrolyzes to yield acids, and SBC rapidly reacts with these acids to generate CO2, producing bubble carriers, each containing a self-assembling water film. The hydrophilic insulin is entrapped in the self-assembled water film, which is stabilized by SDS. The SDS in the bubble carrier system can act as a dissolution enhancer in the dispersion of insulin molecules, as a surfactant that stabilizes the bubble carriers, as a protease inhibitor that protects the protein drug, and as a permeation enhancer that augments its oral bioavailability. Hence, a significant increase in the plasma insulin level and an excellent blood glucose-lowering response in diabetic rats are effectively achieved. Moreover, the enhancement of epithelial permeation by this SDS-containing formulation does not promote the absorption of intestinal endotoxins. The above facts indicate that the bubble carrier system that is stabilized by SDS can be used as a safe and potent carrier in the oral delivery of therapeutic proteins.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Drug Carriers/administration & dosage , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Administration, Oral , Animals , Blood Glucose/analysis , Caco-2 Cells , Diabetes Mellitus, Experimental/blood , Drug Carriers/chemistry , Drug Carriers/therapeutic use , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Insulin/chemistry , Insulin/therapeutic use , Pentetic Acid/administration & dosage , Pentetic Acid/chemistry , Pentetic Acid/therapeutic use , Rats , Rats, Wistar , Sodium Bicarbonate/administration & dosage , Sodium Bicarbonate/chemistry , Sodium Bicarbonate/therapeutic use , Sodium Dodecyl Sulfate/administration & dosage , Sodium Dodecyl Sulfate/chemistry , Sodium Dodecyl Sulfate/therapeutic use , Trypsin/chemistry
14.
Nanomedicine (Lond) ; 11(16): 2035-47, 2016 08.
Article in English | MEDLINE | ID: mdl-27463088

ABSTRACT

AIM: Gold nanoparticles have attracted significant interest in cancer diagnosis and treatment. Herein, we evaluated the theranostic potential of dithiolated diethylenetriamine pentaacetic acid (DTDTPA) conjugated AuNPs (Au@DTDTPA) for CT-contrast enhancement and radiosensitization in prostate cancer. MATERIALS & METHODS: In vitro assays determined Au@DTDTPA uptake, cytotoxicity, radiosensitizing potential and DNA damage profiles. Human PC3 xenograft tumor models were used to determine CT enhancement and radiation modulating effects in vivo. RESULTS: Cells exposed to nanoparticles and radiation observed significant additional reduction in survival compared with radiation only. Au@DTDTPA produced a CT enhancement of 10% and a significant extension in tumor growth delay from 16.9 days to 38.3 compared with radiation only. CONCLUSION: This study demonstrates the potential of Au@DTDTPA to enhance CT-image contrast and simultaneously increases the radiosensitivity of prostate tumors.


Subject(s)
Gold/therapeutic use , Metal Nanoparticles/therapeutic use , Pentetic Acid/therapeutic use , Prostate/diagnostic imaging , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/radiotherapy , Radiation-Sensitizing Agents/therapeutic use , Animals , Cell Line, Tumor , Cone-Beam Computed Tomography , Gold/chemistry , Gold/pharmacokinetics , Humans , Male , Metal Nanoparticles/chemistry , Metal Nanoparticles/ultrastructure , Mice, SCID , Pentetic Acid/analogs & derivatives , Pentetic Acid/pharmacokinetics , Phantoms, Imaging , Prostate/pathology , Prostate/radiation effects , Prostatic Neoplasms/pathology , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacokinetics , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacokinetics , Sulfhydryl Compounds/therapeutic use , Theranostic Nanomedicine
15.
Appl Radiat Isot ; 114: 196-201, 2016 08.
Article in English | MEDLINE | ID: mdl-27258216

ABSTRACT

This study aimed at the preparation and evaluation of (177)Lu-CHX-A''-DTPA-Bevacizumab for targeting VEGF over-expressing cancers. Bevacizumab conjugated to p-NCS-Bn-CHX-A''-DTPA was radiolabeled with (177)Lu. The radioimmunoconjugate characterized by SE-HPLC exhibited radiochemical purity of 98.0±0.6%. In vitro stability was retained upto 4 days at 37°C. In vitro cell binding studies showed good uptake by VEGF expressing U937 tumor cells. Biodistribution studies in melanoma model showed significant uptake and retention of (177)Lu-CHX-A''-DTPA-Bevacizumab in tumor with reduction in uptake in presence of cold Bevacizumab confirming its specificity to VEGF.


Subject(s)
Bevacizumab/therapeutic use , Lutetium/therapeutic use , Pentetic Acid/analogs & derivatives , Radioimmunotherapy/methods , Radioisotopes/therapeutic use , Radiopharmaceuticals/therapeutic use , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Bevacizumab/pharmacokinetics , Cell Line, Tumor , Humans , Immunoconjugates/isolation & purification , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Lutetium/pharmacokinetics , Melanoma, Experimental/metabolism , Melanoma, Experimental/radiotherapy , Mice , Mice, Inbred C57BL , Pentetic Acid/pharmacokinetics , Pentetic Acid/therapeutic use , Radioisotopes/pharmacokinetics , Radiopharmaceuticals/isolation & purification , Radiopharmaceuticals/pharmacokinetics , U937 Cells , Vascular Endothelial Growth Factor A/immunology
16.
Appl Radiat Isot ; 110: 1-7, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26748017

ABSTRACT

Chimeric IgG1 monoclonal antibody CSL360 recognizes the CD123(+)/CD131(-) phenotype expressed by leukemic stem cells (LSC). Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates incorporating nuclear translocation sequence (NLS) peptides bound specifically to Raji cells transfected with CD123 and exhibited a KD of 11nmols/L in a competition receptor-binding assay using CD123-transfected CHO cells. (111)In-DTPA-NLS-CSL360 was bound, internalized and transported to the nucleus of human AML-5 myeloid leukemia cells. The clonogenic survival of AML-5 cells was reduced by (111)In-DTPA-NLS-CSL360 up to 3.7-fold. Isotype control (111)In-DTPA-chIgG1 was 2-fold less cytotoxic, and unlabeled CSL360, DTPA-NLS-CSL360 or free (111)In acetate did not decrease cell survival. These results are promising for further evaluation of (111)In-DTPA-NLS-CSL360 for Auger electron radioimmunotherapy of AML targeting the critical LSC subpopulation.


Subject(s)
Leukemia, Myeloid, Acute/radiotherapy , Antibodies, Monoclonal/therapeutic use , Cell Line, Tumor , Cytokine Receptor Common beta Subunit/metabolism , Humans , Immunoconjugates/therapeutic use , Indium Radioisotopes/therapeutic use , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia, Myeloid, Acute/immunology , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/radiation effects , Pentetic Acid/therapeutic use , Radioimmunotherapy , Radiopharmaceuticals , Tumor Stem Cell Assay
17.
Appl Biochem Biotechnol ; 179(2): 251-69, 2016 May.
Article in English | MEDLINE | ID: mdl-26801817

ABSTRACT

Recombinant therapeutic proteins have been considered as an efficient category of medications used for the treatment of various diseases. Despite their effectiveness, there are some reports on the systemic adverse effects of recombinant therapeutic proteins limiting their wide clinical applications. Among different cytokines used for cancer immunotherapy, interleukin-12 (IL-12) has shown great ability as a powerful antitumor and antiangiogenic agent. However, significant toxic reactions following the systemic administration of IL-12 have led researchers to seek for alternative approaches such as the delivery and local expression of the IL-12 gene inside the tumor tissues. In order to transfer the plasmid encoding IL-12 gene, the most extensively investigated polycationic polymer, polyethylenimine (PEI), was modified by diethylene triamine penta-acetic acid (DTPA) to modulate the hydrophobic-hydrophilic balance of the polymer as well as its toxicity. DTPA-conjugated PEI derivatives were able to form complexes in the size range around 100-180 nm with great condensation ability and protection of the plasmid against enzymatic degradation. The highest gene transfer ability was achieved by the DTPA-conjugated PEI at the conjugation degree of 0.1 % where the level of IL-12 production increased up to twofold compared with that of the unmodified PEI. Results of the present study demonstrated that modulation of the surface positive charge of PEI along with the improvement of the polymer hydrophobic balance could be considered as a successful strategy to develop safe and powerful nanocarriers.


Subject(s)
Gene Transfer Techniques , Interleukin-12/genetics , Nanoparticles/chemistry , Neoplasms/therapy , Cell Proliferation/genetics , Genetic Vectors , Hep G2 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Interleukin-12/biosynthesis , Interleukin-12/therapeutic use , Nanoparticles/therapeutic use , Neoplasms/genetics , Particle Size , Pentetic Acid/chemistry , Pentetic Acid/therapeutic use , Plasmids , Polyethyleneimine/chemistry , Polyethyleneimine/therapeutic use
18.
Clin Nucl Med ; 41(3): 194-200, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26673241

ABSTRACT

AIM: In patients with progressive, metastatic neuroendocrine tumors (NET), intra-arterial radionuclide infusions with high activities of In-[DTPA]-octreotide and more recently with non-carrier added (nca) Lu-[DOTA,Tyr]-octreotate have been performed with encouraging results. However, the affinity profiles (IC50) of these radiopeptides for human sst2 receptors are markedly different (In-[DTPA]-octreotide, 22 ± 3.6 nM and nca Lu-[DOTA,Tyr]-octreotate, 1.5 ± 4.0 nM). The total administered activity is determined by organ dose limits (kidneys and bone marrow), and our aim therefore was to compare and evaluate the therapeutic efficacy of both radiopeptides in metastatic NETs. METHODS: Thirty patients with gastroenteropancreatic (GEP) somatostatin-positive NETs with liver metastases confirmed on biopsy and In-pentetreotide scan were included. They were treated with In-[DTPA]-octreotide (n = 17) or nca Lu-[DOTA,Tyr]-octreotate (n = 13). Blood samples were collected 2, 4, 8, and 24 hours postadministration to calculate residence time in blood and in red marrow. The maximum percentage uptake in organs and tumors was estimated by region of interest analysis, and tumor dosimetry calculations were performed using OLINDA/EXM/ 1.0 software. RESULTS: ncaLu-[DOTA,Tyr3]-octreotate blood radioactivity, expressed as a percentage of the injected dose, was significantly lower than In-[DTPA]-octreotide (P < 0.05), as clearly depicted from the time-activity curves; the background-corrected tumor uptake was significantly higher than In-[DTPA]-octreotide but without any significant difference in other organs (spleen, kidneys, and liver). CONCLUSIONS: Using Lu-[DOTA,Tyr]-octreotate, a 3-fold higher absorbed dose to tumor tissue was achieved compared with In-[DTPA] octreotide. Residence time of nca Lu-[DOTA,Tyr]-octreotate results in a significantly higher absorbed dose to bone marrow compared with In-[DTPA]-octreotide. However, a drawback of In-[DTPA]-octreotide therapy is that the number of administrations would need to be almost doubled to achieve an equal therapeutic outcome as compared with Lu-[DOTA,Tyr]-octreotate.


Subject(s)
Liver Neoplasms/radiotherapy , Neuroendocrine Tumors/drug therapy , Octreotide/analogs & derivatives , Pentetic Acid/analogs & derivatives , Radiopharmaceuticals/therapeutic use , Adult , Aged , Female , Humans , Liver Neoplasms/secondary , Male , Neuroendocrine Tumors/pathology , Octreotide/administration & dosage , Octreotide/adverse effects , Octreotide/therapeutic use , Pentetic Acid/administration & dosage , Pentetic Acid/adverse effects , Pentetic Acid/therapeutic use , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/adverse effects
19.
Health Phys ; 106(6): 638-44, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24776894

ABSTRACT

There is an important requirement following accidental actinide contamination of wounds to limit the dissemination and retention of such alpha-emitting radionuclides. To reduce wound and systemic contamination, treatment approaches include chelation therapy with or without wound excision. However, it has been hypothesized that wound excision could lead to increased contaminant release and systemic organ retention. This study in the rat addresses this question. Anesthetized rats were contaminated with plutonium nitrate following wounding by deep incision of hind leg muscle. Excision of tissue at the contaminated site was performed 7 d later with or without Diethylene Triamine Pentaacetic Acid (DTPA) treatment (30 µmol kg⁻¹ i.v.). Pu urinary excretion was then measured for a further 3 d, and animals were euthanized at 14 d after contamination. Tissue samples were evaluated for Pu activity and histology. At 7 d after contamination, around 50% of the initial activity remained at the wound site. An average of 16% of this activity was then removed by surgery. Surgery alone resulted in increased urinary excretion, suggesting release from the wound site, but no subsequent increases in organ retention (bone, liver) were observed at 14 d. Indeed, organ Pu activity was slightly reduced. The combination of surgery and DTPA or DTPA treatment alone was much more effective than excision alone as shown by the markedly increased urinary Pu excretion and decreased tissue levels. This is the first report in an experimental rodent model of resection of Pu-contaminated wound. Urinary excretion data provide evidence for the release of activity as a result of surgery, but this does not appear to lead to further Pu organ retention. However, a combination of prior DTPA treatment with wound excision is particularly effective.


Subject(s)
Pentetic Acid/pharmacology , Plutonium/toxicity , Wounds and Injuries/drug therapy , Wounds and Injuries/surgery , Animals , Disease Models, Animal , Histones/metabolism , Male , Pentetic Acid/therapeutic use , Phosphoproteins/metabolism , Plutonium/urine , Radioactive Hazard Release , Rats , Rats, Sprague-Dawley , Wounds and Injuries/metabolism , Wounds and Injuries/pathology
20.
Calcif Tissue Int ; 93(5): 426-35, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23963635

ABSTRACT

Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly(lactic-co-glycolic acid) nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.


Subject(s)
Aortic Diseases/drug therapy , Chelating Agents/therapeutic use , Vascular Calcification/drug therapy , Aged , Animals , Aortic Diseases/pathology , Calcium/metabolism , Chelating Agents/pharmacology , Drug Evaluation, Preclinical , Edetic Acid/pharmacology , Edetic Acid/therapeutic use , Female , Humans , Male , Middle Aged , Pentetic Acid/pharmacology , Pentetic Acid/therapeutic use , Rats , Rats, Sprague-Dawley , Swine , Treatment Outcome , Vascular Calcification/pathology
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