Administration Of 99mTc Research Articles

Assessment of extremity exposure to technologists working manually with 99mTc-labelled radiopharmaceuticals and with an automatic injection system for 18F-FDG

The hands of nuclear medicine (NM) personnel involved in radiopharmaceutical preparation and administration can receive significant radiation doses. The dose distribution across the hand is nonuniform and the Hp(0.07) doses obtained by an individual passive ring dosimeter do not always present a real situation. The aim of this study was to assess the extremity exposure of NM workers working with 99mTc-labelled radiopharmaceuticals and with an automatic IRIDE (COMECER, Italy) 18F-FDG injection system. Hp(0.07) doses were measured using calibrated thermoluminescent dosimeters-100 (TLD-100) and were read by a RIALTO TLD (NE Technology) reader. It was found that the most exposed parts of the hand during work with 18F and 99mTc radionuclides are the fingertips of the thumb, index finger and middle finger. The maximum fingertip doses were 1.3–2.4 times higher compared with the doses from the typical monitoring position (base of the middle finger of the dominant hand). When working with 99mTc, the average hand doses were relatively high, i.e. 0.17 ± 0.04 and 0.37 ± 0.13 mSv Gbq−1 for the left and the right hand, respectively, during preparation, and 58 ± 20 and 53 ± 13 µSv GBq−1 for the left and the right hand, respectively, during administration of 99mTc labelled radiopharmaceuticals. Meanwhile, the lowest doses were found for hands during administration of 18F-FDG (average hand dose 28 ± 13 µSv GBq−1 for the left hand and 28 ± 7 µSv GBq−1 for the right hand), which shows the advantages of automated injection/infusion systems, thus implementation of automatic infusion/injection in hospitals could be an expedient way to optimize Hp(0.07) doses to NM workers.

Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes

Hydroxamamide (Ham) is a thiol-free chelating agent that forms technetium-99m (99mTc)-complexes with a metal-to-ligand ratio of 1:2 under moderate reaction conditions. Therefore, Ham-based chelating agents will produce 99mTc-labeled compounds with a bivalent targeting scaffold. For their universal usage, we developed a novel Ham-based bifunctional chelating agent, “Ham-Mal”, with a maleimide group that can easily conjugate with a thiol group, for to preparing 99mTc-labeled bivalent ligand probes. Ham-Mal was synthesized by a four-step reaction, and then reacted with cysteine or c(RGDfC) to produce Ham-Cys or Ham-RGD. These precursors were reacted with 99mTcO4- for 10 min under room temperature to obtain 99mTc-(Ham-Cys)2 and 99mTc -(Ham-RGD)2. The cellular uptake level of 99mTc-(Ham-RGD)2 by U87MG (high Integrin ɑvβ3 expression) cells was significantly higher than that by PC3 (low Integrin ɑvβ3 expression) cells at 60 min after the incubation, and the uptake was significantly suppressed by pre-treatment for 15 min with excess c(RGDfK) peptide. In the in vivo study with U87MG/PC3 dual xenografted BALB/c-nu mice, the radioactivity of U87MG tumor tissue was significantly higher than that of PC3 tumor tissue at 360 min after the administration of 99mTc-(Ham-RGD)2. These results suggest Ham-Mal may have potential as a bifunctional chelating agent for 99mTc-labeled bivalent ligand probes.

RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature.

Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability. We next investigated the biomechanics of RBC adhesion in the context of local inflammatory cytokines after treatment with RRx-001 as a potential mechanism for preferential tumor aggregation. Human HEP-G2 and HT-29 tumor cells were subcutaneously implanted into nu/nu mice and were infused with RRx-001-treated and Technetium-99m (99mTc)-labeled blood. RBC adhesion was quantified in an in vitro human umbilical vein endothelial cell (HUVEC) assay under both normoxic and hypoxic conditions with administration of either lipopolysaccharide (LPS) or Tumor necrosis alpha (TNF) to mimic the known inflammation in the tumor microenvironment. One hour following administration of 99mTc labeled RBCs treated with 10 mg/kg RRx-001, we observed an approximate 2.0-fold and 1.5-fold increase in 99mTc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. Furthermore, we observed an approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001. To quantify RBC adhesive potential, we determined , or the shear stress required for 50% disassociation of RBCs from HUVECs. After administration of TNF-α under normoxia, was determined to be 4.5 dynes/cm2 (95% CI: 4.3–4.7 dynes/cm2) for RBCs treated with 10 M RRx-001, which was significantly different (p < 0.05) from in the absence of treatment. Under hypoxic conditions, the difference of with (4.8 dynes/cm2; 95% CI: 4.6–5.1 dynes/cm2) and without (2.6 dynes/cm2; 95% CI: 2.4–2.8 dynes/cm2) 10 M RRx-001 treatment was exacerbated (p = 0.05). In conclusion, we demonstrated that RBCs treated with RRx-001 preferentially aggregate in HEP-G2 and HT-29 tumors, likely due to interactions between RRx-001 and cysteine residues within RBCs. Furthermore, RRx-001 treated RBCs demonstrated increased adhesive potential to endothelial cells upon introduction of TNF-α and hypoxia suggesting that RRx-001 may induce preferential adhesion in the tumor but not in other tissues with endothelial dysfunction due to conditions prevalent in older cancer patients such as heart disease or diabetic vasculopathy.

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic® 904 (T904) and Tetronic® 701 (T701) and one hydrophilic poloxamer; Synperonic® PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert® software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m (99mTc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 μg/cm2.h compared to 7.324 μg/cm2.h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula (99mTc–M5) in brain and brain/blood ratio following IN administration of 99mTc–M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

Preparation and characterization of radiolabeled magnetic nanoparticles as an imaging agent

Magnetic nanoparticles were prepared by a reduction–precipitation method and coated with an amino silane coupling agent. Guanine (Gua) was conjugated to the magnetic nanoparticles (MNPs) using glutaraldehyde as a cross-linker. Common techniques (Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and vibrating electron microscopy) were used to assess the properties of the particles. Structural investigations showed that amino silane-coated MNPs had a particle size of about 40–60 nm in diameter with a spherical morphology. The guanine-conjugated MNPs were radiolabeled with 99mTc(I)-tricarbonyl core (99mTc(CO)3-MNP-Gua) with a labeling yield of 72 ± 4 %. Pure radiolabeled magnetic particles were obtained by washing them with saline solution, and the radiochemical purity of 99mTc(CO)3-MNP-Gua was 98 ± 2 % in the final solution. The biologic distribution of guanine MNPs was assessed in New Zealand rabbits using a gamma camera. In the in vivo experiment, a high level of radioactivity was observed in the lungs and liver soon after intravenous administration of 99mTc(CO)3-MNP-Gua.

The Effect of 99mTc on Dual-Energy X-Ray Absorptiometry Measurement of Body Composition and Bone Mineral Density

Whether the γ-emission by radioisotopes influences the outcome of dual-energy X-ray absorptiometry (DXA) measurements is not fully elucidated. The aim of this study was to evaluate the effect of antecedent administration of 99mTc on DXA measurements regarding body composition and bone mineral density (BMD) using a K-edge filter scanner. The phantom measurements were performed by placing a urinary bladder phantom containing 40mL of radioisotope solution on the pelvic region of a whole-body phantom. Twenty-seven patients attending our department for a routine examination involving the administration of a tracer marked with 99mTc were included. The patients underwent a whole-body DXA scan before and within 2h after tracer injection using a GE/Lunar Prodigy scanner. Control scans were performed on 40 volunteers, who had not received any radioactive tracer. In both phantom and patient measurements, we found a significant dose-related decrease in fat mass and BMD and a corresponding increase in fat-free mass (p<0.001). Based on the linear regression analysis, we suggest upper dose limits for the measurement of BMD at 0.77μSv/h and body composition at 0.21μSv/h (dose rate measured at a distance of 1m from the patient). Caution should be taken when interpreting the results of DXA scans performed in close temporal proximity to procedures involving the administration of 99mTc.

Scientific Presentation Abstracts 2009 American College of Veterinary Surgeons Veterinary Symposium October 8–10, Washington, DC

Osteomyelitis is an infective process characterized by chronic morbidity. The persistence of this disease despite antimicrobial therapy may be attributed to poor tissue concentration, impaired local immune response, biofilm formation, changes in rate of bacterial growth and their quorum sensing abilities, and intracellular localization of pathogens. Therefore, the development of a new strategy for targeting antimicrobial agents to bone tissues is urgent. Liposomes have been extensively used as carriers of antimicrobial and antineoplastic drugs. Liposomes are phospholipid nanoparticles that extravasate at sites of increased vascular permeability, such as sites of infection. Liposomal encapsulation of antimicrobials is a drug delivery system that increases the therapeutic index of these drugs by increasing their concentration at the site of infection and reducing potential negative side effects. This study is the first to describe the intravenous administration of 99mTc-labelled polyethylene-glycol PEG) coated liposomes in horses. There were minimal adverse effects associated with intravenous administration of 99mTc labeled liposomes in healthy adult horses. This study establishes normal scintigraphic findings after administration of 99mTc PEG liposomes to which clinical images can be compared, with the goal of utilizing 99mTc-PEG liposomes as a diagnostic aid. Liposomes have significant potential in horses, as a diagnostic tool and for targeted drug delivery in the management of refractory infections and neoplasia. Having addressed safety issues associated with intravenous liposome administration in horses, we now plan to study distribution patterns and efficacy of intravenous liposome administration for targeted delivery of drugs in the treatment of refractory orthopedic and soft tissue infections.

Scintigraphic evaluation of mandibular bone turnover inhibition by bisphosphonates in patients with solid tumors

9519 Background: Bisphosphonates (BP) have been associated with the occurrence of osteonecrosis of the jaw (ONJ), possibly by causing an excessive inhibition of local bone turnover. However, little in vivo evidence currently exists to support this theory. Methods: Whole-body scintigrams acquired after administration of 99mTc labeled medronate of 120 patients were studied. Patients with skeletal metastases from a solid tumor (n=40) were individually matched with cancer patients without BP exposure (n=40) and controls with neither a malignancy nor BP use (n=40). Controls were matched for age, gender, malignancy, steroid and hormonal therapy use, where appropriate. Patients with established ONJ or intense focal abnormalities in the studied regions were excluded. Mandibular bone turnover (MBT) was quantified relative to the femurs by defining regions-of-interest on the scintigrams with correction for background activity. The study had a power of 90% to detect a 10% reduction in MBT after BP use. Results were analyzed using a repeated-measures ANOVA with a two-sided significance level of p&lt;0.05. Results: The patients with BP exposure (34 female, 6 male) had a median age of 62 years (range 25–80) and received a median number of 11 zoledronic acid administrations (range 1–48). Malignancies included: breast (n=30), prostate (n=4), colon (n=2) and bladder cancer (n=2); and neuroendocrine carcinoma (n=2). The mean MBT was significantly lower in BP using cancer patients (2.59) compared with matched controls from oncological patients without BP use 3.01 (difference 0.42; 95% CI 0.13 - 0.72; p=0.006), or patients without cancer or BP exposure 3.09 (difference 0.50; 95% CI 0.21 - 0.78; p=0.001). In contrast, there was no significant difference in MBT between non-BP users (difference 0.08; 95% CI -0.31 - 0.46; p=0.7). Likewise, no correlation between MBT and the number of BP administrations could be demonstrated (r2=0.01; p=0.4), suggesting a stochastic rather than a deterministic effect. Conclusions: This in vivo data suggests that BP cause a higher inhibition of bone turnover in the mandible relative to the femur, which strengthens the hypothesis that the inhibition of bone turnover may be important in the pathophysiology of ONJ. [Table: see text]

Evaluation of the efficacy of 99mTc-labeled ascorbic acid on common cold–cough drugs in rats

Multiple-drug therapy is common in current clinical practice. Because of this, people have been ready to embrace simplistic approaches to cold treatment, such as vitamin C and zinc. Ascorbic acid (vitamin C) is mostly administrated together with cough–cold drugs. The aim of this study was to investigate the effect of cough–cold drugs on the uptake of ascorbic acid using 99mTc-ascorbic acid (99mTc-AA) in male albino Wistar rats. Ascorbic acid was labeled with Tc-99m and the distribution of 99mTc-AA was investigated. The uptake of 99mTc-AA was evaluated when administrated alone (group I), with chlorpheniramine maleate (CPR) (group II), with phenylpropanolamine hydrochloride (PPA) (group III), and with acetaminophen (APAP) (group IV). In some organs (apart from kidneys, intestinal system, and stomach) the uptake of 99mTc-AA was not significantly affected by the administration of 99mTc with CPR or 99mTc with APAP at 120 min. On the other hand, there was significant difference in the uptake of 99mTc-AA between groups I and III. The administration of 99mTc-AA with PPA in rats caused an increase of the uptake of 99mTc-AA at 120 min in the investigated organs compared to the administration of 99mTc-AA alone. The present data show that vitamin C might be more effective for the treatment of common cold when coadministered with PPA compared to with CPR, with APAP, or alone.

Induction of unstable and stable chromosomal aberrations by 99mTc: in-vitro and in-vivo studies

Biological dosimetry, which determines the dose of acquired radiation by measuring radiation-induced variation of biological parameters, can help assess radiation damage in an individual. Evaluation of radiation exposure requires setting up reference curves for each type of radiation. To evaluate the potential induction of chromosome aberrations by a clinical diagnostic dose of 99mTc. Dicentrics, rings, excess fragments, complete reciprocal translocations and incomplete reciprocal translocations were scored in peripheral blood lymphocytes from patients exposed to a 99mTc bone scintigraphy. A specific relationship between the radiation dose delivered by 99mTc and the frequency of stable and unstable chromosomal aberrations was established in vitro to estimate whole-body dose. Chromosome analysis using fluorescence plus Giemsa and fluorescence in-situ hybridization was undertaken on six patients before and after a 99mTc bone scintigraphy. Dicentrics, rings, excess fragments, and translocations were scored in blood lymphocytes after in vitro 99mTc external irradiation in order to construct dose calibration curves. Analysis of the in-vitro data shows that the number of both unstable and stable aberrations has a quadratic linear relationship to the dose. Our in-vivo irradiation studies showed that activities of 99mTc-hexamethylene diphosphonate (99mTc-HDP) used for bone investigations do not induce any additional unstable chromosome aberrations and translocations. The frequencies obtained did not differ significantly from background values. 99mTc can produce unstable and stable chromosomal aberrations in vitro. 99mTc-HDP administration does not induce supplementary chromosomal aberrations. The dose-response curves will allow a more accurate evaluation of the risk related to in-vivo administration of 99mTc labelled radiopharmaceuticals, and they can be used to assess the safe upper limit of injected activity in humans.

Monitoring the effect of PEGylation on polyethylenimine in vivo using nuclear imaging technique

Polyethyleneimine (PEI) has been extensively investigated for use as a nonviral gene delivery vector due to its “proton sponge” mechanism. This work monitored the effect of PEGylation in vivo using nuclear imaging technique. We synthesized galactosylated PEI-PEG with different levels of PEG substitution ranging from 4.1 to 13.3 mol% of PEI amino groups. Validation of the differences of the in vivo distribution in the varying degrees of PEG substitution was performed using nuclear imaging with a gamma camera. PEGylated PEIs could easily label with reduced 99mTc because of their interaction with PEI amino groups. After systemic administration of 99mTc PEGylated Gal-PEIs, rapid accumulation in the liver, spleen, and lung was observed. However, with increasing amounts of PEG, the lung uptake was markedly reduced. These results demonstrate that nuclear imaging technique may be used as a basic screening tool for determining the optimized system of PEGylated Gal-PEIs. Once optimized, this system could be used as a hepatocyte targeted non-viral gene delivery vector which minimizes unspecific interactions with cellular blood components such as vessel endothelia and plasma proteins.

In vivo kinetics of 99mTc labeled recombinant tissue plasminogen activator in rabbits.

Our previous studies demonstrated that 99mTc labeled recombinant tissue plasminogen activator (rt-PA) retained high affinity with fibrin in vitro but showed unexpectedly low uptake in fresh thrombi in vivo. The present study was performed to determine the in vivo kinetics of radiolabeled t-PA in the rabbit. Sequential images and blood samples after the intravenous administration of 99mTc labeled rt-PA in thrombus-bearing rabbits were taken. The radioactivity and immunological level of t-PA and PAI-1 in the solution eluted to each fraction by gel permeation chromatography were measured by means of a well scintillation counter and enzyme-linked immunosorbent assay (ELISA). Most of the radioactivity was eluted in the fraction (Fr. 7) of larger molecular weight than that (Fr. 9) of intact t-PA. The level of intact rt-PA was increased with a regimen involving the preadministration of cold rt-PA which was followed by the administration of hot rt-PA. The level of PAI-1 in plasma showed an increased rebound 15 minutes after the intravenous injection. These results suggest two possible reasons why rt-PA retains high affinity with fibrin in vitro, once radiolabeled, but was ineffective in delineating fresh thrombi with a gamma camera: 1) some plasma components such as PAI-1 combine with circulating radiolabeled rt-PA and form a larger molecule immediately and/or 2) radiolabeled rt-PA is modulated as a consequence of the radiolabeling and forms a larger molecule than intact rt-PA.

Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA) 2− and 99MTc(DTPA) in rats

Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co-administration of 99mTc(DTPA) and 153Gd-labeled Gd(DTPA) 2− at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better ( P < 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA) 2− had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA) 2− doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.

Nuclear medicine studies of aging—IV.Femoral proximal to distal radionuclide uptake gradient

Analyses of radionuclide bone scans were carried out to determine if, with the aging process, there were measurable changes in the femoral gradient of activity from proximal to distal portions of bone. Images of the femoral region were obtained using a gamma camera 2-3 h after i.v. administration of 99mTc labeled MDP. Sixty patients (1-85 years old) were selected based on the criteria that their femoral images appeared normal and there was no history of limb disease. Radionuclide concentrations at the upper, middle, and lower regions of the femur were determined from the femoral scans by using an optical densitometer, and background corrected. Results were expressed as ratios of upper to middle, lower to middle, and upper to lower regions of the femur. The analysis showed that the lower to middle ratio declined with age.

Red Blood Cell Labelling by Intravenous Injection Of 99mTC-PAEP

In vivo red blood cell (RBC) labelling after the intravenous administration of PAEP (N- phosphorylamino -ethyl -phosphate) and the subsequent injection of sodium pertechnetate 24 hrs later was studied. The results in rats were found to be similar to those obtained after i.v. administration of 99mTc -PYP, a radiopharmaceutical routinely used for in vivo RBC labelling.

Radioisotope serial brainscanning.

A technique is described for the detection and vascular characterisation of intracranial lesions which consists of the administration of 99mTc (15 mCi) by intravenous bolus injection followed by rapid sequential recording using an Anger Camera, 1600 channel analyser and a magnetic tape transport and memory system. Using this method, and after correlation with 10 normals it was possible to demonstrate in 46 patients with proved intracranial lesions an increase or decrease of activity corresponding to the nature of the lesion.

Retrospective evaluation of isotope images of the brain in 852 patients.

The value of brain scanning in the evaluation of intracranial disorders has been well established (12–15). Introduction of the scintillation camera further enhanced the diagnostic value of isotope imaging of the brain. Addition of technetium99m in the pertechnetate form to the armamentarium of radioisotopes available for brain studies allowed the use of a larger dose of isotopes with a markedly lowered patient dose and resulted in brain images of finer detail and, consequently, more accurate diagnoses. Materials and Methods Between March 1965 and March 1966 isotope-imaging of the brain was carried out in a total of 942 patients. Ninety of these patients, referred from outside hospitals, were lost to follow-up and were therefore eliminated from the study, leaving a total of 852 patients included. All were followed for a minimum of one year after the brain examination, and many have been followed for as long as two years. Technetium 99m was the radioisotope employed in the great majority of the patients, but 197Hg chlormerodrin was used in a few instances. Isotope images were obtained by employing a rectilinear scanner (Picker Mag-nascanner—3 × 2-inch crystal and 19-hole collimator) or a scintillation camera (Nuclear-Chicago) with an 11 × 1/2-inch diameter crystal and 3-inch-thick multichannel collimator with 1,600 holes (1). In some instances both modes were used in examining a patient. One millicurie of 197Hg chlormerodrin or 10 microcuries of 99mTc pertechnetate was administered intravenously. Scanning was performed one hour after administration of 99mTc and two to four hours after administration of 197Hg chlormerodrin. The patients ranged in age from infancy to seventy-five years. Isotope images originally reported as being definitely positive or negative were accepted as valid and not reviewed further. Those studies reported as equivocal or thought on other bases to be possibly in error were reviewed and analyzed in retrospect. Known normal and abnormal isotope images were included randomly among those reviewed by the authors in order to maintain objectivity in the re-evaluation. This re-evaluation was felt to be justified on the basis of learning by experience how to better interpret isotope images of the brain. Results Of the 852 brain imaging studies analyzed, 642 (75.4 per cent) were interpreted as negative. The majority of these patients were followed in the neurology and medical clinics, and some were seen at postmortem examination. In no instance was gross brain pathology found. In 125 patients (14.6 per cent) the results were definitely positive and were verified by either surgery, autopsy, or strong clinical and/or x-ray evidence (TABLE I). The findings on the isotope images were equivocal in 58 patients (6.8 per cent).