99mTc-Radiolabeled TPGS Nanomicelles Outperform 99mTc-Sestamibi as Breast Cancer Imaging Agent.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) is a Food and Drug Administration (FDA) approved biomaterial that can form nanosized micelles in aqueous solution. TPGS micelles stand as an interesting system to perform drug delivery as they can carry lipophilic drugs and overcome P glycoprotein efflux as well. Therefore, TPGS micelles combined with other copolymers have been reported in many cancer research studies as a carrier for therapeutic drugs. Their ability to reach tumoral tissue can also be exploited to develop imaging agents with diagnostic application. A radiolabeling method with 99mTc for TPGS nanosized micelles and their biodistribution in a healthy animal model as well as their pharmacokinetics and radiolabeling stability in vivo was previously reported. The aim of this work was to evaluate the performance of this radioactive probe as a diagnostic imaging agent compared to routinely available SPECT radiopharmaceutical, 99mTc-sestamibi. A small field of view gamma camera was used for scintigraphy studies using radiolabeled TPGS micelles in two animal models of breast cancer: syngeneic 4T1 murine cell line (injected in BALB/c mice) and chemically NMU-induced (Sprague-Dawley rats). Ex vivo radioactivity accumulation in organs of interest was measured by a solid scintillation counter, and a semiquantitative analysis was performed over acquired images as well. Results showed an absence of tumoral visualization in 4T1 model for both radioactive probes by gamma camera imaging. On the contrary, NMU-induced tumors had a clear tumor visualization by scintigraphy. A higher tumor/background ratio and more homogeneous uptake were found for radiolabeled TPGS micelles compared to 99mTc-sestamibi. In conclusion, 99mTc-radiolabeled TPGS micelles might be a potential SPECT imaging probe for diagnostic purposes.

St. John's Wort accelerates the liver clearance of technetium-99-sestamibi in rats.

BACKGROUND: The intense liver uptake of technetium-99-sestamibi (Tc-MIBI) and photon scattering from the liver cause problems in quantitative perfusion interpretation. Hence, Tc-MIBI is a substrate for P-glycoprotein pump; variations in P-glycoprotein levels may affect liver clearance. METHODS AND RESULTS: Adult female Wistar rats were divided into seven main groups [control and St. John's Wort (SJW) treated] and each SJW-treated group included three subgroups that were killed at 15, 30, and 45 min after Tc-MIBI injection. Treated groups received an SJW extract suspension at two doses of 100 and 400 mg/kg once daily for 5, 10, and 14 days, respectively. Tc-MIBI was injected intravenously to all rats 24 h after the final treatment. The rats were anesthetized at the mentioned time after tracer injection, and heart and liver tissues were removed, weighed, and their radioactivity was counted. One rat from each group was selected randomly for myocardial perfusion imaging. A significant increase in liver clearance and heart-to-liver ratio was observed in all SJW-treated groups compared with the control, especially at 10 days after SJW treatment. The heart radioactivity decreased in SJW-receiving groups at 14 days after SJW treatment. CONCLUSION: This study showed that SJW extract accelerates the liver clearance of Tc-MIBI and significantly reduces photon scattering from the liver.

Relation between Tc-99m sestamibi uptake and biological factors in hyperparathyroidism.

PURPOSE: The aim of this study was to evaluate the relation between uptake ratios of Tc-99m sestamibi (MIBI) and tumor volume, serum biochemical values (i-PTH, Ca, P) and oxyphil cell content. MATERIALS AND METHODS: The study population consisted of 19 patients (2 M, 17 F; mean +/- SD: 47 +/- 12 y). Anterior planar images of the neck and chest were acquired early (15 min) and triple late phase (1, 2 and 3-4 h) after intravenous injections of 740 MBq MIBI. Each of the surgical materials was reviewed retrospectively. The percentage of cell type (chief, oxyphil and clear cells) in the tumors was calculated by light microscopy. RESULTS: The uptake ratio obtained from L1 (1 hour) phase was found to be higher than the uptake ratio obtained from early phase, and the difference was statistically significant (1.57 +/- 0.34 and 1.43 +/- 0.29, p = 0.004, respectively). There was no significant correlation between uptake ratios that were obtained from 4 different imaging phases and lesion volumes, i-PTH levels and calcium levels (p > 0.05). However, there was a significant adverse correlation between L2 and L3 uptake ratios and serum phosphorus values (r = -0.44, p = 0.04 and r = -0.46, p = 0.04, respectively). Additionally, no significant correlation between MIBI uptake ratios of each imaging phase and the laboratory data, volume of lesion or oxyphil percentage volume was found after the multiple regression analysis (E: p = 0.46, r = 0.49; L1: p = 0.24, r = 0.58; L2: p = 0.27, r = 0.57; L3: p = 0.32, r = 0.55, respectively. There was no correlation between gland oxyphil percentage volume and MIBI uptake ratios (p > 0.05). CONCLUSION: The results of our study show that the optimal imaging times after intravenous injection of MIBI are 15 minutes and 1 hour because of the shorter examination time without loss of diagnostic ability. In the present study, there was no significant correlation between MIBI uptake ratios and increased gland volume, or serum Ca and i-PTH levels. Besides, we think that oxyphil cell content may not have a main effect on MIBI uptake and retention. The fact of an adverse relation between phosphorus and MIBI retention in our study suggests that phosphorus level should be considered prior to MIBI imaging.

[MIBI and parathyroid gland function in secondary hyperparathyroidism]. / MIBI y funcionalismo de las glándulas paratiroideas en el hiperparatiroidismo secundario.

The role of the double phase parathyroid scintigraphy with MIBI in the primary hyperparathyroidism has been well studied. The present work analyzes the benefit of this image technique in the diagnosis and therapeutic approach to uremia associated hyperparathyroidism. We studied 18 dialysis patients with clinical and analytical data of hyperparathyroidism. All of them were receiving treatment with i.v. vitamin D. We carried out two scintigraphic studies, the first under basal conditions (without changes in treatment) and the second one, a week later after the stimulation of the parathyroid gland through the cessation of the treatment with vitamin D and phosphorus binders, and the use of a low-calcium dialysate. In the basal study, fourteen patients had a positive uptake test in at least one of the four glands. These patients had significantly higher PTHi levels than those with a negative scintigraphic study. After the stimulation test, we found a statistically significative rise in PHTi (644 vs 979 p < 0.001) and phosphorus levels (5.8 vs 7.3; p < 0.01), a slight fall in calcium levels (p = NS) and a statistically significative increment in the score of scintigraphic captation (5.5 +/- 4.5 vs 6.8 +/- 5; p < 0.05). We found a statistically significative correlation between the PTHi level and the score of scintigraphic uptake, in the basal study (r = 0.6, p < 0.01) and after stimulation (r = 0.6, p < 0.01). The only variable associated with the scintigraphic uptake was PTHi, justifying 31.1% of the variance in the first study and 32.7% in the second. In conclusion, the MIBI scintigraphic is a useful exploration in the uremic patient with hyperparathyroidism, as it predicts the functional state of the parathyroid glands according to uptake intensity. The stimulation test could be useful in planning therapy, but some of its characteristics need to be established, such as the precise time to reach the maximum level of parathyroid stimulation.

Impaired Tc-99m MIBI uptake in the thyroid and parathyroid glands during early phase imaging in hemodialysis patients.

The purpose of this study is to evaluate the possible reasons of an observation of diminished uptake of Tc-99m MIBI in the early phase of parathyroid scintigraphy in the thyroid and parathyroid glands in patients with chronic renal failure who are being evaluated for hyperparathyroidism. Fourteen patients with secondary hyperparathyroidism all on hemodialysis with supplement therapy consisting of mainly vitamin D and calcium carbonate were studied. Neck and mediastinum images obtained at early and late phases were evaluated both visually and semiquantitatively. Patients with high PTH levels on hemodialysis showed diminished accumulation of radioactivity in the thyroid glands in the early phase compared to the soft tissue with a ratio of 1.54 +/- 0.39 (mean +/- std). A control group consisting of 10 patients with osteoporosis and Rickets' disease on vitamin D therapy was taken as control group A, as well as 11 patients with no problems other than cardiac who were not on any medication as control group B and 8 patients on hemodialysis only with normal PTH levels as control group C. Patients in control group A and C showed diminished accumulation of radioactivity in the thyroid glands in the early phase compared to the soft tissue with a ratio of 1.57 +/- 0.43 and 1.34 +/- 0.13, respectively, while patients in control group B showed good uptake 3.18 +/- 0.43. None of the studies showed parathyroid pathology. The results of this study show that patients with chronic renal failure under hemodialysis treatment are prone to show decreased uptake of the radioactivity. Another finding is that vitamin D supplements can cause diminished uptake of Tc-99m MIBI. A possible explanation is mentioned in the literature by an increase in PGP level and multi-drug resistance, so we suggest that it may play a role in impaired Tc-99m MIBI uptake in the thyroid phase and recommend cessation of vitamin D3 metabolites before performing parathyroid scintigraphy.

Mitochondrial uptake of sestamibi distinguishes between normal, inflammatory breast changes, pre-cancers, and infiltrating breast cancer.

The evaluation of breast tissue using nuclear imaging is dependent upon the delivery and uptake of the isotope by breast tissue. This is dependent upon blood flow to the breast and functioning mitochondria. This 2-part study investigated (1) differences in uptake of sestamibi when blood flow is enhanced (breast enhanced scintigraphy test [BEST]), and (2) differences in isotope uptake in normal (Nl) breast tissue, inflammatory changes in breast tissue (ICB), and breast cancer (CA). In the first part of the study, 10 women were compared using both Miraluma and BEST imaging; in the second part, 195 people were studied using BEST imaging only. The results were compared with histopathologic specimens. Little difference was noted between Miraluma and BEST imaging in the first part. Women with ICB showed a statistically significant (P <.05) increase in isotope uptake using BEST imaging. This difference was even more significant (P <.005) in women with CA. During the second part of the study, BEST imaging demonstrated an exponential increase in tracer uptake. When maximal count activity was compared, there was a statistically significant (P <.001) difference between Nl and ICB, between ICB and atypia (A), and between A and CA. BEST imaging demonstrated significant increases in isotope delivery when compared with Miraluma imaging. These differences allowed differentiation of breast tissue, including the detection of early changes in breast tissue.

Scintimammography with 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestrad iol: a complementary role to 99mTc-methoxyisobutyl isonitrile in the characterization of breast tumors.

UNLABELLED: The aim of this study was to investigate a possible relationship between 99mTc-methoxyisobutyl isonitrile (MIBI) uptake and the estrogen receptor (ER) status of breast tumors as determined by 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestradi ol (MIVE) scintimammography. METHODS: Thirteen patients referred for MIVE scintimammography after abnormal mammography or finding of a suspect mass on physical examination were injected intravenously with MIVE. Planar images of the breasts and axillary region were taken with both radiopharmaceuticals and compared with pathologic examination of the tumor tissue and in vitro ER quantification. RESULTS: The presence of cancerous tissue, as indicated by MIBI uptake, is a prerequisite for the accumulation of MIVE by the breast tumors. There was no statistically significant correlation between the MIBI and MIVE tumor uptake ratios. However, the latter correlate well with the presence of ER, as determined by an in vitro assay. CONCLUSION: MIVE scans add unique information concerning the tumor ER status in breast cancer patients, which could contribute to a better characterization of the tumor and aid in the selection of the most appropriate treatment protocol.

Microprobe analysis of Tc-MIBI in heart cells: calculation of mitochondrial membrane potential.

Hexakis (2-methoxyisobutylisonitrile) technetium-99m (99mTc-MIBI) is a gamma-emitting radiopharmaceutical probe currently in clinical use to evaluate myocardial perfusion. Biochemical and cellular pharmacological studies have suggested that Tc-MIBI, a lipophilic cation, is sequestered in mitochondria in response to transmembrane potentials. To assess directly the subcellular distribution of the probe in heart tissue, cultured chick heart cells were analyzed by electron-probe X-ray microanalysis (EPXMA) following equilibration in micromolar concentrations of carrier-added 99Tc-MIBI, the ground-state radiopharmaceutical. Quantitation of the physiological elements Na, Ca, Mg, K, S, P, and Cl was correlated with exposure to increasing concentrations of 99Tc-MIBI. EPXMA signals indicated that 99Tc-MIBI was concentrated up to 1,000 times into mitochondria in a dose-dependent fashion based on measured Tc content in the mitochondria. Inner membrane potential (delta psi) of individual mitochondria was calculated as -117 mV using the Nernst equation. Concentrations of 99Tc-MIBI > 36 microM caused a significant efflux of K and Mg from the cell, as well as an increase in Cl in the mitochondria. Comparison of cell ultrastructure with conventional electron microscopy at extracellular 99Tc-MIBI concentrations of 36-72 microM showed no changes compared with control. 99Tc-MIBI allows valuable in situ investigation of cellular bioenergetics with EPXMA by quantitation of delta psi.

Comparison of single-photon emission computed tomographic (SPECT) myocardial perfusion imaging with thallium-201 and technetium-99m sestamibi in dogs.

OBJECTIVES: The purpose of the present study was to compare single-photon emission computed tomographic (SPECT) myocardial images of technetium-99m (Tc-99m) sestamibi and thallium-201 (Tl-201) isotopes in the same dog undergoing partial coronary occlusion during pharmacologic vasodilation. BACKGROUND: To date, no controlled study has been reported comparing SPECT Tc-99m sestamibi with SPECT Tl-201 imaging during stress with anatomic and physiologic standards. METHODS: Mongrel dogs were anesthetized with chloralose and instrumented to record left anterior descending coronary blood flow and aortic pressure. Partial coronary occlusion with a hydraulic cuff reduced coronary vascular conductance, which is equal to the coronary blood flow normalized to aortic pressure during peak vasodilation with intravenous adenosine. Each dog received 5 mCi of Tl-201, then 30 mCi of Tc-99m sestamibi during partial coronary occlusion at peak vasodilation. Tomographic myocardial imaging was performed in a 180 degrees anterior arc scan for 33.5 min, first with Tl-201, and later, without moving the dog, for 33.5 min with Tc-99m sestamibi. Postmortem staining defined the region underperfused because of its dependence on the artery that was partially occluded. RESULTS: In seven dogs with moderate reduction in coronary blood flow, coronary vascular conductance decreased with partial coronary occlusion (47 +/- 12%) during Tl-201 imaging and (47 +/- 8%, p = NS) during Tc-99m sestamibi imaging. The underperfused region was 23.9 +/- 6.4% of total left ventricular mass. Counts in the defects were 39% higher (0.86 +/- 0.08 of normal counts) for Tc-99m sestamibi than for Tl-201 (0.64 +/- 0.09 of normal counts, p < 0.001), and the defect on SPECT Tc-99m sestamibi images occupied only a fraction (0.37 +/- 0.30) of the area of the defect on the Tl-201 images of the same dog. Bull's-eye displays constructed from the pathologic slices showed that the Tl-201 defect size was closer to the underperfused region of the left ventricular mass determined pathologically than was the Tc-99m sestamibi defect size. In four additional dogs a severe, near total coronary occlusion was created during Tl-201 and Tc-99m sestamibi administration. In these dogs, similar defect contrast (0.55 +/- 0.12 vs. 0.62 +/- 0.09, p = NS) and areas (0.18 +/- 0.07 vs. 0.18 +/- 0.11, p = NS) were observed with Tl-201 and Tc-99m sestamibi, respectively. CONCLUSIONS: Tomographic myocardial imaging with Tc-99m sestamibi during moderately severe partial coronary occlusion underestimated the area of the defect relative to Tl-201 or to the pathologic reference standard in dogs. Defect contrast was sharper with tomographic myocardial Tl-201 than with tomographic myocardial Tc-99m sestamibi during moderately severe partial coronary occlusion.

Comparison of technetium-99m sestamibi and thallium-201 retention characteristics in canine myocardium.

OBJECTIVES: The aim of this study was to compare the myocardial retention of technetium-99m (Tc-99m) sestamibi and thallium-201 over a wide range of blood flow at different time points after tracer injection. BACKGROUND: Technetium-99m sestamibi has been proposed as a new perfusion tracer with better physical characteristics than those of thallium-201 for scintigraphic imaging. However, no studies have simultaneously compared the ability of both tracers to assess myocardial blood flow during pharmacologic vasodilation. METHODS: The myocardial retention of Tc-99m sestamibi and thallium-201 were compared over a wide range of blood flow induced by regional coronary occlusion and dipyridamole infusion in an open chest dog model. Myocardial retention of both tracers was determined by in vitro tissue counting at 2, 5, and 20 min after tracer injection and was correlated with microsphere-determined blood flow. RESULTS: Thallium-201 demonstrated greater absolute tissue retention than did Tc-99m sestamibi. At 2 min after tracer injection, there was an almost linear relation between the retention of both tracers and myocardial blood flow over a wide flow range. However, this relation was not maintained over time. At 20 min after injection, the retention of both tracers underestimated myocardial blood flow at higher flow rates. At 2, 5 and 20 min after injection, increments of relative tracer retention between the different levels of flow were always greater for thallium-201 than for Tc-99m sestamibi. CONCLUSIONS: Thallium-201 displays more suitable physiologic characteristics as a flow tracer and may allow better differentiation of myocardial regions with different levels of coronary flow reserve. For both tracers, early cardiac imaging may minimize underestimation of blood flow at higher flow rates.