The presence of iodinated contrast agents amplifies DNA radiation damage in computed tomography

The purpose of this study was to determine the influence of iodinated contrast agents on the formation of DNA double-strand breaks in vitro in lymphocytes and to verify these results in patients undergoing diagnostic computed tomography examinations. Blood samples were irradiated in vitro in the presence of iodinated X-ray contrast agent. Controls were irradiated without contrast agent. Fourteen patients were investigated using contrast-enhanced computed tomography (CT), and 14 other patients with unenhanced CT. Blood samples were taken prior to and 5 min and 1, 2 and 24 h after the CT examination. In these blood samples the average number of γH2Ax-foci per lymphocyte was enumerated by fluorescence microscopy. Statistical differences between foci numbers developed in the presence and absence of contrast agent were tested using an independent sample t-test. In vitro foci numbers after irradiation were significantly higher when contrast agent was present during irradiation. In vivo, γH2Ax-foci levels were 58% higher in patients undergoing contrast-enhanced CT compared with those undergoing unenhanced CT. In the presence of iodinated contrast agents DNA, damage is increased and the radiation dose is not the only factor affecting the amount of DNA damage. Individual patient characteristics and biological dosimetry applications, e.g. the analysis of γH2Ax-foci, have to be considered.

Intravenous Iodinated Contrast Agents Amplify DNA Radiation Damage at CT

PURPOSE To determine the effect of the use of iodinated contrast agents on the formation of DNA double-strand breaks during chest computed tomography (CT). MATERIALS AND METHODS This study was approved by the institutional review board, and written informed consent was obtained from all patients. This single-center study was performed at a university hospital. A total of 179 patients underwent contrast material-enhanced CT, and 66 patients underwent unenhanced CT. Blood samples were taken from these patients prior to and immediately after CT. In these blood samples, the average number of phosphorylated histone H2AX (γH2AX) foci per lymphocyte was determined with fluorescence microscopy. Significant differences between the number of foci that developed in both the presence and the absence of the contrast agent were tested by using an independent sample t test. RESULTS γH2AX foci levels were increased in both groups after CT. Patients who underwent contrast-enhanced CT had an increased amount of DNA radiation damage (mean increase ± standard error of the mean, 0.056 foci per cell ± 0.009). This increase was 107% ± 19 higher than that in patients who underwent unenhanced CT (mean increase, 0.027 foci per cell ± 0.014). CONCLUSION The application of iodinated contrast agents during diagnostic x-ray procedures, such as chest CT, leads to a clear increase in the level of radiation-induced DNA damage as assessed with γH2AX foci formation.

Contrast agents and ionization with respect to safety for patients and doctors

In hemodialysis patients, radiographic imaging with iodinated contrast medium (ICM) application plays a central role in the diagnosis and/or follow-up of disease-related conditions. Therefore, safety aspects concerning ICM administration and radiation exposure have a great impact on this group of patients. Current hardware and software improvements including the design and synthesis of modern contrast compounds allow the use of very small amounts of ICM in concert with low radiation exposure. Undesirable ICM side effects are divided into type A (predictable reactions such as heat feeling, headache, and contrast-induced acute kidney injury, for example) and type B (nonpredictable or hypersensitivity) reactions; this chapter deals with the latter. The first onset cannot be prevented. To prevent hypersensitivity upon reexposure of ICM, an allergological workup is recommended. If this is not possible and ICM is necessary, the patient should receive a premedication (H1 antihistamine with or without corticosteroids). Current imaging hardware and software improvements (e.g. such as additional filtration of the X-ray beam) allow the use of very small amount of ICM and small X-ray doses. Proper communication among the team involved in the treatment of a patient may allow to apply imaging protocols and efficient imaging strategies limiting radiation exposure to a minimum. Practical recommendations will guide the reader how to use radiation and ICM efficiently to improve both patient and staff safety.

Synthesis and evaluation of Gd-DTPA-labeled arabinogalactans as potential MRI contrast agents

Arabinogalactan derivatives conjugated with gad olinium-diethylenetriaminepentaacetic acid (Gd-DTPA) by ethylenediamine (Gd-DTPA-CMAG-A(2)) or hexylamine (Gd-DTPA-CMAG-A(6)) have been synthesized and characterized by means of Fourier transform infrared spectra (FTIR), C-13 nuclear magnetic resonance (C-13 NMR), size exclusion chromatography (SEC), and inductively coupled plasma atomic emission spectrometry (ICP-AES).

Mn(II)-monosubstituted polyoxometalates as candidates for contrast agents in magnetic resonance imaging

Two mono-substituted manganese polyoxometalates, K6MnSiW11O39 (MnSiW11) and K8MnP2W17O61 (MnP2W17), have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific contrast agents for magnetic resonance imaging (MRI). T-1-relaxivities of 12.1 mM(-1) s(-1) for MnSiW11 and 4.7 mM(-1) s(-1) for MnP2W17 (400 MHz, 25 degrees C) were higher than or similar to that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in BSA and hTf solutions were also reported. After administration of MnSiW11 and MnP2W17 to Wistar rats, MR imaging showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 74.0 +/- 4.9% for the liver during the whole imaging period (90 min) and by 67.2 +/- 5.3% for kidney within 20-70 min after injection at 40 +/- 3 mu mol kg(-1) dose for MnSiW11. MnP2W17 induced 71.5 +/- 15.1%. enhancement for the liver in 10-45 min range and 73.1 +/- 3.2% enhancement for kidney within 5-40 min after injection at 39 +/- 3 mu mol kg(-1) dose. In vitro and in vivo study showed MnSiW11 and MnP2W17 being favorable candidates as the tissue-specific contrast agents for MRI.

The gadolinium complexes with polyoxometalates as potential MRI contrast agents

The two gadolinium (Gd) polyoxometalates, K-15[Gd(BW11O39)(2)] [Gd(BW11)(2)] and K-17[Gd(CuW11O39)(2)] [Gd(CuW11)(2)] have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific magnetic resonance imaging (MRI) contrast agents. T-1 relaxivities of 17.12 mM(-1) . s(-1) for Gd(BW11)(2) and 19.95 mM(-1) . s(-1) for Gd(CuW11)(2) (400MHz, 25 degrees C) were much higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin solutions were also reported. After administration of Gd(BW11)(2) and Gd(CuW11)(2) to Wistar rats, MRI showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 37.63 +/- 3.45% for the liver during the whole imaging period (100 min) and by 61.47 +/- 10.03% for kidney within 5-40 min after injection at 40 +/- 1-mu mol . kg(-1) dose for Gd(CuW11)(2), and Gd(BW11)(2) induced 50.44 +/- 3.51% enhancement in the liver in 5-50-min range and 61.47 +/- 10.03% enhancement for kidney within 5-40 min after injection at 39 +/- 4 mu mol . kg(-1) dose. In vitro and in vivo study showed that Gd(BW11)(2) and Gd(CuW11)(2) are favorable candidates as tissue-specific contrast agents for MRI.

Investigation of sandwiched gadolinium(III) complexes with tungstosilicates as potential MRI contrast agents

Two gadolinium-sandwiched complexes with tungstosilicates, K-13[Gd(SiW11O39)(2)] (Gd(SiW11)(2)) and K11H6[Gd2O3(SiW9O34)(2)] (Gd-3(SiW9)(2)), have been investigated by in vitro and in vivo experiments as potential contrast agents for magnetic resonance imaging (MRI). T-1-relaxivity of Gd(SiW11)(2)was 6.59 mM(-1) . s(-1) in aqueous solution and 6.85 mM(-1) . s(-1) in 0.725 mmol . L-1 bovine serum albumin solution at 25degreesC and 9.39 T, respectively. The corresponding T-1-relaxivity of Gd-3(SiW9)(2) was 12.6 and 19.3 mM(-1) . s(-1) per Gd, respectively. MRI for Sprague-Dawley rats showed longer and more remarkable enhancement in rat liver after i.v. injection of these two complexes: 39.4 +/- 3.9% and 57.4 +/- 11.6% within the first 30 min after injection, 31.2 +/- 2.6% and 39.9 +/- 7.6% in the next 60 min for Gd(SiW11)(2) and Gd-3(SiW9)(2) at doses of 0.081 and 0.084 mmol Gd/kg, respectively. Our preliminary in vitro and in vivo study indicates that Gd(SiW11)(2) and Gd-3(SiW9)(2) are favorable candidates for hepatic contrast agents for MRI. However, the two complexes exhibit higher acute toxicity and need to be modified and studied further before clinical use.

Comparison between Gd-DTPA and several bisamide derivatives as potential MRI contrast agents

Four neutral gadolinium complexes of diethylenetriaminepentaacetic acid (DTPA)-bisamide derivatives have been synthesized and characterized. Their potential application as tissue-specific and low-osmolarity MRI contrast agents has been evaluated by in vitro and in vivo experiments. Their measured relaxivities in D2O, bovine serum albumin and human serum transferrin solutions showed favorable relaxation ability. In vivo studies have proven that Gd(DTPA-BDMA), Gd(DTPA-BIN), and Gd(cyclic-DTPA-1,2-pn) could be promising liver-specific MRI contrast agents and Gd(DTPA-BDMA), and Gd(cyclic-DTPA-1,2-pn) have favorable renal excretion capability. Among them, Gd(cyclic-DTPA-1,2-pn) is a more powerful hepatic contrast agent and Gd(DTPA-BIN) provides the stable imaging contrast for several hours. They also show a lower toxicity.

Comparison between GdDTPA and two gadolinium polyoxometalates as potential MRI contrast agents

Two gadolinium polyoxometalates, Gd2P2W18O62 and K-15[(GdO)(3)(PW9O34)(2)], have been evaluated by in vivo as well as in vitro experiments as the candidates of tissue-specific magnetic resonance imaging (MRI) contrast agents. T-1-relaxivities of 28.4 mM(-1)-s(-1) for Gd2P2W18O62 and 11.2 mM(-1)-s(-1) for K-15[(GdO)(3)(PW9O34)(2)] (400 MHz, 25 degreesC) were higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin were also reported. The favorable liver-specific contrast enhancement and renal excretion capability in in vivo MRI with Sprague-Dawley rats after i.v. administration of K-15[(GdO)(3)(PW9O34)(2)] was demonstrated. In vivo and in vitro assay showed that K-15[(GdO)(3)(PW9O34)(2)] is a promising liver-specific MRI contrast agent. However, Gd2P2W18O62 did not show the favorable quality in vivo as expected from its high relaxivity in vitro, which was attributed to low bioavailability, indicating that it is of limited value as tissue-specific MRI contrast agent.

In vivo small animal micro-CT using nanoparticle contrast agents.

Computed tomography (CT) is one of the most valuable modalities for in vivo imaging because it is fast, high-resolution, cost-effective, and non-invasive. Moreover, CT is heavily used not only in the clinic (for both diagnostics and treatment planning) but also in preclinical research as micro-CT. Although CT is inherently effective for lung and bone imaging, soft tissue imaging requires the use of contrast agents. For small animal micro-CT, nanoparticle contrast agents are used in order to avoid rapid renal clearance. A variety of nanoparticles have been used for micro-CT imaging, but the majority of research has focused on the use of iodine-containing nanoparticles and gold nanoparticles. Both nanoparticle types can act as highly effective blood pool contrast agents or can be targeted using a wide variety of targeting mechanisms. CT imaging can be further enhanced by adding spectral capabilities to separate multiple co-injected nanoparticles in vivo. Spectral CT, using both energy-integrating and energy-resolving detectors, has been used with multiple contrast agents to enable functional and molecular imaging. This review focuses on new developments for in vivo small animal micro-CT using novel nanoparticle probes applied in preclinical research.

Radiotherapy in the presence of contrast agents: a general figure of merit and its application to gold nanoparticles

Delivering sufficient dose to tumours while sparing surrounding tissue is one of the primary challenges of radiotherapy, and in common practice this is typically achieved by using highly penetrating MV photon beams and spatially shaping dose. However, there has been a recent increase in interest in the possibility of using contrast agents with high atomic number to enhance the dose deposited in tumours when used in conjunction with kV x-rays, which see a significant increase in absorption due to the heavy element's high-photoelectric cross-section at such energies. Unfortunately, the introduction of such contrast agents significantly complicates the comparison of different source types for treatment efficacy, as the dose deposited now depends very strongly on the exact composition of the spectrum, making traditional metrics such as beam quality less valuable. To address this, a 'figure of merit' is proposed, which yields a value which enables the direct comparison of different source types for tumours at different depths inside a patient. This figure of merit is evaluated for a 15 MV LINAC source and two 150 kVp sources (both of which make use of a tungsten target, one with conventional aluminium filtration, while the other uses a more aggressive thorium filter) through analytical methods as well as numerical models, considering tissue treated with a realistic concentration and uptake ratio of gold nanoparticle contrast agents (10 mg ml(-1) concentration in 'tumour' volume, 10: 1 uptake ratio). Finally, a test case of human neck phantom is considered with a similar contrast agent to compare the abstract figure to a more realistic treatment situation. Good agreement was found both between the different approaches to calculate the figure of merit, and between the figure of merit and the effectiveness in a more realistic patient scenario. Together, these observations suggest that there is the potential for contrast-enhanced kilovoltage radiation to be a useful therapeutic tool for a number of classes of tumour on dosimetric considerations alone, and they point to the need for further research in this area.

Assessment of DNA double-strand breaks induced by intravascular iodinated contrast media following in vitro irradiation and in vivo, during paediatric cardiac catheterization

Paediatric cardiac catheterizations may result in the administration of substantial amounts of iodinated contrast media and ionizing radiation. The aim of this work was to investigate the effect of iodinated contrast media in combination with in vitro and in vivo X-ray radiation on lymphocyte DNA. Six concentrations of iodine (15, 17.5, 30, 35, 45, and 52.5 mg of iodine per mL blood) represented volumes of iodinated contrast media used in the clinical setting. Blood obtained from healthy volunteers was mixed with iodinated contrast media and exposed to radiation doses commonly used in paediatric cardiac catheterizations (0 mGy, 70 mGy, 140 mGy, 250 mGy and 450 mGy). Control samples contained no iodine. For in vivo experimentation, pre and post blood samples were collected from children undergoing cardiac catheterization, receiving iodine concentrations of up to 51 mg of iodine per mL blood and radiation doses of up to 400 mGy. Fluorescence microscopy was performed to assess γH2AX-foci induction, which corresponded to the number of DNA double-strand breaks. The presence of iodine in vitro resulted in significant increases of DNA double-strand breaks beyond that induced by radiation for ≥17.5 mg/mL iodine to blood. The in vivo effects of contrast media on children undergoing cardiac catheterization resulted in a 19% increase in DNA double-strand breaks in children receiving an average concentration of 19 mg/mL iodine to blood. A larger investigation is required to provide further information of the potential benefit of lowering the amount of iodinated contrast media received during X-ray radiation investigations. 

Partial volume correction using bimodal contrast agents in PET-MRI

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2014