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WO2025079088A1 - Agent de contraste pour tomodensitométrie et son procédé de préparation - Google Patents

Agent de contraste pour tomodensitométrie et son procédé de préparation Download PDF

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Publication number
WO2025079088A1
WO2025079088A1 PCT/IN2024/052020 IN2024052020W WO2025079088A1 WO 2025079088 A1 WO2025079088 A1 WO 2025079088A1 IN 2024052020 W IN2024052020 W IN 2024052020W WO 2025079088 A1 WO2025079088 A1 WO 2025079088A1
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Prior art keywords
contrast agent
emulsion
tocopheryl
solution
triiodobenzoate
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WO2025079088A4 (fr
Inventor
Rajasree S
Parvathy Prasad
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Bioroot Exploration India Private Ltd
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Bioroot Exploration India Private Ltd
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Publication of WO2025079088A1 publication Critical patent/WO2025079088A1/fr
Publication of WO2025079088A4 publication Critical patent/WO2025079088A4/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol

Definitions

  • a CONTRAST AGENT FOR COMPUTED TOMOGRAPHY AND PROCESS OF PREPARATION THEREOF FIELD OF INVENTION [0001]
  • the present invention relates to contrast agents for medical diagnostics. More specifically the invention relates to emulsion-based contrast agent which is of nano scale. The invention also relates to a method of preparing the emulsion based contrast agent.
  • a computed tomography scan (CT scan) is a medical imaging technique used to obtain detailed internal images of the body. CT scan uses a combination of X-rays and computer technology to produce images inside the body. CT scanning technology has revolutionized diagnostic imaging technology and contributed significantly to deepen our understanding of various diseases.
  • Contrast agents are substances used for diagnostic imaging procedures for enhancing the visibility of vascular structures and organs and have various applications in diagnostic imaging.
  • the contrast agents currently in use in CT imaging are based on heavy metals. These substances can be administered to the patient orally, rectally, or intravenously.
  • Common contrast material substances include iodine, barium, and gadolinium.
  • Iodine-based contrast agents available in the market are imported and water-soluble (Iohexol, Iopamidol, Iodixanol, Iopromide, Ioxilan, etc).
  • the high contrast media concentrations required for CT place it at a disadvantage as compared to other imaging techniques such as MRI (mmol conc. range), nuclear imaging ( ⁇ mol conc.
  • Oil based contrast agents available in the market are primarily made of poppyseed oil, such as lipiodol. These are liposomes co-loaded with water-soluble iopamidol and water- insoluble iodinated poppy-seed oil.
  • the oil-based contrast agent cannot be given intravenously since the oil particle may cause blocks in the arteries which may lead to myocardial infraction. Hence the oil-based contrast dyes are generally injected into the hepatic artery.
  • WO2015188040A2 relates to a composition for use in imaging.
  • the compound or composition of the invention which can be applied to any surface, can be used for visualizing surfaces, biological tissue, structures, and organs that would not necessarily be visible on an image produced by an imaging procedure.
  • US5512268A relates to polymeric shells for medical imaging prepared from synthetic polymers.
  • the composition disclosed is useful as contrast agents for magnetic resonance imaging (MRI), ultrasonography, and X-ray computed tomography.
  • MRI magnetic resonance imaging
  • ultrasonography ultrasonography
  • X-ray computed tomography X-ray computed tomography.
  • the polyunsaturated fatty acids and the form of iodine used in these products cause deleterious effects in kidneys and other vital organs such as lipid accumulation and free radical generation in organs.
  • contrast agents are imported, and therefore, highly priced and unaffordable for common man. Further, contrast agents available cannot be used in renal insufficiency patients as it is toxic to the kidneys. [0009] There are no emulsion based contrasts dyes available in the market at present, though studies related to Perfluorocarbon Emulsion Contrast Agents for CT, MRI, X-RAY are mentioned in research papers (Holman R et al., 2022). Oil-based contrast agents available in the market are mainly made of popyseed oil (Eg:- Lipiodol).
  • the polyunsaturated fatty acids and the form of iodine used in these products cause deleterious effects on the kidney and other vital organs as well as lipid accumulation and free radical generation in organs.
  • the product is highly priced and is unaffordable for the common man.
  • the available contrast agents in the market are water-based for cardiac purpose and the one oil-based are used as a biomarker for hepatic tumour detection, Trans Arterial Chemo Embolization (TACE), Glue dilution which is imported and highly-priced.
  • TACE Trans Arterial Chemo Embolization
  • Glue dilution which is imported and highly-priced.
  • the present invention discloses a composition of a contrast agent, which has reduced toxicity and is compatible to be used for renal insufficiency patients.
  • Contrast agents are mainly used for diagnostic imaging procedures for enhancing the visibility of vascular structures and organs and have various applications in diagnostic imaging.
  • Present disclosure relates to a lipid nano-emulsion-based contrast agent which is a novel non- ionic computed tomography (CT) contrast agent.
  • CT computed tomography
  • the composition of the contrast agent of the present invention comprises medium chain triglyceride, alpha-tocopherol, 2, 3, 5-triiodobenzoic acid and polyethylene glycol. Animal studies showed that the composition provides good imageability which is comparable to the existing product in the market.
  • CT imaging for diagnosis of atherosclerotic lesions and tumour detection even in renal insufficiency patients.
  • a contrast agent for computed tomography comprising, 30 - 40% of 2, 3, 5-triiodobenzoic acid, 20 -25% of ⁇ -tocopherol, 10 - 20 % coconut oil, and 3 -10% polyethylene glycol.
  • Embodiment B relates to the contrast agent of previous embodiment, wherein the contrast agent is in the form of nano emulsion particles.
  • Embodiment C relates to the contrast agent of previous embodiment, wherein the nano- emulsion particles have a size ranging from 20 - 200nm.
  • Embodiment D relates to the contrast agent of the previous embodiment, wherein osmolality of the contrast agent ranges from 350-600 mOsmol.
  • Embodiment E relates a method of preparing a contrast agent as recited in previous embodiments, comprising steps of, preparation of ⁇ -tocopheryl 2,3,5- triiodobenzoate, preparation of an emulsion, incorporation of ⁇ -tocopheryl 2,3,5- triiodobenzoate with emulsion; wherein the step of preparation of ⁇ -tocopheryl 2,3,5- triiodobenzoate comprises, a) adding about 20 - 25 g of DL ⁇ -tocopheryl preferably 24.5g in to about 1600 - 2000ml of dicholoromethane, b) to the mixture of step a), add sequentially, 30-40g of 2,3,5-triiodobenzoic acid, 1-1.5g of 4-dimethylaminopyridine preferably
  • step iv) add lecithin solution of step i) to sodium oleate - glycerol solution of step iii) and mix and maintain at 55-60 ⁇ C to obtain an emulsifying solution
  • step v) add about 10 to 20 g of coconut oil preferably 15g with addition of 22- 25 mg alpha tocopherol (Vitamin E); vi) the oil mixture of step v) is added drop by drop to emulsifying solution of step iv) with intermittent stirring and maintaining the temperature at 55-60 ⁇ C to obtain an emulsion;
  • the step of incorporation of ⁇ -tocopheryl 2,3,5- triiodobenzoate with emulsion comprises, A) to the solution of step v) above, add ⁇ -tocopheryl 2, 3, 5- triiodobenzoate of step e), B) the solution of step A) is sonicated at 55-60 ⁇ C temperature to obtain a fine emulsion based contrast agent, C) sterilize the
  • Embodiment F relates to the method as recited in previous embodiment, wherein gradient elution is carried out on silica gel using cyclohexane and ethyl acetate as an eluent in the ratio of 5:1.
  • gradient elution is carried out on silica gel using cyclohexane and ethyl acetate as an eluent in the ratio of 5:1.
  • Fig 1 (A-C) shows sterility of the contrast agent in different media such as A) nutrient agar, B) soya bean casein and C) potato dextrose agar;
  • Fig 2 shows a graph of particle size of emulsion-based contrast dye using DLS (Dynamic Light Scattering);
  • Fig 3 (A-D) shows images of particle size of emulsion-based contrast dye from different areas of the same solution and analysed using TEM (Transmission Electron Microscope) A) Particles size between 52 nm to 80 nm, B) Particle size between 100 to 150nm, C) Particle size between 100nm to 150nm D) Particle size between 150 to 300nm;
  • Fig 4 (A-E) illustrates images of stability test of the contrast agent after orbital shaking; The orbital shaking stability of the nano-emulsion was examined through size distribution in function with incubation time for 1hr (B), 6
  • Fig 10 illustrates graphical representation of studies on chronic toxicity of the contrast dye in liver and renal functions after two weeks; A) chloride and sodium, B) urea and calcium, C) creatinine, D) SGOT, SGPT and ALP, E) tot. protein, albumin and tot. billirubin.
  • Fig 11 shows micro-CT of liver of NOD SCID mice (11a. contrast agent in accordance with invention and 11b. comparator). DETAILED DESCRIPTION OF INVENTION [0036] The present invention will now be described more fully herein after.
  • the terms “comprises”, “comprising”, “includes”, “including”, “containing”, “characterized by”, “having” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • the term ‘room temperature’ or ‘atmospheric temperature’ referred herein is a temperature of 25-30 ⁇ C.
  • Contrast agents are mainly used for diagnostic imaging procedures for enhancing the visibility of vascular structures and organs and have various applications. Most of the iodine- based contrast agents available in the market are water soluble (for angiography) and the main limitation of these contrast agents is the low efficiency to detect tumours.
  • Oil-based contrast agent available in the market is primarily made of popyseed oil (for Trans Arterial Chemo Embolization and glue dilution), which is not preferred for renal insufficiency patients as it can cause endothelial dysfunction. Moreover, the product is highly priced and is unaffordable for common man. [0043] Inventors of the invention have successfully formulated an indigenous, non-toxic, safe and cost effective nano lipid-emulsion based contrast agent for preclinical X-ray imaging.
  • the specific inventive steps are by formulating a non-toxic lipophilic molecule naturally present in the body ⁇ tocopheryl (Vit E) to graft a high concentration of X-ray contrasting material ie, 2, 3, 5-triodobenzoic acid using simplest chemical reaction.
  • a nano lipid-emulsion based contrast dye was formulated using this alpha tocopheryl 2, 3, 5-triodobenzoic acid compound incorporating hairy Polyethylene glycol (PEG) layer to achieve stealth properties to avoid opsonization and enhance permeability and retention (EPR) effect.
  • the composition of the contrast agent as per the present invention comprises 2, 3, 5- triiodobenzoic acid, ⁇ -tocopherol, coconut oil and polyethylene glycol.2, 3, 5-triiodobenzoic acid is the iodine source in the composition.
  • the composition comprises 30 - 40% of 2, 3, 5- triiodobenzoic acid.
  • the iodine helps to increase the contrast in tissues by photoelectric absorption.
  • the iodine compound used in this invention is fat soluble and is least toxic compared to the commercially available water-soluble contrast agents.
  • ⁇ -tocopherol is used in the composition as an antioxidant.
  • the ⁇ -tocopherol or vitamin E combines with coconut oil and iodine to form iodinated ⁇ -tocopherol nano-emulsions.
  • the composition comprises 20 -25% of ⁇ -tocopherol.
  • coconut oil is used in the composition as a source of medium chain fatty acid.
  • About 60% of total fatty acid composition of coconut oil are medium-chain fatty acids (MCFA) with a chain length of 6 to 12 carbon atoms.
  • the contrast agent composition of the present invention comprises 10 - 20 % coconut oil. The oil interacts with other components in the composition to form an emulsion.
  • the contrast agent of the present invention also includes polyethylene glycol (PEG).
  • PEG comprises 3 -10% of the composition.
  • the contrast agent is a lipid nano-emulsion which is formulated using alpha tocopheryl and 2, 3, 5-triodobenzoic acid compound, surrounded by hairy polyethylene glycol (PEG) layer to achieve stealth properties to avoid opsonisation and to enhance the permeability and retention of the contrast agent.
  • PEG polyethylene glycol
  • the contrast agent in accordance with the present invention is prepared in three main steps of stages.
  • the first step is to prepare the contrast dye by preparing a mixture of ⁇ -tocopheryl 2, 3, 5- tri-iodobenzoate.
  • the second step is to prepare an emulsifying agent and the third step is incorporating the mixture of ⁇ -tocopheryl 2, 3, 5- triiodobenzoate from first step and the emulsifying agent from the second step together to form the contrast agent as per the present invention.
  • the first step in the preparation of the contrast agent is the preparation of ⁇ -tocopheryl 2, 3, 5- triiodobenzoate. To about 1600-2000ml of dicholoromethane, about 20 - 25g of DL ⁇ - tocopheryl, preferably 24.5g added and mixed well.
  • the gradient elution in the above discussed step is carried out on silica gel using cyclohexane and ethyl acetate as an eluent in the ratio of 5:1, using chromatography technique.
  • the second step in the process of preparing contrast agent as per the present invention is preparation of emulsifying agent.
  • De-ionised, pyrogen free water is heated to about 55-60 ⁇ C temperature.
  • pyrogen free water of temperature of about 55- 60 ⁇ C about 0.5 - 1.0 g preferably 0.6 g egg yolk lecithin is added.
  • lecithin solution The temperature of the water is maintained, and the lecithin is dissolved by stirring, to obtain lecithin solution.
  • lecithin solution To about 25-35 ml of deionised, pyrogen free water, maintained at a temperature of 55- 60 ⁇ C, about 0.5-1.0g of sodium oleate preferably 0.75g is added. Sodium oleate is dissolved in the water which is maintained at a temperature of 55-60 ⁇ C, by stirring the solution, to obtain sodium oleate solution. To the sodium oleate solution, about 1.5 - 2.5gof glycerol preferably 2.2g is added.
  • the lecithin solution and sodium oleate - glycerol solution is mixed and maintained at 55 - 60 ⁇ C to obtain an emulsion.
  • To this emulsion add about 10 – 20g preferably 15g of coconut oil with an addition of 22-25 mg alpha tocopherol (vitamin E).
  • the oil mixture from the previous step is added drop by drop to the emulsifying solution, with intermittent stirring along with maintaining the temperature at 55-60 ⁇ C to obtain the emulsion.
  • the third step of preparation of the contrast agent includes incorporation of ⁇ - tocopheryl 2, 3, 5- tri-iodobenzoate with emulsion.
  • ⁇ -tocopheryl 2,3,5- triiodobenzoate obtained from first step is incorporated.
  • the incorporated mixture is sonicated at 55-60 ⁇ C temperature to obtain a fine emulsion particles of nano size range.
  • the emulsion obtained has a size of 20 - 200nm.
  • the nano sized emulsion particle which is the contrast agent is sterilized using autoclave at 12-16 lbs pressure for 15-30 minutes.
  • the sterilized contrast agent is stored at temperature ranging from 8-25 ⁇ C, till use.
  • Example 1 Sterility test
  • the sterility test of the contrast agent was tested by inoculating the same in separate petri dishes containing nutrient agar, soyabean casein and potato dextrose agar medium ( Figure 1). The sample is spread on different media plates and incubated for 24hrs in a microbial incubator. Nutrient agar medium is used for checking the presence of bacteria, soyabean casein medium for checking the presence of aerobes and fungi and potato dextrose agar medium for checking the presence of fungal growth. The absence of growth of organisms in the plates showed that the sample is sterile.
  • the orbital shaking stability (Fig 4) of the nano-emulsion was examined through size distribution in function with incubation time for1hr (B), 6hrs (C), 12hrs (D), 24hrs (E) and (A) representing contrast agent before shaking.
  • the samples were constantly homogenized to avoid sedimentation of large aggregates. Before analysis, the presence of aggregates was examined visually.
  • Example 5 Evaluation of particle size of nano emulsion contrast agent using DLS
  • Each analysis was performed in triplicate, using TPN prepared on different days.
  • DLS measurements were carried out using a Zetasizer 3000Hs (Malvern Instruments, Worcestershire, United Kingdom), which uses a helium-neon laser light and an integrated analysis software.
  • the temperature was adjusted to 25°C and the scattering angle was set to 90°, in the DLS equipment, before measurements were taken.
  • the chosen data analysis method was the monomodal or cumulant analysis [25]. The data were expressed as z- average and polydispersity.
  • the samples, 1 mL, were collected from the TPN bags, under laminar flow hood, in a clean room, with sterile syringes and needles and appropriately diluted with filtered WFI (0.2 ⁇ M) 1:500 to obtain the Kcps (a measure of the sample concentration, obtained by the equipment) from 250 to 350.
  • Each analysis was performed in triplicate, using TPN prepared on different days.
  • DLS measurements were carried out using a Zetasizer 3000Hs (Malvern Instruments, Worcestershire, United Kingdom), which uses a helium-neon laser light and an integrated analysis software. The temperature was adjusted to 25°Cand the scattering angle was set to 90°, in the DLS equipment, before measurements were taken. The chosen data analysis method was the monomodal or cumulant analysis [25].
  • the data were expressed as z-average and polydispersity [0067] 1 mL sample was taken, under laminar flow hood, in a clean room, with sterile syringes and needles and appropriately diluted with filtered WFI (0.2 ⁇ M) 1:500 to obtain the Kcps (a measure of the sample concentration, obtained by the equipment) from 250 to 350.
  • DLS measurements were carried out using a Zetasizer 3000Hs (Malvern Instruments, Worcestershire, United Kingdom), which uses a helium-neon laser light and an integrated analysis software. The temperature was adjusted to 25°C and the scattering angle was set to 90°, in the DLS equipment, before measurements were taken.
  • the chosen data analysis method was the monomodal or cumulant analysis.
  • Example 6 Evaluation of particle size of nano emulsion contrast dye using TEM [0069] Small quantity of specimens is optimally placed rapidly into glutaraldehyde and fixed for at least 1 hr at room temperature (23 °C) and then post-fixed in osmium tetroxide. Fixed cells are embedded in agar and processed based on the tissue type. The specimens are dehydrated in graded concentrations of ethanol and propylene oxide, and embedded in Spurr's plastic. Semi-thin sections are cut from blocks with a glass knife and the blocks are selected for thinning.
  • Example 7 Osmolality test
  • Osmolality was assessed by vapor pressure osmometry (Vapro 5600, Wescor) with the instrument calibrated with vendor-supplied standards prior to measurement of triplicate samples, which were pipetted to the sample holder as undiluted 10- ⁇ l aliquots. Osmolality of proposed product found to be in between 396 and 575 mOsmol/kg.
  • Osmolality values higher than 600 mOsmol/kg has been associated to hypertonicity-induced pain.
  • Table 1 shows osmolality of the contrast dye (A5 and B5 - sample code).
  • Table 1 shows osmolality of the contrast dye Sl. No Sample ID Test Instrument Result Used 1 A5 Osmolality Osmomat 396 mOsmol/kg 3000 - 2 B5 575 mOsmol/kg Gonotec
  • Example 8 X-ray imaging of the contrast agent as per the invention and comparator product (Iohexol, 350 mgI/ml).
  • Example 9 Micro CT imaging of liver of NOD SCID mice.
  • Example 10 Histopathological analysis of contrast agent administrated liver of NOD-SCID mice.
  • the specimens were embedded in paraffin blocks using an embedding station (Sakura, Japan) and serial sections of 4 ⁇ m thickness were cut using a microtome (ModelRM2245, Leica Biosystems, Wetzlar, Germany). We used an autostainer (Model 5020, Leica Biosystems, Wetzlar, Germany) for Hematoxylin and Eosin staining of the sections. The mounted specimens were observed and were scored under light microscopy.
  • Table 2 shows Histopathological analysis of contrast agent administrated liver of NOD-SCID mice. [0079] Table 2 shows Histopathological analysis of contrast agent administrated liver of NOD-SCID mice.
  • Fig 9 Referring to Fig 9 (A-D), the acute toxicity (2 weeks) of the contrast dye in liver function (T. Billirubin, SGOT, SGPT, ALP, Total protein, albumin and globulin) and renal function (urea, creatinine and uric acid) in comparison with the control showing no toxicity.
  • Fig 10 Referring to Fig 10 (A-E), the chronic toxicity (8 weeks) of the contrast dye in liver function and renal function in comparison with the control showed no toxicity.
  • the contrast agent of the present invention shows outstanding contrasting properties, biocompatibility and low toxicity, long residence time and high opacification.
  • the form of iodine used in the composition is fat-soluble and very less toxic compared to the commercially available water-soluble contrast agent which uses a more toxic form.
  • Preclinical studies in animal studies showed that the contrast agent as per the invention has good imageability which is comparable to the existing product in the market.
  • the contrast agent of the present invention can be used for multiple applications such as CT angiography of atherosclerotic lesions/occlusion and hepatic tumor detection even in renal insufficiency patients.
  • the contrast agent in accordance with the invention is sterile and stable for more than six months. It shows low osmolarity. Characterization study shows an optimum range of particle size and the pharmacodynamics study showed no deleterious effects. Thus, it is safe to use, cost-effective and is developed indigenously compared to the existing imported product in the market.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un agent de contraste pour la tomodensitométrie et son procédé de préparation. La composition comprend 30 à 40 % d'acide 2, 3, 5-triiodobenzoïque, 20 à 25 % d'α-tocophérol, 10 à 20 % d'huile de noix de coco, et 3 à 10 % de polyéthylène glycol. Le procédé de préparation comprend les étapes de préparation d'α-tocophéryl 2,3,5-triiodobenzoate, de préparation d'une émulsion, d'incorporation d'α-tocophéryl 2,3,5-triiodobenzoate avec une émulsion. L'agent de contraste de la présente invention présente des propriétés de contraste exceptionnelles, une biocompatibilité et une faible toxicité, un temps de séjour long et une opacification élevée.
PCT/IN2024/052020 2023-10-11 2024-10-08 Agent de contraste pour tomodensitométrie et son procédé de préparation Pending WO2025079088A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009015397A1 (fr) * 2007-07-26 2009-01-29 Nanoscan Imaging, Llc Procédés d'imagerie utilisant des agents de contraste nanoparticulaires améliorés
IN2003CH00093A (en) * 2003-02-04 2009-05-20 A process for praparation of intravenous lipid emulsion
WO2013121284A1 (fr) * 2012-02-14 2013-08-22 Universite De Strasbourg Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation
IN201941042129A (fr) * 2019-10-17 2019-11-22
US11654202B2 (en) * 2017-08-07 2023-05-23 University Of Geneva Nanoemulsion of iodinated fatty acids for CT imaging

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2003CH00093A (en) * 2003-02-04 2009-05-20 A process for praparation of intravenous lipid emulsion
WO2009015397A1 (fr) * 2007-07-26 2009-01-29 Nanoscan Imaging, Llc Procédés d'imagerie utilisant des agents de contraste nanoparticulaires améliorés
WO2013121284A1 (fr) * 2012-02-14 2013-08-22 Universite De Strasbourg Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation
US11654202B2 (en) * 2017-08-07 2023-05-23 University Of Geneva Nanoemulsion of iodinated fatty acids for CT imaging
IN201941042129A (fr) * 2019-10-17 2019-11-22

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIESSLING, F., PICHLER, B.: "Small Animal Imaging: Basics and Practical Guide", 16 December 2010, SPRINGER, Berlin, Heidelberg, ISBN: 3642129447, article PIETSCHG, H.: "11. CT Contrast Agents", pages: 141 - 149, XP009562996 *
LI XIANG; ANTON NICOLAS; ZUBER GUY; ZHAO MINJIE; MESSADDEQ NADIA; HALLOUARD FRANÇOIS; FESSI HATEM; VANDAMME THIERRY F.: "Iodinatedα-tocopherol nano-emulsions as non-toxic contrast agents for preclinical X-ray imaging", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 34, no. 2, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 481 - 491, XP028956133, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2012.09.026 *

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