MRI contrast agent composition

Abstract

To provide an MRI contrast agent composition that contains an MRI contrast agent and allows the MRI contrast agent to be easily incorporated into a cancer cell.SOLUTION: An MRI contrast agent composition contains a monosaccharide and an MRI contrast agent, the monosaccharide not forming a covalent bond with another molecule. The MRI contrast agent composition may contain the MRI contrast agent and the monosaccharide at a mass ratio of 1: 0.01-1: 100. The MRI contrast agent may be a gadolinium contrast agent, and the monosaccharide may be glucose.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present invention relates to an MRI contrast agent composition. [Background technology]

[0002] For in vivo diagnosis of diseases or conditions, for example, PET (positron emission tomography), X-ray CT (computed tomography), a combination of these called PET-CT, or MRI (magnetic resonance imaging) are used, and in particular, PET-CT and MRI are used for diagnosing cancer.

[0003] However, PET-CT, which combines PET and X-ray CT, is known to have the following problems. First, PET requires the administration of a radioisotope such as fluorodeoxyglucose (18F-FDG), which generates positrons, into the body as a tracer, which raises concerns about the management of radioisotopes and internal exposure to gamma rays from positrons. Second, X-ray CT has the problem of external exposure due to X-ray irradiation during the examination, which results in a high radiation dose. Furthermore, it is known that the spatial resolution of PET is low, at around 5 mm.

[0004] On the other hand, MRI is a technique that applies a high-frequency magnetic field to cause a resonance phenomenon in hydrogen atoms in the body, picks up the radio waves generated at that time with a receiving coil, and constructs the obtained signal data into an image.Unlike PET-CT, it is thought that there is no radiation exposure.In addition, it is known that the spatial resolution of MRI is high, about 0.5 mm.

[0005] Meanwhile, in MRI, contrast agents may be used to see blood flow and the spread of blood vessels to organs, which are not normally visible. Various contrast agents are used in MRI examinations / diagnoses for the purpose of enhancing the contrast, tissue specificity, etc. of MRI images. Representative contrast agents include gadolinium contrast agents such as gadopentetate meglumine (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA), which have the effect of shortening the T1 relaxation time and increase the contrast (signal intensity) in T1 weighted images (Patent Document 1). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication WO2009 / 025168 Summary of the Invention [Problem to be solved by the invention]

[0007] However, because MRI contrast agents are difficult to take up by cancer cells, there was a problem in that the use of MRI contrast agents did not provide sufficient contrast effects.

[0008] The present invention has been made in consideration of the above problems, and has an object to provide an MRI contrast agent composition that facilitates uptake of the MRI contrast agent contained therein into cancer cells. [Means for solving the problem]

[0009] In order to achieve the above object, the present invention provides an MRI contrast agent composition comprising a monosaccharide and an MRI contrast agent, wherein the monosaccharide is not covalently bonded to other molecules (Invention 1).

[0010] According to the invention (Invention 1), the MRI contrast agent composition contains an MRI contrast agent and a monosaccharide, which makes it easier for the MRI contrast agent to be taken up by cancer cells. As a result, a high contrast effect can be obtained, enabling examinations and research using clearer images.

[0011] In the above invention (Invention 1), the monosaccharide may contain at least one of glucose and fructose (Invention 2).

[0012] In the above inventions (Inventions 1 and 2), the monosaccharide may be glucose (Invention 3).

[0013] In the above inventions (Inventions 1 to 3), the MRI contrast agent may be a gadolinium contrast agent (Invention 4).

[0014] In the above invention (Invention 4), the gadolinium contrast agent may contain at least one of gadopentetate meglumine, gadoterate meglumine, gadoxetate sodium, gadodiamide hydrate, gadoteridol, and gadobutrol (Invention 5).

[0015] In the above inventions (Inventions 4 and 5), the gadolinium contrast agent may be meglumine gadopentetate (Invention 6).

[0016] In the above inventions (Inventions 1 to 6), the MRI contrast agent and the monosaccharide may be contained in a mass ratio of 1:0.01 to 1:100 (Invention 7).

[0017] In the above inventions (Inventions 1 to 7), the MRI contrast agent and the monosaccharide may be contained in a mass ratio of 1:1 to 1:10 (Invention 8). Effect of the Invention

[0018] According to the present invention, it is possible to provide an MRI contrast agent composition that facilitates uptake of the MRI contrast agent contained therein into cancer cells, thereby enabling examination, diagnosis, and research using images with high contrast effect. [Brief description of the drawings]

[0019] [Figure 1] This is a photograph of VX2 cancer (specimen 1) taken by MRI. [Diagram 2] This is a photograph of VX2 cancer (specimen 1) taken by MRI after administration of comparative agent 1. [Diagram 3] This is a photograph of VX2 cancer (specimen 2) taken by MRI. [Figure 4] This is a photograph of VX2 cancer (specimen 2) taken by MRI after administration of comparison agent 2. [Diagram 5] 1 is a photograph of VX2 cancer (specimen 2) taken by MRI after administration of MRI contrast agent composition 1 according to one embodiment of the present invention. [Figure 6] This is a photograph of VX2 cancer (specimen 3) taken by MRI. [Figure 7] 1 is a photograph of VX2 cancer (specimen 3) taken by MRI 30 minutes after administration of MRI contrast agent composition 2 according to one embodiment of the present invention. [Figure 8] 1 is a photograph of VX2 cancer (specimen 3) taken by MRI 90 minutes after administration of MRI contrast agent composition 2 according to one embodiment of the present invention. [Figure 9] This is a photograph of VX2 cancer (specimen 4) taken by MRI. [Figure 10] This is a photograph of VX2 cancer (specimen 4) taken by MRI 10 minutes after administration of comparative agent 3. [Figure 11] This is a photograph of VX2 cancer (specimen 4) taken by MRI 30 minutes after administration of comparative agent 3. [Figure 12] 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 60 minutes after administration of comparative agent 3. [Figure 13] 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 90 minutes after administration of comparative agent 3. [Figure 14] This is a photograph of VX2 cancer (specimen 4) taken by MRI two days after the photograph in Figure 9 was taken. [Figure 15] 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 10 minutes after administration of MRI contrast agent composition 3 according to one embodiment of the present invention. [Figure 16]1 is a photograph of VX2 cancer (specimen 4) taken by MRI 30 minutes after administration of MRI contrast agent composition 3 according to one embodiment of the present invention. [Figure 17] 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 60 minutes after administration of MRI contrast agent composition 3 according to one embodiment of the present invention. [Figure 18] 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 90 minutes after administration of MRI contrast agent composition 3 according to one embodiment of the present invention. [Figure 19] This is a photograph of VX2 cancer (specimen 5) taken by MRI. [Figure 20] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 10 minutes after administration of comparative agent 4. [Figure 21] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 30 minutes after administration of comparative agent 4. [Figure 22] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 60 minutes after administration of comparative agent 4. [Diagram 23] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 90 minutes after administration of comparative agent 4. [Figure 24] This is a photograph of VX2 cancer (specimen 5) taken by MRI one day after the photograph of Figure 19 was taken. [Diagram 25] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 10 minutes after administration of MRI contrast agent composition 4 according to one embodiment of the present invention. [Figure 26] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 30 minutes after administration of MRI contrast agent composition 4 according to one embodiment of the present invention. [Figure 27] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 60 minutes after administration of MRI contrast agent composition 4 according to one embodiment of the present invention. [Figure 28] 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 90 minutes after administration of MRI contrast agent composition 4 according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Hereinafter, an embodiment of the present invention will be described. The MRI contrast agent composition according to this embodiment contains a monosaccharide and an MRI contrast agent, and is characterized in that the monosaccharide is not covalently bonded to other molecules.

[0021] In this embodiment, the MRI contrast agent composition contains monosaccharides in addition to the MRI contrast agent, which makes it easier for the MRI contrast agent to be taken up by cells, and thus allows for a superior contrast effect to be obtained. In particular, since cancer cells have a higher uptake of monosaccharides (particularly glucose) than normal cells, the MRI contrast agent is more easily taken up together with the monosaccharides, and thus a superior contrast effect can be obtained.

[0022] (1) Monosaccharide The monosaccharides used in the present embodiment are not particularly limited, and examples thereof include glucose, fructose, mannose, galactose, xylose, ribose, arabinose, rhamnose, xylulose, deoxyribose, fucose, acetylglucosamine, acetylgalactosamine, etc. These monosaccharides may be used alone or in combination of two or more.

[0023] Of the above monosaccharides, glucose and fructose are preferred from the viewpoint of their use in general infusions, and glucose is particularly preferred from the viewpoint of active uptake by cancer cells.

[0024] The concentration of the monosaccharide in the MRI contrast agent composition may vary depending on the administration method described below, but may be, for example, 0.05 mg / ml to 2000 mg / ml, preferably 0.5 mg / ml to 1000 mg / ml, more preferably 5 mg / ml to 500 mg / ml, and even more preferably 10 mg / ml to 100 mg / ml. Within this range, the MRI contrast agent is more actively taken up into cells, the amount of other components can be sufficiently secured, and administration to a living body can be easily performed.

[0025] Furthermore, the monosaccharide used in this embodiment does not have a covalent bond with other molecules present in the MRI contrast agent composition. Not having a covalent bond with other molecules means that the monosaccharide does not have a covalent bond with the monosaccharide, MRI contrast agent, additives, solvent, etc. present in the MRI contrast agent composition. For example, a glycosidic bond between monosaccharides does not form a disaccharide such as maltose or lactose, a polysaccharide such as glycogen or cellulose, or a sugar chain, etc., is an example of a monosaccharide not having a covalent bond with other molecules.

[0026] That is, in this embodiment, since the work of covalently bonding monosaccharides with other molecules is not required when preparing the MRI contrast agent composition, the MRI contrast agent composition can be prepared more easily. For example, in one embodiment of the present invention, the MRI contrast agent composition can be prepared by simply mixing the MRI contrast agent and a glucose injection solution (infusion solution) so that the MRI contrast agent and glucose have a desired concentration and mass ratio.

[0027] (2) MRI contrast agents In the present invention, an MRI contrast agent is a substance (medicine) administered in an in-vivo imaging diagnostic method using an MRI device or an NMR (Nuclear Magnetic Resonance) device used in clinical sites, laboratories, etc. When the substance is present in an MRI measurement subject, the way the measurement subject appears on the measurement image appears to have changed significantly due to contrast compared to when the substance is not present, so it is possible to add contrast to the image, and this effect is referred to as the contrast effect in this specification.

[0028] The MRI contrast agent used in the present embodiment is not particularly limited, and examples thereof include gadolinium contrast agents, contrast agents using iron-platinum particles, contrast agents using manganese, etc. Among these, gadolinium contrast agents are often used as injections or drip infusions, and from the viewpoint of using the MRI contrast agent composition as an injection or drip infusion in a living body, gadolinium contrast agents are preferred.

[0029] The gadolinium contrast agent is not particularly limited as long as it contains gadolinium, and examples thereof include meglumine gadopentetate, meglumine gadoterate, sodium gadoxetate, gadodiamide hydrate, gadoteridol, and gadobutrol.

[0030] In the examples described below, results are shown for an MRI contrast agent composition containing meglumine gadopentetate as an MRI contrast agent. However, even when an MRI contrast agent composition containing sodium gadoxetate or gadobutrol is used as an MRI contrast agent, similar results are obtained as when an MRI contrast agent composition containing meglumine gadopentetate is used.

[0031] The above MRI contrast agents may be used alone or in combination of two or more.

[0032] The concentration of the MRI contrast agent in the MRI contrast agent composition may be, for example, 0.01 mg / ml to 1500 mg / ml, preferably 0.1 mg / ml to 750 mg / ml, and more preferably 1 mg / ml to 200 mg / ml, depending on the administration method described below. Within this range, a contrast effect can be expected without causing significant adverse effects on the living body.

[0033] In one embodiment of the MRI contrast agent composition of the present invention, the ratio of the MRI contrast agent to the monosaccharide (MRI contrast agent:monosaccharide) is preferably 1:0.01 to 1:100 by mass, more preferably 1:0.1 to 1:10, and even more preferably 1:1 to 1:10. Within this range, the monosaccharide and the MRI contrast agent are efficiently taken up into cells (particularly cancer cells), and a sufficient contrast effect can be expected.

[0034] The dosage of the MRI contrast agent composition of the present invention may be in accordance with the dosage recommended for each MRI contrast agent, but the ratio of the mass of the MRI contrast agent to the subject's body weight (mass of the MRI contrast agent: subject's body weight) is preferably 1:1000 to 1:50000, more preferably 1:2000 to 1:35000. Within this range, side effects on the subject can be avoided and a sufficient contrast effect can be expected.

[0035] (3) Other ingredients The MRI contrast agent composition according to the present embodiment may be used in a state of being suspended or dissolved in a solvent such as distilled water for injection, physiological saline, or Ringer's solution. If necessary, it may further contain additives such as pharmacologically acceptable carriers and excipients. The MRI contrast agent composition may be applied to cells, etc., and may be administered into a living body by intravascular (vein, artery) administration, oral administration, intrarectal administration, intravaginal administration, intralymphatic administration, intra-articular administration, etc., and may be preferably administered in the form of a solution, emulsion, suspension, etc.

[0036] The MRI contrast agent composition according to the present embodiment may contain additives. The additives vary depending on the administration route, administration form, etc., but specifically, in the case of an injection, a buffer, a stabilizer, an antibacterial agent, a solubilizing agent, an excipient, etc. may be contained alone or in combination, and in the case of an orally administered agent (specifically, a liquid, an emulsion, a syrup, a suspension, etc.), a stabilizer, a colorant, a preservative, a suspending agent, an emulsifier, a thickening agent, an aroma agent, a sweetener, etc. may be contained alone or in combination. Various additives that are usually used in the field may be contained.

[0037] In addition, the MRI contrast agent composition according to this embodiment can be used as an MRI contrast agent composition for various animals other than humans, and the administration form, administration route, administration amount, etc. can be appropriately selected depending on the body weight and condition of the target animal.

[0038] (4) Method of administering MRI contrast agent composition The MRI contrast agent composition according to this embodiment can be administered, imaged, and photographed in the same manner as a conventional MRI contrast agent. The administration may be local or systemic. There is no particular limitation on the administration method, and the composition may be administered orally or parenterally, but parenteral administration is preferred. Examples of parenteral administration routes include subcutaneous, intraperitoneal, venous, arterial or spinal fluid injection, infusion, and the like. The specific dosage can be increased or decreased as appropriate depending on the age and body size of the subject to be administered, and the site to be imaged. In addition, the dosage of the MRI contrast agent composition is preferably administered to the living body so as to be within the dosage of the MRI contrast agent recommended in the instruction manual for the MRI contrast agent, etc.

[0039] The MRI contrast agent composition according to this embodiment is believed to promote the uptake of the MRI contrast agent into cells through the following mechanism of action.

[0040] Cells obtain energy from monosaccharides (glucose) present in the blood. In particular, it is known that cancer cells take up 3 to 8 times as much monosaccharides (glucose) from the blood as normal cells. The MRI contrast agent composition according to this embodiment has been made with attention to the uptake of monosaccharides (glucose) by cells as described above. By administering a composition in which an MRI contrast agent and a monosaccharide (glucose) are mixed into a living body, the cells attempt to take up the monosaccharides (glucose) from the blood, and at that time, the MRI contrast agent mixed with the monosaccharide (glucose) can also be taken up. This makes it easier for the MRI contrast agent to be taken up by the cells, and it is believed that an excellent contrast effect can be obtained during MRI imaging. EXAMPLES

[0041] The present invention will be described in more detail below by showing Production (Preparation) Examples, Experimental Examples, etc., however, the present invention is not limited to the following Production (Preparation) Examples, Experimental Examples, etc.

[0042] <Verification 1> Using the following Example 1, Comparative Example 1, and Comparative Example 2, verification was carried out based on Comparative Experimental Method 1 and Experimental Method 1.

[0043] Example 1 Preparation of MRI contrast agent composition 1 2.0 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous injection solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of glucose injection solution (glucose solution) (Otsuka Pharmaceutical, Otsuka glucose solution 5%, containing 1 g of purified glucose per 20 ml) to obtain 52 ml of MRI contrast agent composition 1.

[0044] Comparative Example 1 Preparation of Comparative Agent 1 2.0 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of physiological saline to obtain 52 ml of Comparative Agent 1.

[0045] Comparative Example 2 Preparation of Comparative Agent 2 Comparative agent 2 was 50 ml of glucose injection (glucose solution) (Otsuka Pharmaceutical Co., Ltd., Otsuka Sugar Solution 5%, containing 1 g of purified glucose per 20 ml).

[0046] (a) Comparative Experimental Method 1 A rabbit (approximately 3 kg, specimen 1) bearing VX2 cancer was used as a test animal. First, an MRI was performed on the site of VX2 cancer in the rabbit using an MRI device (GE), and the image shown in FIG. 1 was obtained. Next, the entire amount of Comparative Agent 1 prepared in Comparative Example 1 was intravenously administered to the rabbit's ear. A few minutes after the intravenous administration was completed, an MRI was performed on the site of VX2 cancer in the rabbit using an MRI device (GE) under the same conditions as in FIG. 1, and the image shown in FIG. 2 was obtained. Both the images in FIG. 1 and FIG. 2 were obtained by T1 weighted imaging.

[0047] (b) Experimental method 1 A rabbit (about 2 kg, specimen 2) with VX2 cancer was used as a test animal. First, an MRI was performed on the site of VX2 cancer engraftment in the rabbit using an MRI device (manufactured by GE), and the image shown in FIG. 3 was obtained. Next, the entire amount of the comparative agent 2 prepared in Comparative Example 2 was intravenously injected into the rabbit's ear. A few minutes after the end of the intravenous injection, an MRI was performed on the site of VX2 cancer engraftment in the rabbit using an MRI device (manufactured by GE) under the same conditions as those for the image shown in FIG. 3, and the image shown in FIG. 4 was obtained. Next, the entire amount of the MRI contrast agent composition 1 prepared in Example 1 was intravenously injected into the rabbit's ear. A few minutes after the end of the intravenous injection, an MRI was performed on the site of VX2 cancer engraftment in the rabbit using an MRI device (manufactured by GE) under the same conditions as those for the image shown in FIG. 3 and FIG. 4, and the image shown in FIG. 5 was obtained. Note that the images in FIG. 3, FIG. 4, and FIG. 5 are all images obtained by T1 weighted photography.

[0048] (c) Results and discussion Comparing Figures 1 and 2, before administration of Comparative Agent 1 (Figure 1, the area inside the white dashed line is the cancerous area; same as Figures 2 to 5), the edge of the cancer was barely observable, but after administration of Comparative Agent 1 (Figure 2), the edge of the cancer turned white, indicating a slight contrast effect.

[0049] Next, Figures 3, 4, and 5 are compared. In the state where nothing is administered (Figure 3), the edge of the cancer is barely observable. After administration of Comparative Agent 2 (Figure 4), the edge of the cancer turns slightly white, but almost no change is observed. In contrast, after administration of MRI contrast agent composition 1 (Figure 5), the edge of the cancer turns clearly white, and it can be seen that the contrast effect is remarkable.

[0050] Next, let us compare Figures 2 and 5. Indeed, even when Comparative Agent 1, which contains only the contrast agent, was administered, a slight contrast effect was observed at the edge of the cancer (Figure 2), but when MRI contrast agent composition 1 of Example 1, which contains the contrast agent and monosaccharide, was administered, a clear white area was observed over a wider area (Figure 5), which means that a significant contrast effect was obtained.

[0051] <Verification 2> Next, verification was carried out using Example 2 based on the following Experimental Method 2.

[0052] Example 2 Preparation of MRI contrast agent composition 2 2.0 ml of gadopentetate meglumine (manufactured by Konica Minolta, gadopentetate meglumine intravenous injection solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of glucose injection solution (glucose solution) (manufactured by Otsuka Pharmaceutical Co., Ltd., Otsuka glucose solution 5%, containing 1 g of purified glucose per 20 ml) to obtain 52 ml of MRI contrast agent composition 2.

[0053] (a) Experimental method 2 A rabbit (approximately 2 kg, specimen 3, VX2 cancer engrafted) was used as a test animal. Using an MRI device (GE), MRI was performed on the VX2 cancer engrafted site of the rabbit, and the image shown in FIG. 6 was obtained. Next, the entire amount of the MRI contrast agent composition 2 prepared in Example 2 was intravenously injected into the rabbit's ear. After the intravenous injection was completed, MRI was performed on the VX2 cancer engrafted site of the rabbit every 30 minutes and 90 minutes using an MRI device (GE) under the same conditions as in FIG. 6. The image taken 30 minutes after the end of the injection is shown in FIG. 7, and the image taken 90 minutes after the end of the injection is shown in FIG. 8. Note that both of FIGS. 6 to 8 are images obtained by T1 weighted imaging.

[0054] (b) Results and discussion When nothing is administered (Fig. 6), the edge of the cancer is barely observable, but after administration of MRI contrast agent composition 2 (Figs. 7 and 8), the edge of the cancer becomes clearly white, and it can be seen that the contrast effect is sufficient. This shows that the MRI contrast agent composition can provide a sufficient contrast effect even without administering glucose to the subject before administration, as in Experimental Method 1.

[0055] <Verification 3> Next, using the following Example 3 and Comparative Example 3, verification was carried out based on Comparative Experimental Method 2 and Experimental Method 3.

[0056] Example 3 Preparation of MRI contrast agent composition 3 1.2 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous injection solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of glucose injection solution (glucose solution) (Otsuka Pharmaceutical, Otsuka glucose solution 5%, containing 1 g of purified glucose per 20 ml) to obtain 51.2 ml of MRI contrast agent composition 3.

[0057] Comparative Example 3 Preparation of Comparative Agent 3 1.2 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of physiological saline to obtain 51.2 ml of Comparative Agent 3.

[0058] (a) Comparative Experimental Method 2 A rabbit (approximately 2.9 kg, specimen 4) with VX2 cancer was used as a test animal. First, an MRI was performed on the VX2 cancer engrafted site of the rabbit using an MRI device (manufactured by GE), and the image shown in FIG. 9 was obtained. Next, the entire amount of the comparative agent 3 prepared in Comparative Example 3 was intravenously injected into the rabbit's ear. After the intravenous injection was completed, MRI was performed on the VX2 cancer engrafted site of the rabbit every 10 minutes, 30 minutes, 60 minutes, and 90 minutes using an MRI device (manufactured by GE) under the same conditions as those for the imaging in FIG. 9. The image 10 minutes after the end of the injection is shown in FIG. 10, the image 30 minutes after the end of the injection is shown in FIG. 11, the image 60 minutes after the end of the injection is shown in FIG. 12, and the image 90 minutes after the end of the injection is shown in FIG. 13. Note that the images in FIGS. 9 to 13 were all obtained by T1 weighted imaging.

[0059] (b) Experimental method 3 The same rabbit (about 2.9 kg, specimen 4, VX2 cancer engrafted) as in Comparative Experiment Method 2 was used as a subject animal. Two days after Comparative Experiment Method 2 was performed, MRI imaging was performed on the VX2 cancer engrafted site of the rabbit using an MRI device (manufactured by GE), and the image shown in FIG. 14 was obtained. Next, the entire amount of the MRI contrast agent composition 3 prepared in Example 3 was intravenously injected into the rabbit's ear. After the intravenous injection was completed, MRI imaging was performed on the VX2 cancer engrafted site of the rabbit every 10 minutes, 30 minutes, 60 minutes, and 90 minutes using an MRI device (manufactured by GE) under the same conditions as in FIG. 14. The image 10 minutes after the end of the injection is shown in FIG. 15, the image 30 minutes after the end of the injection is shown in FIG. 16, the image 60 minutes after the end of the injection is shown in FIG. 17, and the image 90 minutes after the end of the injection is shown in FIG. 18. Note that the images in FIGS. 14 to 18 are all images obtained by T1 weighted imaging.

[0060] (c) Results and discussion When comparing Figs. 10 and 15 with Figs. 9 and 14 before administration of Comparative Agent 3 and MRI Contrast Agent Composition 3, white areas are observed, and the effect of the contrast agent can be confirmed (the area inside the dashed line is the cancer area. Same as Figs. 9 to 18). However, the area where the contrast effect is observed is limited in Figs. 10 to 13 where Comparative Agent 3 is administered, whereas the contrast effect can be confirmed over a wide area in Figs. 15 to 18 where MRI Contrast Agent Composition 3 is administered. In particular, the contrast effect is stronger in the area close to the body surface of the cancer subject when MRI Contrast Agent Composition 3 is administered than when Comparative Agent 3 is administered, and a significant difference can be confirmed. This is considered to be the result of the contrast agent being sufficiently taken up by the cancer cells when MRI Contrast Agent Composition 3 is used.

[0061] <Verification 4> Next, verification was carried out based on Comparative Experimental Method 3 and Experimental Method 4 using the following Example 4 and Comparative Example 4.

[0062] Example 4 Preparation of MRI contrast agent composition 4 1.0 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous injection solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of glucose injection solution (glucose solution) (Otsuka Pharmaceutical, Otsuka glucose solution 5%, containing 1 g of purified glucose per 20 ml) to obtain 51 ml of MRI contrast agent composition 4.

[0063] Comparative Example 4 Preparation of Comparative Agent 4 1.0 ml of gadopentetate meglumine (Konica Minolta, gadopentetate meglumine intravenous solution "F" 37.14%, containing 371.40 mg of gadopentetate meglumine per ml) was dissolved in 50 ml of physiological saline to obtain 51 ml of Comparative Agent 4.

[0064] (a) Comparative Experimental Method 3 A rabbit (approximately 3.4 kg, specimen 5) with engrafted VX2 cancer was used as a test animal. First, an MRI was performed on the engrafted site of the rabbit with VX2 cancer using an MRI device (GE), and the image shown in FIG. 19 was obtained. Next, the entire amount of the comparative agent 4 prepared in Comparative Example 4 was intravenously injected into the rabbit's ear. After the intravenous injection was completed, MRI was performed on the engrafted site of the rabbit with VX2 cancer every 10 minutes, 30 minutes, 60 minutes, and 90 minutes using an MRI device (GE) under the same conditions as those for the imaging in FIG. 19. The image 10 minutes after the end of the injection is shown in FIG. 20, the image 30 minutes after the end of the injection is shown in FIG. 21, the image 60 minutes after the end of the injection is shown in FIG. 22, and the image 90 minutes after the end of the injection is shown in FIG. 23. Note that the images in FIGS. 19 to 23 were all obtained by T1 weighted imaging.

[0065] (b) Experimental method 4 The same rabbit (about 2.9 kg, specimen 5, VX2 cancer engrafted) as in Comparative Experimental Method 3 was used as a subject animal. One day after Comparative Experimental Method 3 was performed, MRI imaging was performed on the VX2 cancer engrafted site of the rabbit using an MRI device (manufactured by GE), and the image shown in FIG. 24 was obtained. Next, the entire amount of the MRI contrast agent composition 4 prepared in Example 4 was intravenously injected into the rabbit's ear. After the intravenous injection was completed, MRI imaging was performed on the VX2 cancer engrafted site of the rabbit every 10 minutes, 30 minutes, 60 minutes, and 90 minutes using an MRI device (manufactured by GE) under the same conditions as in FIG. 21. The image 10 minutes after the end of the injection is shown in FIG. 25, the image 30 minutes after the end of the injection is shown in FIG. 26, the image 60 minutes after the end of the injection is shown in FIG. 27, and the image 90 minutes after the end of the injection is shown in FIG. 28. Note that the images in FIGS. 24 to 28 are all images obtained by T1 weighted imaging.

[0066] (c) Results and discussion When comparing Fig. 20 and Fig. 25 with Fig. 19 and Fig. 24 before administration of Comparative Agent 4 and MRI Contrast Agent Composition 4, white areas are observed, and the effect of the contrast agent can be confirmed (the area inside the dashed line is the cancer area. Same as Fig. 19 to 28). However, in Fig. 20 to 23 where Comparative Agent 4 is administered, the area where the contrast effect is observed is limited, whereas in Fig. 25 to 28 where MRI Contrast Agent Composition 4 is administered, the contrast effect can be confirmed in a wider area. In particular, when MRI Contrast Agent Composition 4 is administered, a more significant contrast effect can be confirmed in the testis area of ​​the subject compared to when Comparative Agent 4 is administered. This is considered to be the result of the contrast agent being taken up more sufficiently by the cancer cells when MRI Contrast Agent Composition 4 is used.

Claims

1. A monosaccharide comprising at least one of glucose and fructose, a gadolinium contrast agent; the monosaccharide is not covalently linked to another molecule; The gadolinium contrast agent and the monosaccharide are contained in a mass ratio of 1:0.01 to 1:

10. MRI contrast agent compositions.

2. The MRI contrast agent composition of claim 1 , wherein the monosaccharide is glucose.

3. 3. The MRI contrast agent composition of claim 1, wherein the gadolinium contrast agent comprises at least one of gadopentetate meglumine, gadoterate meglumine, gadoxetate sodium, gadodiamide hydrate, gadoteridol, and gadobutrol.

4. 4. The MRI contrast agent composition according to claim 1, wherein the gadolinium contrast agent is gadopentetate meglumine.

5. 5. The MRI contrast agent composition according to claim 1, comprising the gadolinium contrast agent and the monosaccharide in a mass ratio of 1:1 to 1:10.

Images