JP7664599B2 - MRI contrast agent composition - Google Patents

Description

Applicable under Article 30, Paragraph 2 of the Patent Act Published in the Proceedings of the 119th Annual Meeting of the Japan Society of Medical Physics Published on April 1, 2020

Application of Article 30, Paragraph 2 of the Patent Act Presentation at the 119th Annual Meeting of the Japan Society of Medical Physics URL: https://jrc2020web.com/ (Website) Presentation date: May 15th to June 14th, 2020

The present invention relates to an MRI contrast agent composition.

For in vivo diagnosis of diseases and 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 PET-CT and MRI are used in particular for diagnosing cancer.

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. Secondly, X-ray CT has the problem of external exposure due to X-ray irradiation during the examination, and the problem of high radiation doses is an issue. Furthermore, it is known that the spatial resolution of PET is low, at around 5 mm.

MRI, on the other hand, is a technique that applies a high-frequency magnetic field to induce a resonance phenomenon in hydrogen atoms inside the body, picks up the radio waves generated during this process with a receiving coil, and assembles the resulting signal data into an image. Unlike PET-CT, it is thought that there is no radiation exposure. MRI is also known to have a high spatial resolution of around 0.5 mm.

In MRI, contrast agents are sometimes used to see blood flow and the spread of blood vessels to organs, which are normally not visible. Various contrast agents are used in MRI examinations/diagnoses to enhance the contrast and tissue specificity of MRI images. Representative contrast agents include gadolinium contrast agents such as gadopentetate meglumine (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA), which shortens the T1 relaxation time and increases the contrast (signal intensity) in T1-weighted images (Patent Document 1).

International Publication WO2009/025168

However, because MRI contrast agents are difficult to take up into cancer cells, there has been a problem in that sufficient contrast effects cannot be obtained even when MRI contrast agents are used.

The present invention was made in consideration of the above problems, and aims to provide an MRI contrast agent composition that makes it easier for the MRI contrast agent contained therein to be taken up by cancer cells.

To solve the above problems, the present invention provides an MRI contrast agent composition that includes a monosaccharide and an MRI contrast agent, the monosaccharide not being covalently bonded to other molecules (Invention 1).

According to this 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, making it possible to carry out examinations and research using clearer images.

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

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

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

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

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

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).

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).

The present invention provides an MRI contrast agent composition that makes it easier for the MRI contrast agent contained therein to be taken up by cancer cells. This makes it possible to carry out examinations, diagnoses, and research using images that have a high contrast effect.

This is a photograph of VX2 cancer (specimen 1) taken by MRI. 1 is a photograph of VX2 cancer (specimen 1) taken by MRI after administration of comparative agent 1. This is a photograph of VX2 cancer (specimen 2) taken by MRI. 1 is a photograph of VX2 cancer (specimen 2) taken by MRI after administration of comparative agent 2. 1 is a photograph of VX2 cancer (specimen 2) taken by MRI after administration of an MRI contrast agent composition 1 according to one embodiment of the present invention. This is a photograph of VX2 cancer (specimen 3) taken by MRI. 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. 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. This is a photograph of VX2 cancer (specimen 4) taken by MRI. 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 10 minutes after administration of comparative agent 3. 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 30 minutes after administration of comparative agent 3. 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 60 minutes after administration of comparative agent 3. 1 is a photograph of VX2 cancer (specimen 4) taken by MRI 90 minutes after administration of comparative agent 3. 10 is a photograph of VX2 cancer (specimen 4) taken by MRI two days after the photograph in FIG. 9 was taken. 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. 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. 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. 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. This is a photograph of VX2 cancer (specimen 5) taken by MRI. 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 10 minutes after administration of comparative agent 4. 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 30 minutes after administration of comparative agent 4. 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 60 minutes after administration of comparative agent 4. 1 is a photograph of VX2 cancer (specimen 5) taken by MRI 90 minutes after administration of comparative agent 4. 20 is a photograph of VX2 cancer (specimen 5) taken by MRI one day after the photograph in FIG. 19 was taken. 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. 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. 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. 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.

The following describes an embodiment of the present invention. 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.

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 an excellent contrast effect can be obtained. In particular, since cancer cells take up monosaccharides (particularly glucose) more actively than normal cells, the MRI contrast agent is more easily taken up together with the monosaccharides, and a more excellent contrast effect can be obtained.

(1) Monosaccharides 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.

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

The concentration of the monosaccharide in the MRI contrast agent composition depends on the administration method described below, but can 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 such a range, the MRI contrast agent is more actively taken up into cells, the amount of other components can be sufficiently ensured, and administration to the living body can be easily performed.

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 disaccharides such as maltose and lactose, polysaccharides such as glycogen and cellulose, sugar chains, etc., which is an example of a monosaccharide not having a covalent bond with other molecules.

In other words, in this embodiment, since the process of covalently bonding monosaccharides to other molecules is not required when preparing the MRI contrast agent composition, the MRI contrast agent composition can be prepared more easily. For example, one embodiment of the present invention can be prepared by simply mixing an 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.

(2) MRI contrast agent 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 a contrast effect in this specification.

The MRI contrast agent used in this embodiment is not particularly limited, but examples include gadolinium contrast agents, contrast agents using iron-platinum particles, and contrast agents using manganese. Of these, gadolinium contrast agents are often used as injections or infusions, and from the viewpoint of using the MRI contrast agent composition as an injection or infusion in a living body, gadolinium contrast agents are preferred.

There are no particular limitations on gadolinium contrast agents as long as they contain gadolinium, but examples include meglumine gadopentetate, meglumine gadoterate, sodium gadoxetate, gadodiamide hydrate, gadoteridol, and gadobutrol.

In the examples described below, the results are shown using an MRI contrast agent composition containing gadopentetate meglumine as the MRI contrast agent, but the same results were obtained when an MRI contrast agent composition containing gadoxetate sodium or gadobutrol was used as the MRI contrast agent.

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

The concentration of the MRI contrast agent in the MRI contrast agent composition depends on the administration method described below, but can 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. Within this range, a contrast effect can be expected without causing significant adverse effects on the living body.

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 by cells (especially cancer cells), and a sufficient contrast effect can be expected.

The dosage of the MRI contrast agent composition of the present invention may follow 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 MRI contrast agent: subject's body weight) is preferably 1:1000 to 1:50000, and 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.

(3) Other Components, etc. The MRI contrast agent composition according to this 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 can be applied to cells, etc., and can be administered into the body by intravascular (vein, artery) administration, oral administration, intrarectal administration, intravaginal administration, intralymphatic administration, intra-articular administration, etc., and can be preferably administered in the form of a solution, emulsion, suspension, etc.

The MRI contrast agent composition according to this embodiment may contain additives. The additives vary depending on the route of administration, the form of administration, etc., but specifically, in the case of an injection, a buffering agent, 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 coloring agent, a preservative, a suspending agent, an emulsifier, a thickening agent, a flavoring agent, a sweetener, etc. may be contained alone or in combination. The various additives may be those normally used in the field.

The MRI contrast agent composition according to this embodiment can also 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.

(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 parenterally 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, it is preferable that the dosage of the MRI contrast agent composition is administered to the living body so as to be within the dosage of the MRI contrast agent recommended in the instruction manual of the MRI contrast agent, etc.

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.

Cells obtain energy from monosaccharides (glucose) present in the blood. In particular, cancer cells are known to take up 3 to 8 times as much monosaccharide (glucose) from the blood as normal cells. The MRI contrast agent composition according to this embodiment has been developed with a focus on 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 the body, the cells attempt to take up the monosaccharide (glucose) from the blood, and at the same 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.

The present invention will be explained in more detail below by showing manufacturing (preparation) examples and experimental examples, but the present invention is not limited to the following manufacturing (preparation) examples and experimental examples.

<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.

Example 1 : Preparation of MRI contrast agent composition 1 2.0 ml of gadopentetate meglumine (manufactured by Konica Minolta, Inc., 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 1.

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.

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

(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 Figure 1 was obtained. Next, the entire amount of Comparative Agent 1 prepared in Comparative Example 1 was intravenously injected into the rabbit's ear. A few minutes after the intravenous injection 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 Figure 1, and the image shown in Figure 2 was obtained. Both the images in Figures 1 and 2 were obtained by T1 weighted photography.

(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. The images in Figs. 3, 4 and 5 were all obtained by T1 weighted imaging.

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

Next, compare Figures 3, 4, and 5. When nothing is administered (Figure 3), the edge of the cancer is barely visible. After administration of Comparative Agent 2 (Figure 4), the edge of the cancer turns slightly white, but there is almost no change. 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.

Next, compare Figures 2 and 5. Indeed, even when Comparative Agent 1, which contains only the contrast agent, is administered, a slight contrast effect can be confirmed at the edge of the cancer (Figure 2). However, when MRI contrast agent composition 1 of Example 1, which contains the contrast agent and monosaccharide, is administered, a clear white area can be confirmed over a wider area (Figure 5), which means that a significant contrast effect was obtained.

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

Example 2 : Preparation of MRI contrast agent composition 2 2.0 ml of gadopentetate meglumine (manufactured by Konica Minolta, Inc., 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.

(a) Experimental Method 2
A rabbit (approximately 2 kg, specimen 3, VX2 cancer engrafted) was used as a test animal. MRI was performed on the engrafted site of the rabbit using an MRI device (GE), and the image shown in FIG. 6 was obtained. Next, the entire amount of 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 engrafted site of the rabbit's VX2 cancer every 30 minutes and 90 minutes using an MRI device (GE) under the same conditions as those for 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 photography.

(b) Results and Discussion When nothing was administered (Fig. 6), the margin of the cancer was barely observable, but after administration of MRI contrast agent composition 2 (Figs. 7 and 8), the margin of the cancer became clearly white, demonstrating a sufficient contrast effect. This shows that the MRI contrast agent composition can provide a sufficient contrast effect even without administering glucose to the subject prior to administration, as in Experimental Method 1.

<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.

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.

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

(a) Comparative Experimental Method 2
A rabbit (approximately 2.9 kg, specimen 4) 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. 9 was obtained. Next, the entire amount of 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 site of VX2 cancer in the rabbit at 10, 30, 60, and 90 minutes using an MRI device (GE) under the same conditions as in FIG. 9. The image taken 10 minutes after the end of the injection is shown in FIG. 10, the image taken 30 minutes after the end of the injection in FIG. 11, the image taken 60 minutes after the end of the injection in FIG. 12, and the image taken 90 minutes after the end of the injection in FIG. 13. The images in FIG. 9 to FIG. 13 were all obtained by T1 weighted imaging.

(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 test animal. Two days after Comparative Experiment Method 2, 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. 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 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. It should be noted that the images in Figures 14 to 18 were all obtained by T1 weighted imaging.

(c) Results and Discussion Comparing Fig. 10 and Fig. 15 with Fig. 9 and Fig. 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 Fig. 9 to 18). However, in Fig. 10 to 13 where Comparative Agent 3 was administered, the contrast effect is observed in a limited area, whereas in Fig. 15 to 18 where MRI contrast agent composition 3 was administered, the contrast effect can be confirmed over a wide area. In particular, in the area close to the body surface of the cancer subject, the contrast effect is stronger 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.

<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.

Example 4 : Preparation of MRI contrast agent composition 4 1.0 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 51 ml of MRI contrast agent composition 4.

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

(a) Comparative Experimental Method 3
A rabbit (approximately 3.4 kg, specimen 5) 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. 19 was obtained. Next, the entire amount of 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 site of VX2 cancer in the rabbit at 10, 30, 60, and 90 minutes using an MRI device (GE) under the same conditions as in FIG. 19. The image taken 10 minutes after the end of the injection is shown in FIG. 20, the image taken 30 minutes after the end of the injection in FIG. 21, the image taken 60 minutes after the end of the injection in FIG. 22, and the image taken 90 minutes after the end of the injection in FIG. 23. The images in FIGS. 19 to 23 were all obtained by T1 weighted imaging.

(b) Experimental Method 4
The same rabbit (approximately 2.9 kg, specimen 5, VX2 cancer engrafted) as in Comparative Experimental Method 3 was used as a test animal. One day after Comparative Experimental Method 3 was performed, 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. 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 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. It should be noted that the images in Figures 24 to 28 were all obtained by T1 weighted imaging.

(c) Results and Discussion 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 was administered, the area where the contrast effect is observed is limited, whereas in Fig. 25 to 28 where MRI contrast agent composition 4 was administered, the contrast effect can be confirmed in a wider area. In particular, when MRI contrast agent composition 4 was administered, a more significant contrast effect was confirmed in the testis area of the subject compared to when Comparative Agent 4 was 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 was used.

Claims (5)

A monosaccharide containing 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. The MRI contrast agent composition of claim 1 , wherein the monosaccharide is glucose. 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. The MRI contrast agent composition according to claim 1 , wherein the gadolinium contrast agent is gadopentetate meglumine. 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 .