JP2006182673A - Medicine attached with marker - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine attached with a marker having less risk for a human body and also exhibiting sufficient medicinal efficacy and a pharmacodynamic-measuring system capable of measuring the existing position or concentration of the medicine in a living body easily by using the medicine attached with the marker. <P>SOLUTION: This medicine attached with the marker is provided by containing a medicinally effective component bonded with fluorescent nano-particles. Preferably, the medicine attached with the marker is characterized in that the wavelength of the fluorescent light emitted from the fluorescent nano-particles and the light absorbing range of the medicinally effective component molecules do not coincide. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention provides a drug with a marker that is less dangerous to the human body and that can exhibit sufficient medicinal effects, and can easily measure the presence site and concentration of the drug in vivo using the drug with a marker. It relates to a system for measuring the kinetics of possible drugs.

A drug administered to a human body by a method such as oral administration or intravenous injection is considered to exhibit a drug effect by acting on a target site in the human body at a certain concentration or more. However, the route through which the drug actually administered is concentrated and acting in which organ is monitored, and when the concentration is reached in that organ, sufficient efficacy is monitored. It's not easy to do. It is also important to check whether a drug that is likely to cause side effects has not been delivered to the dangerous part (organ), and whether it has been excreted without being accumulated in the human body. It is.

As a method for examining the movement, metabolism, and the like of a medicine in a living body, for example, a method using a medicine in which a part of a medicinal component molecule is labeled with a radioactive substance has been proposed (for example, Patent Document 1). However, such radioactive substances are extremely dangerous, and the number of institutions that can handle them is limited. In addition, the molecules labeled with radioactive substances decomposed and absorbed by metabolism accumulate in the human body, and the danger of having a tremendous impact on the human body. There was also a problem that there was.

On the other hand, in an in vitro system, a method of using a fluorescent substance or the like as a marker instead of such a radiation marker has been studied. In recent years, various fluorescent substances having high fluorescence intensity have been developed, and the apparatus for analyzing fluorescence has been improved. Therefore, the fluorescent substance marker has occupied an important field in in vitro analysis. However, when such a fluorescent substance is used as a pharmaceutical marker, many fluorescent substances have carcinogenicity and the like, and when they are absorbed and accumulated in the human body, some influence may be concerned. In addition, most medicinal components of pharmaceuticals change their functions by binding fluorescent substances and often no longer show effective medicinal properties, making it difficult to apply to actual treatment and research. It was.

Republished WO99 / 59642

In view of the above-described situation, the present invention has a marker-equipped medicine that is less dangerous to the human body and that can exhibit a sufficient medicinal effect, and facilitates the existence site and concentration of the drug in the living body using the drug with the marker. It is an object of the present invention to provide a pharmacokinetic measurement system that can be measured in a simple manner.

The present invention is a pharmaceutical with a marker containing a medicinal component molecule to which fluorescent nanoparticles are bound.
The present invention is a drug dynamics measurement system comprising a marker-containing drug containing a medicinal component molecule to which fluorescent nanoparticles are bound, and a device for measuring fluorescence emitted from the fluorescent nanoparticles from outside the living body.
The present invention is described in detail below.

As a result of intensive studies, the present inventors have found that fluorescent nanoparticles have high fluorescence performance, can be easily bound without impeding the medicinal effects of most medicinal component molecules, and accumulate in the living body. Therefore, the present inventors have found that a useful drug with a marker can be obtained by binding to a medicinal component molecule, thereby completing the present invention.

In this specification, the fluorescent nanoparticle is a semiconductor material such as CdS, ZnS, CdSc, Si or the like made into fine particles having a particle size on the order of one digit nanometer, and means a substance that emits fluorescence.
Particles made of a semiconductor material have a property of emitting fluorescence by photoexcitation when the particle diameter is about 10 nm or less. The wavelength necessary for exciting such fluorescent nanoparticles is broad on the ultraviolet side, and the longer the particle diameter, the longer the wavelength end of the excitation spectrum shifts to the longer wavelength side. The fluorescence wavelength also shifts to the longer wavelength side as the particle size of the fluorescent nanoparticles increases. As described above, the fluorescent nanoparticles have a feature that the fluorescence wavelength and the excitation light wavelength vary depending on the particle diameter. Therefore, when fluorescent nanoparticles having different particle diameters are bound to medicinal component molecules, analysis with a plurality of wavelengths is possible, and the measurement accuracy can be dramatically improved.

The fluorescent nanoparticles emit fluorescence with extremely high brightness when irradiated with excitation light, and thus can be suitably used for highly sensitive measurement of trace components. In addition, since the excitation light wavelength and the fluorescence wavelength can be adjusted by the particle diameter, it is possible to sufficiently take the wavelength difference between the excitation light and the fluorescence.

Examples of fluorescent nanoparticles used in the pharmaceutical with a marker of the present invention include, for example, a group I-VII compound semiconductor such as CuCl, a group II-VI such as CdS and CdSe, a group III-V compound semiconductor such as InAs, a group IV semiconductor, etc. of the semiconductor crystal, a metal oxide such as TiO _2, made of a phthalocyanine, an organic compound such as azo compounds, or the like composite material thereof can be cited. As such a composite material, for example, CdS is core-CdSe shell, CdSe is core-CdS shell, CdS is core-ZnS shell, CdSe is core-ZnS shell, CdSe nanocrystal is core-ZnS. a shell, the core -ZnSe shell nanocrystals CdSe, core the core -SiO ₂ shell and Si - such as those having a shell structure.

The preferable lower limit of the particle diameter of the fluorescent nanoparticles is 1 nm, and the upper limit is 10 nm.
The shape of the fluorescent nanoparticles is not particularly limited, and examples thereof include a spherical shape, a rod shape, a plate shape, a thin film shape, a fiber shape, and a tube shape. Of these, spherical is preferable.

The medicinal component molecules that bind the fluorescent nanoparticles are particularly those that can bind the fluorescent nanoparticles directly or indirectly and that do not interfere with their medicinal properties by binding the fluorescent nanoparticles. It is not limited.
In addition, if the fluorescence emitted by the fluorescent nanoparticles is absorbed by the medicinal component molecule, sufficient fluorescence intensity may not be obtained, so the wavelength of the fluorescence emitted by the fluorescent nanoparticle, the absorption range of the medicinal component molecule, and It is preferable to select a combination of medicinal component molecules and fluorescent nanoparticles so that they do not match.

Taking the case of using captolyl as a medicinal component molecule as an example, the marker-attached medicament of the present invention will be further described.

Captolyl is a molecule having a structure represented by the following formula (1) and is known to have a therapeutic effect on hypertension.

Since captolyl has a thiol group that is a metal binding group, it can easily bind to fluorescent nanoparticles, and even when fluorescent nanoparticles are bound, the effect of lowering blood pressure is impaired. Therefore, it is possible to exert a sufficient effect as a therapeutic agent for hypertension. Such a marker for treating hypertension with a marker having captolyl bound with fluorescent nanoparticles as a medicinal component is also one aspect of the present invention.

Like the captolyl, a medicinal component molecule having a metal binding group such as a sulfur molecule-containing group such as a mercapto group or a thiol group can be bound to the fluorescent nanoparticles very easily. Further, even if the medicinal component molecule does not have a metal binding group, if the medicinal component molecule has an amino group or a carboxyl group, cysteine having a thiol group is used as an adapter molecule, and the amino acid of cysteine is used. By bonding a peptide to a group or a carboxyl group, it becomes possible to bond the medicinal component molecule and the fluorescent nanoparticle via cysteine. In addition, if the medicinal component molecule has an amino group, an adapter molecule having a sulfur molecule-containing group and a sulfone group at the end is used to imide bond the sulfone group and amino group of the adapter molecule, It becomes possible to bind the medicinal component molecule and the fluorescent nanoparticle via the adapter molecule.

The drug with a marker of the present invention can be obtained by colloidal chemical methods such as reverse micelle method (Lianos, P. et al., Chem. Phys. Lett., 125, 299 (1986)) or hot soap method (Peng, X Et al., J. Am.Chem.Soc., 119, 7019 (1997)) and the like.

An example of a method for producing a marker-treated hypertension drug in which captolyl represented by the above formula (1) is bound to the surface of a fluorescent nanoparticle will be described in detail with reference to the schematic diagram shown in FIG. .
First, the raw material of the fluorescent nanoparticles is dispersed in a coordinating solvent containing tri-n-octylphosphine oxide (TOPO) or the like, and the fine particles of the raw material are micellized with TOPO (TOPO micelle).
Next, the TOPO micelles are heated under argon gas sealing conditions to grow the fine particles of the raw material in the TOPO micelles, thereby obtaining fluorescent nanoparticles having TOPO bonded to the surface. At this time, by controlling the particle diameter of the fluorescent nanoparticles, the wavelength of the fluorescence emitted by the excitation light irradiation can be controlled. The fluorescent nanoparticles in this state are soluble in an organic solvent such as toluene or tetrahydrofuran (THF).
Next, fluorescent nanoparticles having TOPO bonded to the obtained surface are dissolved in a solvent such as THF and heated to 85 ° C., and then captolyl dissolved in ethanol is dropped therein and refluxed for about 12 hours. TOPO bonded to the surface of the fluorescent nanoparticle is exchanged for captolyl by a thiol exchange reaction.
Then, by adding sodium hydroxide aqueous solution, heating to evaporate THF, and purifying and concentrating unreacted substances using filtration, a column, etc., the captolyl is bonded to the surface of the fluorescent nanoparticles. Antihypertensive drugs with markers can be obtained.

In the thus obtained antihypertensive drug with a marker of the present invention, the thiol group of the captolyl is coordinated to the surface of the fluorescent nanoparticle, and the hydrophilic carboxyl group forms the outermost surface. The hydrophilicity to an aqueous solvent such as a medium is excellent. Therefore, even if fluorescent nanoparticles are bound, the effect of captolyl on hypertension is hardly impaired as verified in the examples described later. Similarly, many medicinal component molecules can be combined with fluorescent nanoparticles without impairing medicinal properties.

The pharmaceutical agent with a marker of the present invention can be administered to the human body by a method such as oral administration or intravenous injection in the same manner as when fluorescent nanoparticles are not bound, and has the same drug efficacy as when fluorescent nanoparticles are not bound. Can be demonstrated. The administered drug can be measured for its location and concentration by fluorescence analysis. Therefore, it is easy to monitor the route through which the administered drug is concentrated and in which organ, and what level of concentration is reached in that organ to obtain sufficient efficacy. can do. In addition, even in the case of a drug that has a fear of side effects, it can be easily confirmed whether it does not reach a dangerous site or is discharged without being accumulated in the human body. Furthermore, since the fluorescent nanoparticles themselves are extremely small, they are easily discharged, and since they are very small, they do not affect the human body.
A drug kinetic measurement system comprising a drug with a marker containing a medicinal component molecule to which fluorescent nanoparticles are bound, and a device for measuring fluorescence emitted from the fluorescent nanoparticles from outside the living body is also one aspect of the present invention.

An example of the pharmacokinetic measurement system of the present invention will be described.
The drug kinetic measurement system of the present invention comprises a marker-containing drug containing a medicinal component molecule to which fluorescent nanoparticles are bound, and a device for measuring fluorescence emitted from the fluorescent nanoparticles from outside the living body.
As the drug with a marker containing a medicinal component molecule to which fluorescent nanoparticles are bound, the drug with a marker of the present invention can be used.
The apparatus for measuring the fluorescence emitted by the fluorescent nanoparticles from outside the living body is not particularly limited, and examples thereof include a CCD camera connected to a computer or the like that can calculate the fluorescence intensity of the measured fluorescence.

Next, the principle of measuring the presence position and concentration in the living body using the drug dynamics measurement system of the present invention will be described.
There are the following methods for measuring the concentration of a drug at an arbitrary point of a living body using fluorescence.
Let i (x, y) be the fluorescence intensity at an arbitrary point (x, y) on the living body.
When an xy coordinate axis is set around the center of gravity of the living body, a new coordinate formed by rotating the xy coordinate axis at an angle θ is defined as an x _θ -y _θ coordinate. At this time, the projection (projection) onto the _xθ axis is I _θ . Here, x _.theta.1 -y _.theta.1 coordinates generated when the theta = theta _1, the sum of y _theta axes fluorescence intensity (projection) I _.theta.1 can be represented by the following formula (2).

That is, the total (projection) I _θ1 of the y _θ axis of the fluorescence intensity is a function of x _θ1 .
On the other hand, I _θ1 can be easily measured by analyzing an image from a CCD camera or the like (FIG. 2).
Therefore, I _θ is measured for an arbitrary θ, and an arbitrary i (x is measured by back projecting I _θ ⁻¹ (back projection) of the data (actually, measuring a plurality of θ and solving the simultaneous equations). , Y) can be determined (FIG. 2).

This concept is the same even in the case of three dimensions.
In other words, i (x, y, z) can be expressed by the following formula (3) using the rotation θ with respect to the z axis.

Therefore, I _θ is measured for an arbitrary θ, and an arbitrary i (x is measured by back projecting I _θ ⁻¹ (back projection) of the data (actually, measuring a plurality of θ and solving the simultaneous equations). , Y, z) can be determined (FIG. 3).

If the drug kinetic measurement system of the present invention is used, the drug blood concentration, organ distribution, and the like can be easily measured.

According to the present invention, a drug with a marker that is less dangerous to the human body and that can exhibit a sufficient medicinal effect, and a site and concentration of the drug in a living body using the drug with a marker are easily measured. It is possible to provide a drug kinetic measurement system that can

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Example 1)
In 7.5 g of tri-n-octylphosphine oxide (TOPO) solution, 250 mg of cadmium oxide and 200 mg of selenium were mixed to prepare a TOPO micelle dispersion solution having CdSe fine particles as a core. To this total amount of the TOPO micelle dispersion solution, 1.1 g of zinc diethyldithiocarbamate was mixed and dispersed, heated to 280 ° C. under argon sealing conditions to grow a ZnS film, and CdSe nanocrystals with TOPO bonded to the surface were formed. Fluorescent nanoparticles having an average particle diameter of 640 nm (red) with core-ZnS as a shell were prepared.

TOPO to which fluorescent nanoparticles were bound was dissolved in THF (tetrahydrofuran), then heated to 85 ° C., and captolyl dissolved in ethanol was added dropwise and refluxed for 12 hours. Thereafter, a pH 10 NaOH aqueous solution was added and heated to 90 ° C. to evaporate THF. About the obtained unpurified fluorescent nanoparticle-bound captolyl, the unreacted product is purified and concentrated using an ultrafiltration membrane (Microcon, manufactured by Millipore) and a Sephadex column (MicroSpin G-25 Columns, manufactured by Amersham Blosesciences). And fluorescent nanoparticle-bound captolyl was obtained.

(Example 2)
Fluorescent nanoparticle-bound captolyl was prepared in the same manner as in Example 1 except that the average particle size of the fluorescent nanoparticles was adjusted to 560 nm (yellow).

(Comparative Example 1)
A fluorescent nanoparticle-bound TOPO was produced in the same manner as in Example 1 except that TOPO bound to the fluorescent nanoparticles was not exchanged with captolyl.

(Evaluation)
(1) Confirmation of fluorescent nanoparticle-bound captolyl (1-1) Visual confirmation 5 mg / g of fluorescent nanoparticle-bound captolyl obtained in Examples 1 and 2 and fluorescent nanoparticle-bound TOPO and captolyl obtained in Comparative Example 1 It melt | dissolved in the purified water so that it might become the density | concentration of mL, diluted 100 times using 250 mM NaOH aqueous solution, and left still at room temperature for 15 minutes, Then, it centrifuged. Next, the sample was irradiated with ultraviolet rays having a wavelength of 365 nm (UV-A) and photographed using a digital camera with an exposure time of 1/25 seconds, and the dispersion state of fluorescent nanoparticle-bound captolyl and the presence or absence of fluorescence were visually observed. confirmed.
The results are shown in FIG. 4 (a: Comparative Example 1, b: Example 1, c: Example 2, d: captolyl).

From FIG. 4, it was found that when a fluorescent nanoparticle-bound captolyl solution was used as the sample solution, it was uniformly dispersed in the solution even after centrifugation (FIG. 4b, c). ). Further, it was also found that the fluorescent nanoparticles and captolyl can be bound regardless of the size of the fluorescent nanoparticles.
On the other hand, when the solution containing the fluorescent nanoparticle-bound TOPO obtained in Comparative Example 1 was used as a sample solution, TOPO was fat-soluble, so it was not dissolved in water and precipitated by centrifugation ( FIG. 4a). Further, when a solution containing captolyl is used, it does not emit light because it does not have fluorescent nanoparticles (FIG. 4d).

(1-2) Confirmation by HPLC The fluorescent nanoparticle-bound captolyl solution and the captolyl solution obtained in Example 2 were subjected to HPLC (Waters 600E Multiplicity Delivery System, Waters 2487 Dual λ absorbence Detector and Waters 2475 Measure 2475 Detection was performed to confirm purification of fluorescent nanoparticle-bound captolyl. For detection, a gel filtration column (MAbTrap Kit, manufactured by Amersham Biosciences) was used, and methanol was used as a developing solvent. The flow rate of the developing solvent was 2 mL / min, and the absorption at 370 nm where the absorption of captolyl was most remarkable was measured. The results are shown in FIG. 5 (a: captolyl, b: Example 2).

FIG. 5 shows that when a captolyl solution is used as a sample solution, a peak is detected around 33 minutes (FIG. 5a), whereas when the fluorescent nanoparticle-bound captolyl solution obtained in Example 2 is used. The molecular weight increased under the influence of the fluorescent nanoparticles, and a peak was detected at 23-24 minutes (FIG. 5b). Further, when the fluorescence intensity at 560 nm, which is the fluorescence peak of the yellow fluorescent nanoparticles, was measured, a strong peak of fluorescent nanoparticle-bound captolyl was detected at the same position as in the case of absorption. From the above, it was confirmed that the fluorescent nanoparticle-bound captolyl was purified.

(2) Measurement of ACE (Angiotensin Converting Enzyme) Inhibitory Activity According to the method of Cushman and Cheung, angiotensin I-converting enzyme (ACE) inhibitory activity was measured.
Specifically, 50 μL of purified water or 50 μL of sample solution is added to 50 μL of 1.2 M NaCl aqueous solution, and further 50 μL of borate buffer solution with pH 8.3 containing 6 mU ACE (manufactured by Sigma) is added. After incubating at 3 ° C. for 3 minutes, 50 μL of a pH 8.3 borate buffer containing 10 mM hippuryl-His-Leu (manufactured by Peptide Institute) was added, and incubated at 37 ° C. for 30 minutes for reaction. Subsequently, 200 μL of 1N hydrochloric acid was added to stop the reaction. After 5 minutes, hippuric acid released with 1 mL of ethyl acetate was extracted. After centrifugation at 1500 rpm for 10 minutes, 500 μL of supernatant ethyl acetate was recovered. The collected hippuric acid was evaporated to dryness with a centrifugal evaporator (CC-181, manufactured by Tommy Seiko Co., Ltd.), dissolved in 1 mL of purified water, and then absorbed at 228 nm using an absorptiometer (Ultratrope 2100 pro, manufactured by Amersham Bioscience). Absorbance was measured. As the sample solution, the fluorescent nanoparticle-bound captolyl solution obtained in Example 1, the fluorescent nanoparticle solution bonded with a hydroxyl group as a negative control, and the captolyl solution as a positive control were used. The ACE inhibition rate (%) was expressed as the rate of decrease in absorbance caused by the sample solution.
The results are shown in FIG.

From FIG. 6, the fluorescent nanoparticle-bound captolyl solution and the captolyl solution obtained in Example 1 showed excellent ACE inhibitory activity due to the ACE inhibitory activity of captolyl, and the fluorescent nanoparticle-bound captolyl obtained in Example 1 It was found that the solution showed almost the same ACE inhibitory activity as the captolyl solution used as a positive control. On the other hand, the fluorescent nanoparticle solution to which a hydroxyl group was bound as a negative control hardly showed ACE inhibitory activity. From the above, it was revealed that the fluorescent nanoparticle-bound captolyl solution obtained in Example 1 retains the ACE inhibitory activity of captolyl in vitro.

(3) Confirmation of blood pressure lowering effect After anesthetizing 12-week-old Stroke-Prone Spontaneously Hypertensive Rats (SHR-SP) (body weight 250 ± 20 g) with ether, the sample solution was administered from the carotid artery to 3 mg / kg. Then, systolic blood pressure (SBP) systolic blood pressure was measured by the tail-cuff method.
As the sample solution, the fluorescent nanoparticle-bound captolyl solution and physiological saline obtained in Example 1 were used, the number of specimens was 4, and the measurement was performed before administration, after 15 minutes, after 30 minutes, and after 60 minutes. went.
The results are shown in FIG.

From FIG. 7, even when physiological saline was administered, systolic blood pressure decreased within 30 after administration due to the effect of anesthesia, but when the fluorescent nanoparticle-bound captolyl solution obtained in Example 1 was administered. The maximum blood pressure drop was significantly large, and the retention time of blood pressure drop was also long. From this, it can be considered that the fluorescent nanoparticle-bound captolyl is bound to the fluorescent nanoparticle while maintaining the medicinal effect of captolyl.

(4) Measurement of fluorescent nanoparticle-bound captolyl concentration in plasma Using a fluorescence intensity meter (FP-6500, manufactured by JASCO), relative fluorescence intensity at 640 nm of fluorescent nanoparticle-bound captolyl obtained in Example 1 in plasma Was measured. First, the fluorescent nanoparticle-bound captolyl of Example 1 to which fluorescent nanoparticles having an average particle size of 640 nm were bound was diluted with plasma collected from SHRSP, and the values at each point were plotted to prepare a dilution series. did.
The results are shown in FIG.

FIG. 8 shows that the dilution series rides on a straight line at R = 0.99 or more.
Based on this result, blood was collected from the untreated rat after 1 hour and 24 hours after administration of the sample solution to SHRSP, centrifuged, and the relative fluorescence intensity of the supernatant plasma was measured using a fluorescence intensity meter. The blood concentration was calculated from the relative fluorescence intensity obtained. Furthermore, ACE inhibitory activity was measured.
The relative fluorescence intensity, blood concentration and ACE inhibition rate are shown in Table 1.
In addition, ultraviolet light having a wavelength of 365 nm (UV-A) was irradiated, and the fluorescence state of plasma was photographed using a digital camera with an exposure time of 1/25 seconds.
The results are shown in FIG. 9 (a: not administered, b: 1 hour later, c: 24 hours later).

From Table 1, the concentration of fluorescent nanoparticle-bound captolyl in rats not administered and 24 hours later was 0 mg / mL, and in rats 1 hour later, it was 0.03 mg / mL. Moreover, since the blood pressure of the administered rat returned to the normal value after 24 hours, consistent results were obtained.
Furthermore, since the ACE inhibition rate was 91.1% 1 hour after administration and 28.8% 24 hours after administration, the captolyl of fluorescent nanoparticle-bound captolyl was not metabolized, and the drug efficacy It was revealed that it was present in the blood while holding

(5) Observation of tissue section of organ The fluorescent nanoparticle-bound captolyl obtained in Example 1 was not administered, and from SHR-SP that had passed 1 hour and 24 hours after administration, the organ (liver, lung, kidney, spleen, Brain) tissue sections were collected. The collected organ was immersed in 4% paraformaldehyde for 4 hours to fix the tissue. Thereafter, it was immersed in 100% ethanol to perform dehydration, and ethanol was exchanged three times every 3 hours. The organ subjected to fixation and dehydration was made into a 10 μm-thick paraffin section, and the section was fixed to a slide glass. Photographing was performed with a digital camera using a fluorescence microscope with an exposure time of 3 seconds, and the presence of fluorescent nanoparticle-bound captolyl was confirmed.
The results are shown in FIG. 10 (a: after 1 hour, b: after 24 hours).

From FIG. 10, fluorescent nanoparticle-bound captolyl was confirmed in the liver 1 hour and 24 hours after administration. In other tissues, the fluorescence of the fluorescent nanoparticles was not confirmed.

(6) Measurement of drug dynamics Fluorescent nanoparticle-bound captolyl prepared in Example 1 and Example 2 was dispersed in purified water to a fixed concentration of 0.1% by weight to prepare a fluorescent nanoparticle-bound captolyl dispersion. did.
After 0.1 mL of each fluorescent nanoparticle-bound captoryl dispersion was administered subcutaneously to the back of the rat and irradiated with ultraviolet rays, fluorescence was detected with a high-sensitivity CCD camera.
Further, 0.1 mL of the fluorescent nanoparticle-bound captolyl dispersion prepared in Example 2 was administered subcutaneously to the back of the rat and from the tail vein to the vein, irradiated with ultraviolet light, and then fluorescence was detected with a high sensitivity CCD camera. .
The results are shown in FIG. In FIG. 11, the left side of (a) is a CCD photograph of a rat administered with the fluorescent nanoparticle-bound captolyl dispersion prepared in Example 1, and the right side of (a) is the fluorescence prepared in Example 2. It is a CCD photograph of a rat administered with a nanoparticle-bound captolyl dispersion, and (b) is a CCD of a rat administered with the fluorescent nanoparticle-bound captolyl dispersion prepared in Example 2 subcutaneously in the back and intravenously from the tail vein. It is a photograph.

From FIG. 11, when the fluorescent nanoparticle-bound captolyl dispersion was administered subcutaneously in the back, fluorescence was clearly observed at the site of administration, and when the fluorescent nanoparticle-bound captolyl dispersion was administered intravenously from the tail vein, Fluorescence was observed in the lungs.

According to the present invention, a drug with a marker that is less dangerous to the human body and that can exhibit a sufficient medicinal effect, and a site and concentration of the drug in a living body using the drug with a marker are easily measured. It is possible to provide a drug kinetic measurement system that can

It is a schematic diagram which shows an example of the pharmaceutical with a marker of this invention. It is a schematic diagram explaining the principle which measures the presence position and density | concentration (two-dimensional) of the chemical | medical agent in a biological body with the dynamics measurement system of the chemical | medical agent of this invention. It is a schematic diagram explaining the principle which measures the presence position and density | concentration (three-dimensional) of the chemical | medical agent in a biological body with the dynamics measurement system of the chemical | medical agent of this invention. 2 is a photograph showing the dispersion state of fluorescent nanoparticle-bound captolyl obtained in Examples 1 and 2, the fluorescent nanoparticle-bound TOPO and captolyl obtained in Comparative Example 1, and the presence or absence of fluorescence. It is a chart which shows the absorption in 370 nm of the fluorescent nanoparticle coupling | bonding captolyl solution and captolyl solution which were obtained in Example 2. FIG. It is a graph which shows the ACE inhibition rate of the fluorescence nanoparticle coupling | bonding captolyl solution obtained in Example 1, the fluorescence nanoparticle solution which the hydroxyl group couple | bonded, and a captolyl solution. 2 is a graph showing SBP systolic blood pressure of fluorescent nanoparticle-bound captolyl solution and physiological saline obtained in Example 1. FIG. 4 is a graph showing the relationship between the relative fluorescence intensity at 640 nm and the concentration of fluorescent nanoparticle-bound captolyl obtained in Example 1. It is a photograph which shows the fluorescence state of the fluorescent nanoparticle binding | bond | coupling captolyl of Example 1 not yet administered, 1 hour after administration, and 24 hours after administration. It is the photograph which image | photographed the liver 1 hour and 24 hours after administration of the fluorescent nanoparticle coupling | bonding captolyl of Example 1. FIG. It is a high sensitivity CCD photograph which shows the mode of the rat which administered the fluorescent nanoparticle coupling | bonding captolyl dispersion liquid of Example 1,2.

Claims (4)

A pharmaceutical with a marker, comprising a medicinal component molecule to which fluorescent nanoparticles are bound. 2. The marker-attached medicament according to claim 1, wherein the fluorescence wavelength emitted from the fluorescent nanoparticle does not match the absorption range of the medicinal component molecule. An antihypertensive drug with a marker, characterized in that captolyl bound with fluorescent nanoparticles is used as a medicinal ingredient. A drug dynamics measurement system comprising: a drug with a marker containing a medicinal component molecule to which fluorescent nanoparticles are bound; and a device for measuring fluorescence emitted from the fluorescent nanoparticles from outside the living body.