JP2001276242A - 166ho-dtpa, method for manufacturing the same and use of the same as liquid radiation source - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe and effective liquid radiation source used for restraining reobstriction after angioplasty using a balloon catheter. SOLUTION: 166Ho-diethylenetriamine pentaacetic acid radiating βand γrays is used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to ¹⁶⁶ Ho-labeled diethylenetriaminepentaacetic acid (DTPA) and a method for producing the same. In particular, the present invention maintains a stable form for a long time and
¹⁶⁶ Ho-DTPA has a characteristic to be discharged to either quickly when leaked into the body, useful for the inhibition of restenosis after angioplasty stenosis vascular diseases as a liquid radiation source (radio instantiation source) ¹⁶⁶ Ho- Regarding DTPA.

[0002]

2. Description of the Related Art Stenosis cardiovascular disease is a type of coronary artery disease and usually occurs when blood vessels become narrow due to accumulation of cholesterol and insoluble calcium. When the coronary arteries become narrow, as in arteriosclerosis, blood flow is impeded, disrupting the supply of oxygen and nutrients that lead to cardiac muscle necrosis, leading to myocardial infarction and angina.

[0003] Stenotic vascular disease of the coronary arteries is primarily treated by percutaneous transluminal coronary angioplasty (PTCA), which inserts a balloon catheter to dilate the vessel.
PTCA has been widely used since Gruentzig performed the first human surgery in 1977. Now 500,
It has been reported that more than 000 people benefit from PTCA (Holmes, DR, et al. Am. J. Ca).
rdiol. , 53: 77C-81C, 1984). This angioplasty method has about 95% clinical success.

[0004] However, a major problem with PTCA treatment is restenosis. Acute closure or restenosis occurs during or after angioplasty with a balloon catheter. 30-45% of patients who have had this surgery have had restenosis within 6 months after the operation. The mechanism by which restenosis occurs after transluminal coronary angioplasty can generally be explained by vascular modification, smooth muscle cell (SMC) proliferation, and extracellular matrix formation (Withers, HR.
Et al., Cancer, 34: 39-47, 1974; Th.
Omes, H .; D. Et al., Int. J. Radiat. O
nco. Biol. Phys. , 7: 1591-15
97, 1981). Normally, intravascular SMCs do not undergo active cell division, but when blood vessels are physically damaged or stimulated,
SMCs cause endovascular inflammation and proliferation to form matrix tissue.

Therefore, suppression of restenosis is as important as dilation of narrowed blood vessels. Various efforts have been made to control restenosis, including antithrombotics, anticoagulants, steroids, calcium channel blockers, cortisin and gene therapy. Since the drug travels in the blood vessel, it is difficult to continuously maintain its efficacy at the site of the blood vessel in question. Therefore, unlike the treatment of tumors, the administration of the drug has only a slight inhibitory effect on intracellular cell proliferation.

Other methods of controlling restenosis are also known, including transluminal excision catheters (TEN), exia laser coronary angioplasty, and stent implantation. In particular, recently, an angiogenesis method using radiation that has necrotically irradiated cells in the vicinity of a site of interest and thereby essentially suppresses the proliferation of SMC has been developed.

[0007] Radionuclides useful for this radiotherapy emit β-rays or γ-rays. Examples of β-emitting radionuclides include ³² P, Sr, ⁹⁰ Y, ¹⁰⁹ Pd,
^{131 I, 1 53 Sm, 165} Dy, 166 Ho, 169 Er,
^{There are 188} Re, ¹⁹⁸ Au and ^99m Tc, and examples of radionuclides emitting gamma rays are ¹⁹² Ir, ⁵⁷ Co, ⁶⁰ Co,
^{There are 48} V and ¹²⁵ I. Among these, ¹⁸⁸ Re and
Radioisotopes with high β-ray energy, such as ¹⁶⁶ Ho, are used in angiogenesis. ¹⁸⁸ Re is ¹⁸⁸ W / ¹
It can be easily obtained from the ⁸⁸ Re generator, but is 10 ¹⁵ n
It requires a neutron flux of / cm ² · sec or more and an atomic reactor with high production cost. Conversely, ¹⁶⁶ Ho is 10
It is advantageous in terms of production cost because it can be mass-produced with a small-scale research reactor having a neutron flux of ¹⁴ n / cm ² · second.

We have used ¹⁶⁶ HO as a liquid radiation source.
A balloon catheter using (NO ₃ ) ₃ was developed and used for angioplasty in patients who had undergone balloon angioplasty or stent implantation at least once due to coronary stenosis and subsequently had restenosis. ¹⁶⁶ Ho (NO
₃ ) In the operation using ₃ , ¹⁶⁶ Ho significantly suppresses restenosis.

[0009] However, if radionuclide leaks due to the balloon of the catheter being ruptured during the operation, the radionuclide stays in the body for a long time and is absorbed by bone marrow and other organs, causing a serious adverse effect on the human body. In order to perform radiation therapy, it is important to ensure the stability of the radioactive material. When radioactive material leaks into the body, it is quickly eliminated from the human body if possible.
¹⁶⁶ Ho (NO ₃ ) ₃ accumulates in major organs such as the kidney, spleen, and bone, and therefore has the disadvantage of being excreted very slowly from the human body.

[0010] ^99m Tc-labeled diethylenetriaminepentaacetic acid (DTPA) is widely used for the diagnosis of kidneys by utilizing its accumulation and excretion through the kidneys or bladder in the body (Majali, MA, J. Radian).
el. Nucl. Chem. , 170, 471). DT
This advantage of PA has been applied to measuring the distribution of ¹⁸⁸ Re-labeled DTPA in the body (Lee J. et al., Kor.
J. Nucl. Med. , 1997, 1427).

However, as described above, Re requires an atomic reactor having a neutron flux of 10 ¹⁵ n / cm ² · sec or more for its production, and therefore its production cost is high. When mixed with human serum, ¹⁸⁸ Re-DTPA
The labeling efficiency drops to 88% or less after 1 hour. This compound therefore has a disadvantage in in vivo stability.

[0012]

Means for Solving the Problems] To overcome the disadvantages of the methods described above present inventors have intensively studied relates Useful liquid radiation sources in angioplasty by radiation therapy, ¹⁶⁶ H
o DTPA with labeling was successfully developed. ¹⁶⁶ Ho-DTP
A is safe for the human body because it highly inhibits restenosis and is rapidly excreted from the human body. According to the present invention, β-ray and γ
¹⁶⁶ Ho-DTPA is provided which can be used as a liquid radiation source useful for radiation emitting radiation therapy.

[0013] Liquid radiation sources consisting of ^{1 66} Ho-DTPA for use in restenosis inhibition after angioplasty stenosis vascular diseases according to the present invention is provided. According to the present invention, diethylenetriaminepentaacetic acid (DTPA) is
Reacting (NO ₃ ) ₃ , HoCl ₃ or a hydrate thereof, preferably in a molar ratio of Ho ( ¹⁶⁶ Ho + ^{1 65} Ho) to DTPA in the range of 1: 1-1: 8.
^A method for producing ¹⁶⁶ Ho-DTPA is provided.

[0014]

DETAILED DESCRIPTION OF THE INVENTION ¹⁶⁶ Ho is the half-life with the largest β-ray energy of 1.86MeV is a radioactive isotope of 26.8 hours. Since this radioisotope emits weak γ-ray energy and high β-ray energy, it is expected to show an excellent radiotherapy effect. Radiation therapy generally at ¹⁸⁸ are used Re ¹⁸⁸ expensive in its manufacturing W /
^Although requiring a ^{1 88} Re generator, ¹⁶⁶ Ho can be manufactured in large quantities in a small research reactor. ¹⁶⁶ A further advantage of Ho is similar to ^99m Tc, which is used as a visual type nuclide γ
It also emits lines so that you can visualize the internal state of the human body.

[0015] It is known that DTPA migrates to the kidney or bladder in the human body. For example, ^99m Tc-DTPA
Is widely used for kidney diagnosis, especially for glomerular filtration. Thus, according to one aspect of the present invention, ¹⁶⁶ Ho and DT
¹⁶⁶ Ho-labeled DTPA (hereinafter referred to as “ ¹⁶⁶ Ho”) serves as a useful liquid radiation source for radiation therapy with a combination effect of PA.
-DTPA ").

When ¹⁶⁶ Ho is combined with DTPA according to the present invention, the resulting complex ¹⁶⁶ Ho-DTPA can exist for more than 24 hours and is stable under neutral conditions (pH 7) and various acidic conditions. Therefore, even when exposed in vivo, ¹⁶⁶ Ho is tightly labeled with DTPA,
The safety of use in liquid radiation sources is ensured. Also ^{1 66}
When Ho-DTPA leaks directly into the human body, it moves toward the kidney or bladder in a short time and is unlikely to accumulate in other organs, and may be excreted via urine. Hence, safety as radiation source ^{1 66} Ho is improved.

[0017] Without the nuclide from damaging the surrounding normal tissues, so that it can be used in the treatment of localized lesions, ¹⁶⁶ Ho emits β- lines and γ- lines, mainly β- lines. Radiation emitted from the ¹⁶⁶ Ho can be necrosis SMC vascular gives often occurs in vascular restenosis solve such in angioplasty procedures. Therefore, in combination with the physiological benefits of DTPA, the effects of ¹⁶⁶ Ho radiation therapy inhibit restenosis after angioplasty procedures such as PTCA using a balloon catheter for stenotic vascular disease including arteriosclerosis. As a safe source of liquid radiation
¹⁶⁶ Ho-DTPA can be used.

When a balloon catheter is used to treat stenotic coronary artery disease, it is very important to determine an irradiation source suitable for preventing restenosis of the coronary artery. Experimental data on the absorbed radiation dose indicate that if the treatment time is limited to less than 150 seconds, the balloon catheter is preferably the H of the present invention.
o-DTPA was increased by 2 based on a therapeutic dose of about 20 Gy.
Contains at an initial irradiation dose of 0-100 mCi.

[0019] In addition to being able to easily produce a liquid radiation source of the balloon catheter, ^{1 66} Ho-DTPA can be filled into the balloon regardless of the shape and size of the balloon. Therefore, when contained in a balloon, the liquid of the invention
¹⁶⁶ Ho-DTPA is irradiated only to the area of interest that is not in direct contact with the inner wall of the blood vessel. Balloon catheters can be manufactured by conventional methods and are commercially available. FIG.
Shows an example of a balloon catheter containing ¹⁶⁶ Ho-DTPA of the present invention as a liquid radiation source.

According to another aspect of the invention, DTPA is H
There is provided a method for producing ¹⁶⁶ Ho-DTPA, which is reacted with O (NO ₃ ) ₃ , HoCl ₃ or a hydrate thereof. Ho ( ¹⁶⁶ Ho + ¹⁶⁵ Ho) versus DTPA in this reaction
Is preferably in the range of 1: 1 to 1: 8,
More preferably, it is in the range of 1: 3 to 1: 6. This labeling reaction is preferably performed under neutral or acidic conditions, ie, pH 7 or less. In the method of the present invention,
Labeling of ¹⁶⁶ Ho is performed in about 100% yield.

[0021]

The following examples are provided to illustrate the present invention, but the invention is not limited thereto. Example 1: ¹⁶⁶ Ho-DTPA 1 of manufacturing 8.1mg of _{^{165 Ho (NO 3) 3 ·}} 5H 2 O and subjected to neutron irradiation ¹⁶⁶ Ho (NO ₃₎ to give the ₃ · 5H ₂ O.
DTPA: Ho ( ¹⁶⁵ Ho + ¹⁶⁶ Ho) molar ratio of 3.9
To obtain an 8: 1 composition, 12 mg of DTPA (calcium trisodium salt hydrate, Aldrich) was added to 2
0.1 ml of a solution of Ho (NO ₃ ) ₃ .5H ₂ O (pH 3) in ml HCl was added, followed by saline buffer solution to a final volume of 1.1 ml. The resulting solution shows a pH range of 5.0-5.5 and the used Ho
_{(NO 3) 3 · 5H 2} O showed radioactivity 1.3MCi.

The reaction composition was subjected to flash thin layer chromatography-silicic acid (I) with a mobile layer of 75% aqueous methanol.
After development on the stationary phase of TLC-SA), the labeling yield was read on an ITLC scanner (EG & G Berthold linear analyzer). Scan data is ¹⁶⁶ Ho for DTPA
-Showed almost complete labeling with DTPA. The free forms of ¹⁶⁶ Ho (NO ₃ ) ₃ and ¹⁶⁵ Ho (NO ₃ ) ₃
f 0-0.2 (FIG. 2a) and 0.9-1.0 (FIG. 2)
Separated in b).

[0023] Example 2: ¹⁶⁶ of the manufacturing 5mg of _{^{Ho-DTPA 2 165 Ho 2 O}} 3 166 toward the neutron irradiation Ho
After obtaining ₂ O ₃ , it was dissolved in 2N HCl. DTPA is added to this solution, and DTPA: Ho ( ¹⁶⁵ Ho + ¹⁶⁶
A composition having a molar ratio of Ho) of 3.98: 1 was obtained. The pH of this solution was adjusted to 5.0-5.5 with dilute NaOH and ¹⁶⁶ Ho
-DTPA was obtained. The labeling yield measured in the same manner as in Example 1 was 99.9%.

[0024] Experimental Example 1: ¹⁶⁶ were analyzed impurities of ¹⁶⁶ Ho made with analysis research reactor of impurities nuclide "Hanaro" included in Ho. In this regard, gamma-ray spectroscopy using a high energy resolution Ge detector (EG & G, Ortec) was used. Table 1 shows the analysis results.

[0025]

[Table 1]

As shown in Table 1, in Hanaro
^The radioactive impurities generated in the production of ¹⁶⁶ Ho had very little radioactivity compared to ¹⁶⁶ Ho and did not affect the determination of the absorbed radiation dose.

Experimental Example 2: ¹⁶⁶ Ho-D over time
TPA Stability The stability of ¹⁶⁶ Ho-DTPA over time was tested as follows. 108 mCi and 202 in lyophilized glass bottle kit each containing 12 mg DTPA
1 ml each of mCi of ¹⁶⁶ Ho (NO ₃ ) ₃ .5H ₂ O (pH 3) was added, followed by the addition of 0.2 ml of acetate buffer to adjust the pH of the solution to 6.0-6.3. 30
After 2 minutes, 3 hours, 6 hours, and 24 hours, the reactants were developed on a stationary phase of ITLC-SA with a mobile layer of 75% aqueous methanol. ¹⁶⁶ Ho using ITLC scanner
-The radiation dose of DTPA was measured. Table 2 shows the results.

[0028]

[Table 2]

At 108 mCi, radiolabeled DTP
A was stable for 24 hours after labeling, as determined to maintain a labeling yield of 98% or greater. 202mC
In i, ¹⁶⁶ Ho-DTPA was 3 hours 9 after labeling.
A labeling yield of 8% or more was maintained, and after 24 hours, a labeling yield of about 70% was maintained. ¹⁶⁶ Ho-DTPA maintained its integrity for an extended period of time without the ¹⁶⁶ Ho separating from DTPA. Therefore, even when ¹⁶⁶ Ho-DTPA leaks into the human body, this complex migrates to the kidney or bladder and hardly migrates to other organs according to the properties of DTPA. As a result, ¹⁶⁶ H
o-DTPA is extremely stable and secure, as demonstrated by the following examples.

Experimental Example 3: ¹⁶⁶ Ho-D against pH change
TPA Stability The stability of ¹⁶⁶ Ho-DTPA to pH changes was tested as follows. 55 mCi of lyophilized glass bottle kit containing 12 mg DTPA each
Each of ¹⁶⁶ Ho (NO ₃ ) ₃ .5H ₂ O (pH 3) 0.1
After addition of 0.9 ml of saline buffer, the pH of the solution was adjusted to 1.67, 3.1, 5.05 and 6.81 by adding different amounts of acetate buffer. After 30 minutes, the reactants were developed on a stationary phase of ITLC-SA with a mobile layer of 75% aqueous methanol. ITLC
The radiation dose of ¹⁶⁶ Ho-DTPA was measured using a scanner. Table 3 shows the results.

[0031]

[Table 3]

As shown in Table 3, ¹⁶⁶ Ho-DTPA was extremely stable under neutral and acidic conditions.

Experimental Example 4: ¹⁶⁶ Ho-D in rat body
Investigation of distribution of TPA Eight male Spragues with an average body weight of 257 ± 7.1 g
-200 ± from Dawley (SD) rats via tail vein
¹⁶⁶ Ho-DTPA was injected at a dose of 20 μCi. At 15 minutes and 90 minutes after intravenous injection, four rats were each sufficiently anesthetized with ether and killed. The main organs of these rats (liver, spleen, kidney, bladder, testicle, lung, heart,
Brain), muscle, fat and bone were weighed and radioactivity was counted with a well-known scintillator (Canbarra). The radioactivity accumulated in each organ or tissue was calculated based on the total injected dose and the percentage of injected dose per gram of each organ or tissue was determined. Table 4 shows the results.

[0034]

[Table 4]

At 15 minutes after intravenous injection, the bladder showed the highest radiation dose (ID / g 54.7%), as shown in Table 4, and was more renal than blood (ID / g 2.20%). A higher radiation dose was detected (ID / g 5.09%).
This value indicates that most of the injected ¹⁶⁶ Ho-DTPA migrated to the kidney and bladder. Ninety minutes after intravenous injection, the radiation dose to the kidney and bladder was 1.46% and 1.46%, respectively.
26% ID / g was shown. ¹⁶⁶ H injected from these
It can be seen that most of o-DTPA moves to the kidney and bladder and is excreted outside the body in a short time. It was also found that the rate of uptake of radioactive substances in other organs or tissues was lower than that of blood.

Experimental Example 5: ¹⁶⁶ Ho-DT in rabbit
Examination of PA distribution Anesthesia treatment was performed by intramuscular injection of ketamine (Yuhan Korea, Ltd.) at 25 mg / kg and lumpoon (Bayer Korea) at 6 mg / kg, followed by three male rabbits (New Zealand white, average weight of 2731 ±). the ^{1 66} Ho-DTPA from the ear vein into each of 52.9g) 2.0 ± 0.2mC
i injection. Thereafter, photographs of the whole body of these rabbits were taken for 30 minutes using a gamma camera (Diacam, Siemens, Germany) to monitor the behavior of the injected drug. In this regard, the camera was equipped with a balanced pinhole collimator and set at an energy level of 80 keV with a 20% window width. An image was obtained using the advantages of the intermediate collimator.
The results are shown in FIG. From the region of interest (ROI) in the right kidney and left kidney of the rabbit, a time-radiation dose curve was obtained, and this was used as a computer system (ICON) as shown in FIG.
Was used to determine the maximum distribution time (T _max ) and half-life (T _1/2 ) for the kidney.

As can be seen from FIG. 3, the injected ¹⁶⁶ Ho
-Most of the DTPA was excreted via the kidney and bladder within 30 minutes after injection. This rapid elimination of injected ¹⁶⁶ Ho-DTPA was evidenced by a time-dose curve.
As is evident from FIG. 4, the radiation dose in the kidney was 30 injections.
After a minute, it fell to the same level as the background activity. T _max and T _1/2 were measured to be 4 and 22 minutes for the left kidney and 4 and 19 minutes for the right kidney, respectively. Therefore, most of the injected ¹⁶⁶ Ho-DTPA was 3
It was observed that it was excreted outside the body via the kidney and bladder within 0 minutes.

[0038] Experimental Example 6: For use as the radiation source of the balloon catheter to inhibit restenosis of determining coronary artery absorbed dose suitable for therapeutic, for ¹⁶⁶ Ho seeking initial radiation dose suitable for radiation treatment in the following ways Was. EGS
Using a four-code system, the distribution of absorbed radiation doses of β and γ rays emitted from ¹⁶⁶ Ho in water was calculated. In this experiment, the initial radiation dose of the radiation source was determined assuming a therapeutically suitable radiation dose of 20 Gy. The radiation source was assumed to be evenly distributed in the cylinder. Ten grids were radially arranged at 0.5 mm intervals around the radiation source, and for each grid, the% of the absorbed radiation dose of the human body per the injected dose of the target was calculated.

The radiation absorbed dose β-rays and γ-rays, ¹⁶⁶ Ho measured for liquid water using EGS4 Code System
10. Each GBq per target radially located within 0.5 mm depth from the surface of the cylindrical sample.
It was found to be 87 cGy / s and 0.29 cGy / s. Therefore, from the experimental results obtained, the initial radiation absorbed dose suitable for radiation therapy was calculated to be 32.31 mCi within a treatment time of 150 s at a total therapeutic radiation dose of 20 Gy. When the initial radiation dose is represented by a radiation volume density of 100 mCi / mL, it is 0.0519 Gy / s for a target radially located within a depth of 0.5 mm from the surface of the sample having an error of 1.66%. calculated.

[0040] without using any special equipment because it is not possible to treat local lesions also liquidus said ¹⁶⁶ Ho-DTPA since dominantly emit β-rays as the damage of normal tissue around ¹⁶⁶ Ho-DTPA can be easily handled. In addition, when ¹⁶⁶ Ho-DTPA leaks into the body, it is rapidly excreted via the kidney, so that the absorption of radioactive substances into normal tissues can be excluded. In addition, by measuring urine radiation dose, injected ¹⁶⁶ Ho-D
Even if information on the leakage of the TPA is obtained, it is possible to take quick measures against the leakage. In conclusion, ¹⁶⁶ of the present invention
Ho-DTPA can be used as a safe liquid radiation source to control restenosis after angioplasty procedures such as PTCA using a balloon catheter for stenotic vascular disease including arteriosclerosis.

Although the present invention has been described by way of example, the present invention is not limited thereto. It should be understood that many modifications are possible within the spirit of the invention.

[Brief description of the drawings]

FIG. 1 is a schematic diagram of a balloon catheter filled with ¹⁶⁶ Ho-DTPA.

FIG. 2 is a liquid chromatogram of ¹⁶⁶ Ho (NO ₃ ) ₃ (a) and a liquid chromatogram of ¹⁶⁶ Ho-DTPA (b).

FIG. 3. ¹⁶⁶ H taken with a gamma camera over time
A photograph of a rabbit injected with o-DTPA.

FIG. 4 is a graph showing changes in radiation dose over time in the right kidney and left kidney of rabbits injected with ¹⁶⁶ Ho-DTPA.

[Explanation of symbols]

1: balloon catheter 2: ¹⁶⁶ Ho-DTPA-filled balloon 3: coronary artery vessel wall 4: stenosis

Continuing on the front page (72) Inventor Symbian Chul Daejeon, Republic of Korea 305-333 Yuseon-Quioen-Don Hanbit Apart # 109-1306 (72) Inventor Han Kwanghi, Republic of Korea Taejong-si 305-340 Yusong -Guk-Dryong-Dong Gongdongwanri Apartment # 7-302 (72) Inventor Park Yen Woo Woo Seoul 139-240 Nwang-Guk Gongren-Don Hanbo Apartment # 103-402 (72) Inventor Choi Sang-mu South Korea Taejong-shi 302 −243 Theo-Kukwangjieo-Dong Taejaon Apart # 106-1903 (72) Inventor Kim Yong Me South Korea Taejon-Shi 305-390 Yusong-Ku Jungmin-Dong Changuana Lae Apartment # 106-1202 (72) Inventor Hong Yong Dong South Korea Daejeon-si 302-122 Theo-Kudangsan 2-Dong Samri Apart # 101- 1203 F-term (reference) 4C082 AA07 AC03 AC06 AE05 AR02 AV08 4C206 AA01 AA02 AA03 AA04 JB20 MA01 MA04 MA36 NA14 ZA40 4H006 AA01 AB23 AC90 BC31 BE62 BE90 BS10 BU32

Claims (5)

[Claims] 1. A ¹⁶⁶ Ho-labeled diethylenetriaminepentaacetic acid ( ¹⁶⁶ Ho-DTP) emitting β- and γ-rays
A). 2. A liquid radiation source comprising the ¹⁶⁶ Ho-DTPA of claim 1. 3. The liquid radiation source according to claim 2, which is used for suppressing restenosis after angioplasty for stenotic vascular disease. 4. Diethylenetriaminepentaacetic acid is converted to Ho
A method for producing ¹⁶⁶ Ho-DTPA, which is reacted with (NO ₃ ) ₃ , HoCl ₃ or a hydrate thereof. 5. The method of claim 4 wherein the molar ratio of Ho ( ¹⁶⁶ Ho + ¹⁶⁵ Ho) to diethylenetriaminepentaacetic acid is in the range of 1: 1-1: 8.