JP2004217663A - 166 Ho-DTPA, METHOD FOR PRODUCING THE SAME AND USE OF THE SAME AS LIQUID RADIATION SOURCE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe and effective liquid radiation source capable of being used in controlling restenosis after an angioplasty operation for which a balloon catheter, etc., is used. <P>SOLUTION: Diethylenetriaminepentaacetic acid labeled with<SP>166</SP>Ho (166Ho-DTPA) radiates β rays and γ rays. The liquid radiation source comprises the 166Ho-DTPA. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

The present invention relates to ¹⁶⁶ Ho-labeled diethylenetriaminepentaacetic acid (DTPA) and a method for producing the same. In particular, the present invention provides a liquid for inhibiting the occurrence of restenosis after angioplasty surgery for stenotic vascular disease, which has a property of maintaining a stable form for a long period of time and having a property of being rapidly discharged when ¹⁶⁶ Ho-DTPA enters the body. ¹⁶⁶ Ho-DTPA useful as a radiation source.

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

  Coronary stenosis vascular disease is primarily treated by percutaneous transluminal coronary angioplasty (PTCA), which inserts a balloon catheter to dilate the blood vessel. PTCA has been widely used since Gruentzig performed the first human surgery in 1977. It has now been reported that over 500,000 people have benefited from PTCA (Holmes, DR, et al. Am. J. Cardiol., 53: 77C-81C, 1984). This angioplasty method has about 95% clinical success.

  However, a major problem with PTCA treatment is restenosis. Acute closure or restenosis occurs during or after angioplasty using a balloon catheter. 30-45% of patients who have had this surgery have restenosis within 6 months after the operation. The mechanism by which restenosis occurs following 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; Thomas, HD, et al., Int. J. Radiat. Onco. Biol., Phys., 7: 1591-1597, 1981). Normally, intravascular SMCs do not undergo active cell division, but when blood vessels are physically damaged or stimulated, SMCs undergo 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. Because the drug travels in the blood vessel, it is difficult to maintain its efficacy continuously 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 cell proliferation in blood vessels.

  Other methods of controlling restenosis are also known, including transluminal excision catheters (TEN), exia laser coronary angioplasty, and stent implantation. In particular, recently, an angioplasty method using radiation, which essentially suppresses the proliferation of SMC by irradiating cells around the site of interest with radiation, has been developed.

Radionuclides useful for this radiotherapy are those that emit β- or γ-rays. Examples of radionuclides that emit β rays include ³² P, Sr, ⁹⁰ Y, ¹⁰⁹ Pd, ¹³¹ I, ¹⁵³ Sm, ¹⁶⁵ Dy, ¹⁶⁶ Ho, ¹⁶⁹ Er, ¹⁸⁸ Re, ¹⁹⁸ Au, and ^99m Tc, and γ rays. examples of radionuclides which emits may ^{192 Ir, 57 Co, 60 Co} , 48 V and ¹²⁵ I. Among them, radioisotopes having high β-ray energy such as ¹⁸⁸ Re and ¹⁶⁶ Ho are used for angiogenesis. ^{Although 188} Re can be easily obtained from a ¹⁸⁸ W / ¹⁸⁸ Re generator, it requires an atomic reactor having a neutron flux of 10 ¹⁵ n / cm ² sec or more and a high production cost. Conversely, ¹⁶⁶ Ho is advantageous in terms of manufacturing cost because it can be mass-produced in a small-scale research reactor having a neutron flux of 10 ¹⁴ n / cm ² · second.

The present inventors have developed a balloon catheter using ¹⁶⁶ HO (NO ₃ ) ₃ as a liquid radiation source, and angioplasty in patients who have undergone balloon angioplasty or stent implantation at least once due to coronary stenosis and subsequently have restenosis. Used for ¹⁶⁶ Ho _{(NO 3)} 3 and used surgery as a liquid radiation source ¹⁶⁶ Ho is markedly inhibit restenosis.

However, if the radionuclide leaks due to a rupture of the catheter balloon 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.

^99m Tc-labeled diethylenetriaminepentaacetic acid (DTPA) is widely used in the diagnosis of kidneys by utilizing its accumulation and excretion through the kidneys or bladder in the body (Majali, MA, J. Radianel. Nucl. Chem., 170, 471). This advantage of DTPA 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 noted above, Re requires an atomic reactor with a neutron flux of 10 ¹⁵ n / cm ² s or more for its production, thus increasing production costs. Also, when mixed with human serum, the labeling efficiency of ¹⁸⁸ Re-DTPA decreases to 88% or less after 1 hour. This compound therefore has a disadvantage in in vivo stability.

In order to overcome the drawbacks of the above-mentioned method, the present inventors have intensively studied a useful liquid radiation source in angioplasty by radiotherapy and succeeded in developing ¹⁶⁶ Ho-labeled DTPA. ¹⁶⁶ Ho-DTPA is safe for the human body because it highly inhibits restenosis and is rapidly eliminated from the human body.
According to the present invention, there is provided ¹⁶⁶ Ho-DTPA which can be used as a liquid radiation source useful for radiotherapy emitting β-rays and γ-rays.

According to the present invention, there is also provided a liquid radiation source comprising ¹⁶⁶ Ho-DTPA for use in suppressing restenosis after angioplasty for stenotic vascular disease.
Also according to the present invention, diethylenetriaminepentaacetic acid (DTPA) is combined with Ho (NO ₃ ) ₃ , HoCl ₃ or their hydrates, preferably with a molar ratio of Ho ( ¹⁶⁶ Ho + ¹⁶⁵ Ho) to DTPA of 1: 1-1-1. : 8, a method for producing ¹⁶⁶ Ho-DTPA is provided.

Embodiment of the Invention

¹⁶⁶ Ho is a radioisotope with a half-life of 26.8 hours with a maximum β-ray energy of 1.86 MeV. Since this radioisotope emits weak γ-ray energy and high β-ray energy, it is expected to show an excellent radiotherapy effect.
¹⁸⁸ Re, which is commonly used in radiation therapy, requires an expensive ¹⁸⁸ W / ¹⁸⁸ Re generator for its production, while ¹⁶⁶ Ho can be produced in large quantities in small research reactors. A further advantage of ^{166 Ho} is a point that can visualize the body of the internal state so also release the same γ-ray and ^{99m Tc,} which is used as a visual type species.

DTPA is known to migrate 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 DTPA combination acts effectively as a useful liquid radiation source to the radiation therapy with ¹⁶⁶ Ho labeled DTPA (hereinafter referred to as ^"166 Ho-DTPA") is provided .

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. Thus, ¹⁶⁶ Ho is tightly labeled with DTPA, thus ensuring safe use in liquid radiation sources even when exposed in vivo. When ¹⁶⁶ Ho-DTPA leaks directly into the human body, it moves toward the kidney or bladder in a short time and is not easily accumulated in other organs, and may be excreted via urine. Therefore, the safety of ¹⁶⁶ Ho as an irradiation source is improved.

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. Thus, 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. ¹⁶⁶ Ho-DTPA can be used as a safe liquid radiation source when doing so.

  When using a balloon catheter to treat stenotic coronary artery disease, it is extremely 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 will preferably receive the Ho-DTPA of the present invention at an initial dose of 20-100 mCi based on a treatment dose of about 20 Gy. Contained in.

In addition to being easily manufactured as a source of liquid radiation for balloon catheters, ¹⁶⁶ Ho-DTPA can be loaded into balloons regardless of balloon shape or size. Therefore, when contained in a balloon, the liquid ¹⁶⁶ Ho-DTPA of the present invention irradiates only those areas of interest that are 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. 1 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 present invention, there is provided a method for producing ¹⁶⁶ Ho-DTPA, wherein DTPA is reacted with HO (NO ₃ ) ₃ , HoCl ₃ or a hydrate thereof. The molar ratio of Ho ( ¹⁶⁶ Ho + ¹⁶⁵ Ho) to DTPA in this reaction is preferably in the range from 1: 1 to 1: 8, more preferably in the range from 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 DTPA with ¹⁶⁶ Ho is performed in about 100% yield.

Next, examples illustrating the present invention will be given, but the present 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. To obtain a composition with a 3.98: 1 molar ratio of DTPA: Ho ( ¹⁶⁵ Ho + ¹⁶⁶ Ho), 12 mg of DTPA (calcium trisodium salt hydrate, Aldrich) was added to Ho (NO ₃ ) _{3 in} 2 ml of HCl. · 5H ₂ O was added to 0.1ml of a solution (pH 3), and then to a final volume of 1.1ml by adding physiological saline buffer solution. The resulting solution exhibited a pH range of _{5.0-5.5, Ho (NO 3) 3} · 5H 2 O was used also showed radioactivity 1.3MCi.

This reaction composition was developed on a stationary phase of flash thin layer chromatography-silicic acid (ITLC-SA) with a mobile layer of 75% aqueous methanol solution, and then labeled with an ITLC scanner (EG & G Berthold linear analyzer). I read the rate. Scan data showed that DTPA was almost completely labeled with ¹⁶⁶ Ho-DTPA. The free forms ¹⁶⁶ Ho (NO ₃ ) ₃ and ¹⁶⁵ Ho (NO ₃ ) ₃ were separated by Rf 0-0.2 (FIG. 2a) and 0.9-1.0 (FIG. 2b), respectively.

Example ^2: 166 After obtaining the Ho-DTPA 2 manufacturing 5mg of ¹⁶⁵ Ho ₂ O ₃ neutron irradiation over the ¹⁶⁶ Ho ₂ O ₃ to which was dissolved in 2N HCl. DTPA was added to this solution to obtain a composition having a molar ratio of 3.98: 1 of DTPA: Ho ( ¹⁶⁵ Ho + ¹⁶⁶ Ho). The pH of this solution was adjusted to 5.0-5.5 with dilute NaOH to obtain ¹⁶⁶ Ho-DTPA. The labeling yield measured in the same manner as in Example 1 was 99.9%.

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.

As shown in Table 1, the radioactive impurities produced in the manufacture of ^{166 Ho} in a Hanaro is very little radioactivity compared with ^{166 Ho,} did not affect the determination of the radiation absorbed dose.

Experimental Example 2: Test of stability in the following manner ¹⁶⁶ Ho-DTPA on the stability time of the ¹⁶⁶ Ho-DTPA in accordance with the time elapsed. To the lyophilized glass bottle kit, each containing 12 mg DTPA, add 1 ml each of ¹⁰⁸ mCi and 202 mCi of ¹⁶⁶ Ho (NO ₃ ) ₃ .5H ₂ O (pH 3), then add 0.2 ml of acetate buffer-0.2 ml. The pH was adjusted to 6.0-6.3. After 30 minutes, 2 hours, 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. The radiation dose of ¹⁶⁶ Ho-DTPA was measured using an ITLC scanner. Table 2 shows the results.

At 108 mCi, the radiolabeled DTPA was stable for 24 hours after labeling, as determined to maintain a labeling yield of 98% or greater. At 202 mCi, ¹⁶⁶ Ho-DTPA maintained a labeling yield of 98% or more for 3 hours after labeling and maintained a labeling yield of about 70% after 24 hours.
¹⁶⁶ Ho-DTPA maintained its integrity for an extended period of time without 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 Ho-DTPA is extremely stable and safe, as demonstrated by the following examples.

Experimental Example 3: Test The stability of ¹⁶⁶ Ho-DTPA against pH change as stability next ¹⁶⁶ Ho-DTPA against pH change. Each 0.1ml of ¹⁶⁶ Ho of 55mCi each lyophilized vial kit containing DTPA of _{12mg (NO 3) 3 · 5H} 2 O (pH3) was added, followed after addition of saline buffer 0.9 ml, 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. The radiation dose of ¹⁶⁶ Ho-DTPA was measured using an ITLC scanner. Table 3 shows the results.

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

Experimental Example 4: Examination of distribution of ¹⁶⁶ Ho-DTPA in rat body Eight male Sprague-Dawley (SD) rats weighing 257 ± 7.1 g were injected into the tail vein at a dose of 200 ± 20 μCi to ¹⁶⁶ Ho-Dawley (SD) rats. -DTPA was injected. At 15 minutes and 90 minutes after intravenous injection, four rats were each sufficiently anesthetized with ether and killed. Thereafter, the major organs (liver, spleen, kidney, bladder, testicle, lung, heart, brain), muscle, fat and bone of these rats 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.

At 15 minutes after intravenous injection, the bladder showed the highest radiation dose (ID / g 54.7%) and higher radiation in the kidney than in the blood (ID / g 2.20%), as shown in Table 4. The amount 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 showed 1.46% and 1.26% ID / g, respectively. It can be seen from these that most of the injected ¹⁶⁶ Ho-DTPA migrates to the kidney and bladder and is excreted out of the body in a short time. It was also found that the rate of uptake of radioactive material in other organs or tissues was lower than that of blood.

Experimental Example 5: Examination of Distribution of ¹⁶⁶ Ho-DTPA in Rabbit Intramuscular injection of 25 mg / kg of ketamine (Yuhan, Korea) and 6 mg / kg of lumpoon (Bayer Korea), followed by anesthesia treatment for 3 animals Each of male rabbits (New Zealand White, average weight 2731 ± 52.9 g) was injected with ¹⁶⁶ Ho-DTPA 2.0 ± 0.2 mCi via the ear vein. Thereafter, photographs of the whole body of these rabbits were taken for 30 minutes using a gamma camera (Diacam, Siemens, Germany), and the behavior of the injected drug was monitored. 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 taking advantage of the intermediate collimator. The results are shown in FIG. From the region of interest (ROI) in the right and left kidneys of the rabbit, a time-radiation dose curve was obtained, which was calculated using a computer system (ICON) as shown in FIG. 4 for the maximum distribution time (T _max ) for the kidney. ) And half-life (T _1/2 ) were determined.

As can be seen from FIG. 3, most of the injected ¹⁶⁶ Ho-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-radiation dose curve. As is evident from FIG. 4, the radiation dose in the kidney dropped to the same level as the background activity 30 minutes after the injection. The T _max and T _1/2 were measured to be 4 minutes and 22 minutes for the left kidney and 4 minutes and 19 minutes for the right kidney, respectively. Therefore, it was confirmed that most of the injected ¹⁶⁶ Ho-DTPA was excreted outside the body via the kidney and the bladder within 30 minutes after the injection.

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} was determined initial radiation dose suitable for radiation treatment in the following ways.
Using the EGS4 code system, the distribution of the absorbed radiation dose 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 source was assumed to be evenly distributed in the cylinder. Ten grids were radially arranged around the radiation source at 0.5 mm intervals, and for each grid the% of the body's absorbed radiation dose per target injected dose was calculated.

The absorbed radiation doses of β and γ rays were 10 per GBq for targets radially located within 0.5 mm depth from the surface of the ¹⁶⁶ Ho cylindrical sample measured on liquid water using the EGS4 code system. 0.87 cGy / s and 0.29 cGy / s. Thus, from the experimental results obtained, the initial absorbed radiation 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.

As described above, ¹⁶⁶ Ho-DTPA can mainly treat local lesions without damaging surrounding normal tissues because it mainly emits β-rays, and is ¹⁶⁶ Ho-DTPA without using a special device because it is in a liquid phase. Can be easily handled. In addition, when ¹⁶⁶ Ho-DTPA enters the body, it is rapidly excreted via the kidney, so that the absorption of radioactive substances into normal tissues can be excluded. Further, by measuring the radiation dose of urine, it is possible to obtain information on the leakage of the injected ¹⁶⁶ Ho-DTPA, and to take quick measures against the leakage. In conclusion, the ¹⁶⁶ Ho-DTPA of the present invention can be used as a safe liquid radiation source for controlling restenosis after angioplasty surgery such as PTCA using a balloon catheter for stenotic vascular disease including arteriosclerosis. it can.

  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.

Schematic diagram of a balloon catheter filled with ¹⁶⁶ Ho-DTPA. Liquid chromatogram of ¹⁶⁶ Ho (NO ₃ ) ₃ (a) and ¹⁶⁶ Ho-DTPA (b). Photograph of a rabbit injected with ¹⁶⁶ Ho-DTPA taken with a gamma camera over time. ^The graph which shows the change of the radiation dose with time progress in the right kidney and the left kidney of the rabbit injected with ¹⁶⁶ Ho-DTPA.

Explanation of reference numerals

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

Claims (5)

¹⁶⁶ Ho labeled diethylenetriaminepentaacetic acid that emit β-rays and γ-rays ⁽¹⁶⁶ Ho-DTPA). 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 stenosis vascular disease. A method for producing ¹⁶⁶ Ho-DTPA, comprising reacting diethylenetriaminepentaacetic acid with Ho (NO ₃ ) ₃ , HoCl ₃ or a hydrate thereof. Ho molar ratio of ^{(166 Ho +} 165 Ho) versus diethylenetriaminepentaacetic acid is 1: 1-1: The method of claim 4 in the 8 range.

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