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

166 Ho-DTPA, METHOD FOR PRODUCING THE SAME AND USE OF THE SAME AS LIQUID RADIATION SOURCE Download PDF

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JP2004217663A
JP2004217663A JP2004028457A JP2004028457A JP2004217663A JP 2004217663 A JP2004217663 A JP 2004217663A JP 2004028457 A JP2004028457 A JP 2004028457A JP 2004028457 A JP2004028457 A JP 2004028457A JP 2004217663 A JP2004217663 A JP 2004217663A
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Kyan Bae Baku
キャン バエ バク
Bian Churu Shin
ビアン チュル シン
Kuwan Hi Han
クワン ヒ ハン
Ien Uu Paku
イエン ウー パク
Samu Muu Choi
サン ムー チョイ
Yon Mii Kim
ヨン ミー キム
Yon Don Hon
ヨン ドン ホン
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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

本発明は166Ho標識付ジエチレントリアミンペンタ酢酸(DTPA)及びその製造方法に関する。特に本発明は長期間安定形を維持し且つ166Ho−DTPAが体内にもれたときに速かに排出される特性をもつ、狭窄血管病の血管形成手術後の再狭窄発生の抑制に液体放射線源(ラジエーションソース)として有用な166Ho−DTPAに関する。 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.

狭窄心臓血管病は冠状動脈病の1つであり通常コレステロールや不溶性カルシウムの蓄積によって血管が狭くなると起こる。冠状動脈が動脈硬化におけるように狭くなると、血流が妨げられ、心臓筋肉の壊死をもたらす酸素と栄養素の供給に支障をきたし、心筋性梗塞形成及び狭心症の原因となる。   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.

冠状動脈の狭窄血管病は血管を広げるためにバルーンカテーテルを挿入する経皮トランスルミナル冠状血管形成法(PTCA)によって主に治療される。Gruentzigが1977年に人の最初の手術を行って以来PTCAは広く用いられている。今や500,000人以上がPTCAの利益を受けていることが報告されている(Holmes,D.R.他Am.J.Cardiol.,53:77C−81C,1984)。この血管形成法は約95%の臨床的成功を収めている。   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.

しかしPTCAを用いる治療の主な問題として再狭窄がある。バルーンカテーテルを用いる血管形成中又はその後に急性の閉鎖即ち再狭窄が起こる。この手術を受けた患者の30−45%が手術後6ヶ月以内に再狭窄になっている。トランスルミナル冠状血管形成手術の後に再狭窄が生ずる機構は一般に血管の改変、滑らかな筋肉細胞(SMC)の増殖及び細胞外マトリックスの生成によって説明できる(Withers,H.R.等,Cancer,34:39−47,1974;Thomes,H.D.等,Int.J.Radiat.Onco.Biol.,Phys.,7:1591−1597,1981)。通常血管内SMCは活性細胞分割を受けないが、血管が物理的に損傷したり刺激されると、SMCは血管内膜炎や増殖を起こしてマトリックス組織を形成する。   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.

それ故、再狭窄の抑制は狭くなった血管の拡張と同様に重要である。再狭窄の抑制のために、抗血栓剤、抗凝血剤、ステロイド剤、カルシウムチャンネルブロッカー、コルチシン及び遺伝子治療を含む種々の努力がなされてきた。薬は血管内を移動するので、問題の血管内部位で連続的に薬効を維持することが困難である。それ故、腫瘍の治療と異なり、薬の投与は血管内の細胞増殖に対してはわずかな阻害効果を示すにすぎない。   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.

再狭窄を抑制する他の方法も知られており、それらの例としてはトランスルミナル摘出カテーテル(TEN)、エクシアレーザー冠状血管形成法及びステント移植等がある。特に、最近、問題となる部位周辺の細胞を放射線照射によって壊死させてSMCの増殖を本質的に抑制する放射線を用いる血管形成法が開発された。   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.

この放射線治療に有用な放射性核種はβ線又はγ線を放出するものである。β線を放出する放射性核種の例としては32P、Sr、90Y、 109Pd、 131I、 153Sm、 165Dy、166Ho、 169Er、 188Re、198Au及び 99mTcがあり、γ線を放出する放射性核種の例としては 192Ir、57Co、60Co、48V及び 125Iがある。これらのなかでは 188Re及び166Hoのように高いβ線エネルギーをもつ放射性同位元素が血管形成法に用いられる。 188Reは 188W/ 188Re発生機から容易に得ることができるが、1015n/cm ・秒以上の中性子フラックスと高い製造コストをもつ原子反応機を必要とする。逆に、166Hoは1014n/cm ・秒の中性子フラックスをもつ小規模の研究用反応機で大量に製造できるので製造コストの点で有利である。 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.

本発明者等は液体放射線源として166HO(NO を用いるバルーンカテーテルを開発し、冠状動脈狭窄によりバルーン血管形成法又はステント移植を少なくとも1回受けその後再狭窄になった患者の血管形成に利用した。液体放射線源として166Ho(NOを用いる手術は166Hoが再狭窄を顕著に抑制する。 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.

しかし、手術中にカテーテルのバルーンが破れて放射性核種がもれると長期間体内に放射性核種がとどまり、骨髄その他の臓器に吸収されて人体に重大な悪影響をもたらす。
放射線治療を行うには、放射性物質の安定性の確保が重要である。放射性物質が体内にもれると、可能である場合は人体から速かに排出される。166Ho(NOは腎臓、脾臓、骨等の主要臓器に蓄積されるので人体から極めてゆっくり排出されるという欠点がある。
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.

99mTc標識付ジエチレントリアミンペンタ酢酸(DTPA)は体内の腎臓又は膀胱を通して蓄積及び排出されることを利用して腎臓の診断に広く用いられている(Majali,M.A.,J.Radianel.Nucl.Chem.,170,471)。DTPAのこの利点は体内での 188Re−標識付DTPAの分配の測定に応用された(Lee J.等、Kor.J.Nucl.Med.,1997,1427)。 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).

しかしながら、上記したように、Reはその製造に1015n/cm ・秒以上の中性子フラックスをもつ原子反応機を必要とし、それ故製造コストが高くなる。また人の血清と混合すると、188Re−DTPAは1時間後に標識効率が88%以下に低下する。従ってこの化合物はインビボ安定性に欠点がある。 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.

前記した方法の欠点を解消するため本発明者等は放射線治療法による血管形成法における有用な液体放射線源に関し鋭意検討し、166Ho標識付DTPAの開発に成功した。166Ho−DTPAは再狭窄を高度に抑制しまた人体から速かに排出されるので人体に安全である。
本発明によれば、β線及びγ線を放出する放射線治療に有用な液体放射線源として用いうる166Ho−DTPAが提供される。
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.

また本発明によれば狭窄血管病の血管形成手術後の再狭窄発生抑制に用いる166Ho−DTPAからなる液体放射線源が提供される。
また本発明によればジエチレントリアミンペンタ酢酸(DTPA)をHo(NO 、HoCl 又はそれらの水和物とを、好ましくはHo(166Ho+165Ho)対DTPAのモル比1:1−1:8の範囲で、反応させることからなる166Ho−DTPAの製造方法が提供される。
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.

発明の実施の形態Embodiment of the Invention

166Hoは、1.86MeVの最大β線エネルギーをもつ半減期が26.8時間の放射性同位元素である。この放射性同位元素は弱いγ線エネルギーと高いβ線エネルギーを放出するので優れた放射線治療効果を示すものと期待される。
放射線治療で一般的に用いられている 188Reはその製造に高価な 188W/ 188Re発生機を必要とするが、166Hoは小規模の研究用反応機で大量に製造できる。166Hoの更なる利点は視覚型核種として用いられている 99mTcと同様のγ線をも放出するので人体の内部状態を視覚化できるという点である。
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.

人体内でDTPAは腎臓又は膀胱へと移動することが知られている。たとえば 99mTc−DTPAは腎臓の診断に、特に糸球体濾過用に広く用いられている。
従って、本発明の1態様に従えば、166HoとDTPAの組合せ効果をもつ放射線治療に有用な液体放射線源として働く166Ho標識付DTPA(以後「166Ho−DTPA」と称する)が提供される。
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 .

本発明に従って166HoをDTPAと結合させると、生成する錯体166Ho−DTPAは24時間以上存在できまた中性条件(pH7)及び種々の酸性条件で安定である。それ故、166HoはDTPAでしっかりと標識付されるのでインビボでさらされた時でさえ、液体放射線源での使用の安全性が確保される。また166Ho−DTPAが直接人体内にもれると、短時間で腎臓又は膀胱に向けて移動し、他の臓器には蓄積されにくいので、尿を経由して排出されうる。これ故、166Hoの照射源としての安全性が改良される。 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.

その核種が周辺の正常組織を損傷することなしに、局所の病変の治療に用いることができるように、166Hoはβ−線とγ−線、主にβ−線を放出する。166Hoから放出された放射線は血管のSMCを壊死させることができ、血管形成手術でしばしば起こる血管の再狭窄の解決等を与える。それ故、DTPAの生理学的利点との組合せで、166Hoの放射線治療の効果が、動脈硬化を含む狭窄血管病のためのたとえばバルーンカテーテルを用いるPTCAのような血管形成手術の後に再狭窄を抑制する際の安全な液体放射線源として、166Ho−DTPAを用いることを可能にする。 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.

狭窄冠状動脈病の治療にバルーンカテーテルを用いる場合、冠状動脈の再狭窄の防止に適する照射源を決めることは極めて重要である。照射吸収線量に関する実験データは、治療時間が150秒以内に限られている場合、バルーンカテーテルは好ましくは本発明のHo−DTPAを、約20Gyの治療照射量に基づき、20−100mCiの初期照射線量で含有する。   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.

バルーンカテーテルの液体放射線源として容易に製造できることに加えて、166Ho−DTPAはバルーンの形状や寸法に関係なくバルーン中に充填できる。それ故バルーン中に含まれる場合、本発明の液体の166Ho−DTPAは血管の内部壁と直接接触していない問題とする領域にのみ照射される。バルーンカテーテルは通常の方法で製造でき、また市販されている。図1には液体放射線源として本発明の166Ho−DTPAを含むバルーンカテーテルの一例を示す。 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.

本発明の別の態様によれば、DTPAをHO(NO 、HoCl 又はそれらの水和物と反応させる166Ho−DTPAの製造方法が提供される。この反応におけるHo(166Ho+165Ho)対DTPAのモル比は好ましくは1:1から1:8の範囲であり、より好ましくは1:3から1:6の範囲である。この標識付反応は好ましくは中性又は酸性条件、即ちpH7以下で行われる。
本発明の方法において、DTPAへの166Hoの標識付は約100%の収率で行われる。
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.

次に本発明を例証する実施例を示すが本発明はこれらによって制限されるものではない。
例1:166Ho−DTPA 1の製造
8.1mgの165Ho(NO・5HOを中性子照射にかけて166Ho(NO・5HOを得た。DTPA:Ho(165Ho+166Ho)のモル比3.98:1の組成物を得るために、12mgのDTPA(カルシウムトリナトリウム塩水和物、アルドリッチ)を2mlのHCl中のHo(NO・5HOの溶液(pH3)の0.1mlに加え、次いで生理食塩バッファ液を加えて1.1mlの最終容積にした。得られた溶液は5.0−5.5のpH範囲を示し、また用いたHo(NO・5HOは1.3mCiの放射能を示した。
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.

この反応組成物を75%のメタノール水溶液の可動層で瞬間薄層クロマトグラフィー−ケイ酸(ITLC−SA)の固定相上に展開した後、ITLCスキャナ(EG&G Berthold線状分析機)で標識化収率を読みとった。走査データはDTPAが166Ho−DTPAでほぼ完全に標識化したことを示した。遊離形の166Ho(NO165Ho(NOをRf 0−0.2(図2a)及び0.9−1.0(図2b)でそれぞれ分離した。 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.

例2:166Ho−DTPA 2の製造
5mgの165Hoを中性子照射にかけて166Hoを得た後これを2N HClに溶かした。この溶液にDTPAを加えてDTPA:Ho(165Ho+166Ho)のモル比3.98:1の組成物を得た。この溶液のpHを希NaOHで5.0−5.5に調節し166Ho−DTPAを得た。例1と同様に測定した標識化収率は99.9%だった。
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%.

実験例1:166Hoに含まれる不純物核種の分析
研究用反応機「Hanaro」でつくった166Hoの不純物を分析した。この点に関し、高エネルギー解像度のGeデテクタ(EG&G、Ortec)を用いたガンマ線分光法を用いた。分析結果を表1に示す。
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.

Figure 2004217663
Figure 2004217663

表1に示すように、Hanaro中での166Hoの製造で生じた放射性不純物は166Hoに比し放射能が極めてわずかであり、放射吸収線量の決定に影響することはなかった。 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.

実験例2:時間経過に従った166Ho−DTPAの安定性
時間に対する166Ho−DTPAの安定性を次のようにテストした。それぞれ12mgのDTPAを含有する凍結乾燥したガラスビンキットに108mCi及び202mCiの166Ho(NO・5HO(pH3)の各1mlを加え、次いで酢酸塩バッファ−0.2mlを加えて溶液のpHを6.0−6.3に調節した。30分、2時間、3時間、6時間及び24時間後に反応体を75%メタノール水溶液の可動層でITLC−SAの固定相上に展開した。ITLCスキャナを用いて166Ho−DTPAの放射線量を測定した。結果を表2に示す。
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.

Figure 2004217663
Figure 2004217663

108mCiにおいて、放射標識付DTPAは98%以上の標識化収率を維持することが測定されたように、標識化後24時間安定であった。202mCiにおいては、166Ho−DTPAは標識化後3時間98%以上の標識化収率を維持し24時間後は約70%の標識化収率を維持した。
166HoがDTPAから分離することなく、166Ho−DTPAは長時間その一体性を維持した。それ故、166Ho−DTPAが人体内にもれた場合でもこの錯体はDTPAの性質に従って腎臓又は膀胱に移動し他の臓器には移動し難い。その結果166Ho−DTPAは次の例からも例証されるように極めて安定且つ安全である。
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.

実験例3:pH変化に対する166Ho−DTPAの安定性
次のようにしてpH変化に対する166Ho−DTPAの安定性をテストした。それぞれ12mgのDTPAを含有する凍結乾燥したガラスビンキットに55mCiの166Ho(NO・5HO(pH3)の各0.1mlを加え、次いで生理食塩水バッファ 0.9mlを加えた後、、異なる量の酢酸塩バッファを加えて溶液のpHを1.67、3.1、5.05及び6.81に調節した。30分後、反応体を75%メタノール水溶液の可動層でITLC−SAの固定相上で展開した。ITLCスキャナを用いて166Ho−DTPAの放射線量を測定した。結果を表3に示す。
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.

Figure 2004217663
Figure 2004217663

表3に示すように、166Ho−DTPAは中性及び酸性条件に極めて安定であった。 As shown in Table 3, 166 Ho-DTPA was extremely stable under neutral and acidic conditions.

実験例4:ラットの体内での166Ho−DTPAの分配の検討
平均体重257±7.1gの8匹の雄のSpraque−Dawley(SD)ラットに尾の静脈から200±20μCiの線量で166Ho−DTPAを注射した。静脈注射後15分及び90分に4匹のラットをそれぞれ十分にエーテル麻酔し死亡させた。その後これらラットの主要臓器(肝臓、脾臓、腎臓、膀胱、睾丸、肺、心臓、脳)、筋肉、脂肪及び骨を計量し、周知のシンチレータ(Canbarra)で放射能をカウントした。各臓器又は組織に蓄積した放射能を合計の注射線量に基づいて計算し、各臓器又は組織のg当りの注射線量の%を求めた。結果を表4に示す。
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.

Figure 2004217663
Figure 2004217663

静脈注射の15分後には、表4に示すように膀胱が最も高い放射線量(ID/g 54.7%)を示しまた血中(ID/g 2.20%)よりも腎臓でより高い放射線量を検知した(ID/g 5.09%)。この値から注射した166Ho−DTPAのほとんどが腎臓と膀胱に移動したことがわかる。静脈注射の90分後では腎臓と膀胱の放射線量がそれぞれ1.46%と1.26%のID/gを示した。これらから注射した166Ho−DTPAのほとんどが腎臓と膀胱に移動し短時間で体外に排出されることがわかる。また血液に比し、他の臓器又は組織は放射性物質の取り込み速度が遅いこともわかった。 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.

実験例5:ウサギ体内での166Ho−DTPAの分配の検討
ケタミン(韓国Yuhan社)を25mg/kg、ルムプーン(バイエル韓国社)を6mg/kg筋肉内注射して麻酔処置した後、3匹の雄のウサギ(ニュージーランドホワイト、平均体重2731±52.9g)の各々に耳の静脈から166Ho−DTPAを2.0±0.2mCi注射した。その後これらのウサギの体全体の写真をガンマカメラ(ドイツ・シーメンス社製Diacam)を用いて30分とり注射した薬の挙動をモニターした。この点に関し、カメラは平衡ピンホールコリメータを備え、20%の窓幅で80keVのエネルギーレベルにセットした。中間コリメータの利点を利用して像を得た。結果を図3に示す。ウサギの右腎及び左腎内の問題領域(ROI)から、時間−放射線量のカーブを得て、これを図4に示すようなコンピュータシステム(ICON)を用いて腎臓について最大分配時間(Tmax)と半減期(T1/2)を求めた。
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.

図3からわかるように、注射した166Ho−DTPAのほとんどは注射後30分以内に腎臓及び膀胱を経て排出された。
注射した166Ho−DTPAのこの速かな排出は時間−放射線量カーブから証明された。図4から明らかなように、腎臓中の放射線量は注射30分後に背景活性と同じレベルにまで低下した。TmaxとT1/2は左腎についてそれぞれ4分と22分、右腎についてそれぞれ4分と19分であることが測定された。従って注射した166Ho−DTPAのほとんどが注射後30分以内に腎臓と膀胱を経て体外に排出されることが認められた。
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.

実験例6:治療的に適する吸収線量の決定
冠状動脈の再狭窄を抑制するためにバルーンカテーテルの放射線源として用いるため、166Hoについて次の方法で放射線治療に適する初期放射線量を求めた。
EGS4コードシステムを用いて、水中の166Hoから放出されたβ線及びγ線の放射吸収線量の分配を計算した。この実験では、放射線源の初期放射線量を治療上適する放射線量が20Gyであると仮定して求めた。放射線源は円筒形中に均一に分配されていると仮定した。10枚のグリッドを放射線源のまわりに0.5mm間隔で放射状に配し、各グリッドについてターゲットの注射した線量当りの人体の放射吸収線量の%を計算した。
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.

β線とγ線の放射吸収線量は、EGS4コードシステムを用いて液体水に関して測定した166Ho円筒体試料の表面から0.5mmの深さ内に放射状に位置しているターゲットにつきそれぞれGBq当り10.87cGy/s及び0.29cGy/sであることが判った。従って、得られた実験結果から、放射線治療に適する初期放射吸収線量は20Gyの全治療放射線量において150秒の処置時間内で32.31mCiであると計算された。また初期放射線量を100mCi/mLの放射線容積密度で示すと、1.66%の誤差をもつ試料の表面から0.5mmの深さ内に放射状に位置するターゲットで0.0519Gy/sであると計算された。 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.

前記したようにβ線を主体的に放出することから166Ho−DTPAは周辺の正常組織を損傷することなく局所病変を治療できまた液相であるので特別の装置を用いることなく166Ho−DTPAを容易に扱える。また、166Ho−DTPAが体内にもれたときは腎臓を経て速かに排出されるので、正常組織中に放射性物質が吸収されることを除くことができる。さらに尿の放射線量を測定することによって、注射した166Ho−DTPAのもれに関する情報を得てもれに対する速かな対策をとることが可能となる。結論として、本発明の166Ho−DTPAは動脈硬化を含む狭窄性血管病のためのバルーンカテーテルを用いるPTCA等の血管形成法の手術後の再狭窄の抑制に安全な液体放射線源として用いることができる。 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.

以上本発明を例示的に説明したが、本発明はそれらによって制限されるものではない。多くの変形が本発明の技術思想内で可能であることは理解されるべきである。   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.

166Ho−DTPAを充填したバルーンカテーテルの概略図。Schematic diagram of a balloon catheter filled with 166 Ho-DTPA. 166Ho(NOの液体クロマトグラム(a)及び166Ho−DTPAの液体クロマトグラム(b)。Liquid chromatogram of 166 Ho (NO 3 ) 3 (a) and 166 Ho-DTPA (b). 時間経過に従ってガンマカメラでとった166Ho−DTPAを注射したウサギの写真。Photograph of a rabbit injected with 166 Ho-DTPA taken with a gamma camera over time. 166Ho−DTPAを注射したウサギの右腎と左腎での時間経過に伴う放射線量の変化を示すグラフ。 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.

符号の説明Explanation of reference numerals

1: バルーンカテーテル
2: 166Ho−DTPAを充填したバルーン
3: 冠状動脈血管壁
4: 狭窄部
1: balloon catheter 2: balloon filled with 166 Ho-DTPA 3: coronary vessel wall 4: stenosis

Claims (5)

β線及びγ線を放出する 166Ho標識付ジエチレントリアミンペンタ酢酸(166Ho−DTPA)。 166 Ho labeled diethylenetriaminepentaacetic acid that emit β-rays and γ-rays (166 Ho-DTPA). 請求項1の166Ho−DTPAからなる液体放射線源。 A liquid radiation source comprising the 166 Ho-DTPA of claim 1. 狭窄血管病の血管形成手術後の再狭窄発生抑制に用いる請求項2の液体放射線源。 3. The liquid radiation source according to claim 2, which is used for suppressing restenosis after stenosis vascular disease. ジエチレントリアミンペンタ酢酸をHo(NO 、HoCl 又はそれらの水和物と反応させることを特徴とする166Ho−DTPAの製造方法。 A method for producing 166 Ho-DTPA, comprising reacting diethylenetriaminepentaacetic acid with Ho (NO 3 ) 3 , HoCl 3 or a hydrate thereof. Ho(166Ho+165Ho)対ジエチレントリアミンペンタ酢酸のモル比が1:1−1:8の範囲にある請求項4の方法。 Ho molar ratio of (166 Ho + 165 Ho) versus diethylenetriaminepentaacetic acid is 1: 1-1: The method of claim 4 in the 8 range.
JP2004028457A 2000-03-31 2004-02-04 166 Ho-DTPA, METHOD FOR PRODUCING THE SAME AND USE OF THE SAME AS LIQUID RADIATION SOURCE Withdrawn JP2004217663A (en)

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