JP5325427B2 - Drug with magnetism - Google Patents
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- JP5325427B2 JP5325427B2 JP2008038502A JP2008038502A JP5325427B2 JP 5325427 B2 JP5325427 B2 JP 5325427B2 JP 2008038502 A JP2008038502 A JP 2008038502A JP 2008038502 A JP2008038502 A JP 2008038502A JP 5325427 B2 JP5325427 B2 JP 5325427B2
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- 239000003814 drug Substances 0.000 title claims description 83
- 229940079593 drug Drugs 0.000 title claims description 82
- 230000005389 magnetism Effects 0.000 title claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 14
- 108010002084 Apoferritins Proteins 0.000 claims description 13
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- 238000011282 treatment Methods 0.000 description 3
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- ACERFIHBIWMFOR-UHFFFAOYSA-N 2-hydroxy-3-[(1-hydroxy-2-methylpropan-2-yl)azaniumyl]propane-1-sulfonate Chemical compound OCC(C)(C)NCC(O)CS(O)(=O)=O ACERFIHBIWMFOR-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、磁性を有する薬剤、薬剤の誘導システム、並びに磁気検出装置に関する。 The present invention relates to a drug having magnetism, a drug guidance system, and a magnetic detection device.
一般に、薬剤は生体内に投与され患部に到達し、その患部局所において薬理効果を発揮することで治療効果を引き起こすが、薬剤が患部以外の組織(つまり正常組織)に到達しても治療にはならない。したがって、いかにして効率的に患部に薬剤を誘導するかが治療戦略上重要となる。このように薬剤を患部に誘導する技術はドラッグ・デリバリと呼ばれ、近年研究開発が盛んに行なわれている。このドラッグ・デリバリには少なくとも二つのメリットがある。一つは患部組織において十分に高い薬剤濃度が得られることである。薬理効果は患部における薬剤濃度が一定以上でないと現れず、低い濃度では治療効果が望めないからである。二つ目は薬剤を患部組織のみに誘導して、不必要に正常組織に誘導させないことである。これにより副作用を抑制することができる。 In general, drugs are administered in vivo to reach the affected area and cause a therapeutic effect by exerting a pharmacological effect in the affected area, but even if the drug reaches tissues other than the affected area (that is, normal tissues) Don't be. Therefore, how to efficiently guide the drug to the affected area is important in the treatment strategy. Such a technique for guiding a drug to an affected area is called drug delivery, and research and development have been actively conducted in recent years. This drug delivery has at least two advantages. One is that a sufficiently high drug concentration is obtained in the affected tissue. This is because the pharmacological effect does not appear unless the drug concentration in the affected area is above a certain level, and a therapeutic effect cannot be expected at a low concentration. The second is to induce the drug only to the affected tissue and not unnecessarily to normal tissue. Thereby, a side effect can be suppressed.
このようなドラッグ・デリバリが最も効果を発揮するのが抗がん剤によるがん治療である。抗がん剤は細胞分裂の活発ながん細胞の細胞増殖を抑制するものが大半であるため、正常組織においても細胞分裂の活発な組織、例えば骨髄あるいは毛根、消化管粘膜などの細胞増殖を抑制してしまう。このため抗がん剤の投与を受けたがん患者には貧血、抜け毛、嘔吐などの副作用が発生する。これら副作用は患者にとって大きな負担となるため投薬量を制限しなければならず、抗がん剤の薬理効果を十分に得ることができないという問題がある。さらに最悪の場合、副作用によって患者が死亡してしまう恐れがある。そこで、ドラッグ・デリバリによって抗がん剤をがん細胞まで誘導し、がん細胞に集中して薬理効果を発揮させることによって、副作用を抑えつつ効果的にがん治療を行うことができると期待されている。 Such drug delivery is most effective in cancer treatment with anticancer agents. Most anticancer drugs inhibit cell proliferation of cancer cells with active cell division, so that even normal tissues, such as bone marrow or hair roots, gastrointestinal mucosa, etc. It will be suppressed. For this reason, side effects such as anemia, hair loss, and vomiting occur in cancer patients who receive anticancer drugs. Since these side effects are a heavy burden on the patient, the dosage must be limited, and the pharmacological effect of the anticancer drug cannot be obtained sufficiently. In the worst case, side effects can cause the patient to die. Therefore, it is expected that cancer treatment can be effectively performed while suppressing side effects by inducing anticancer drugs to cancer cells by drug delivery and concentrating on cancer cells to exert pharmacological effects. Has been.
抗がん剤以外では、例えば男性勃起不全治療薬への応用が考えられる。男性勃起不全治療薬は、ニトロ製剤との併用により重篤な全身低血圧を引き起こし死亡にいたる例があり、とりわけ中高年以上の心疾患をもつ男性に問題となる。これは勃起不全治療薬が必ずしも患部に集中せず、全身の血管に作用してニトロ製剤のもつ血管拡張作用を増幅してしまうためである。そこで、ドラッグ・デリバリによって男性勃起不全治療薬を患部まで誘導し、患部に集中して薬理効果を発揮させることによって、ニトロ製剤との併用による副作用の発生を抑えることができると考えられる。 Other than anticancer agents, for example, it can be applied to male erectile dysfunction drugs. Male erectile dysfunction drugs cause serious systemic hypotension when used in combination with nitro drugs, leading to death, and are particularly problematic for men with middle-aged and older heart disease. This is because the drug for erectile dysfunction does not necessarily concentrate on the affected part, but acts on the blood vessels throughout the body to amplify the vasodilatory action of the nitro preparation. Therefore, it is considered that side effects caused by the combined use with a nitro preparation can be suppressed by inducing a drug for male erectile dysfunction to the affected area by drug delivery and concentrating on the affected area to exert a pharmacological effect.
ドラッグ・デリバリの具体的な手法としては、例えば担体(キャリア)を用いた患部組織へ誘導が検討されているが、これは患部に集中しやすい担体に薬剤を乗せて、担体に薬剤を患部まで運ばせようというものである。担体としては各種抗体やマイクロスフェア、あるいは磁性体を使用することが検討されている。なかでも有力視されているのが磁性体であり、薬剤に磁性体である担体を付着させ、磁場によって患部に集積させる方法が検討されている(例えば下記特許文献1参照)。この方法は誘導方法の簡便性と患部を標的にした治療が可能であることから、細胞毒性の高い抗がん剤にはとりわけ有効な手法として考えられている。 As a specific method of drug delivery, for example, guidance to a diseased tissue using a carrier (carrier) has been studied. This is because a drug is placed on a carrier that tends to concentrate on the affected area, and the drug is placed on the carrier to the affected area. It is about letting you carry it. The use of various antibodies, microspheres, or magnetic materials as the carrier has been studied. Among them, a magnetic material is considered promising, and a method in which a carrier, which is a magnetic material, is attached to a drug and accumulated in an affected area by a magnetic field has been studied (for example, see Patent Document 1 below). This method is considered to be a particularly effective method for anti-cancer agents having high cytotoxicity because of the simplicity of the induction method and the possibility of treatment targeting the affected area.
また、アポフェリチンで酸化鉄を内包することが報告(例えば、非特許文献1〜3)されているが、アポフェリチンで医薬化合物を内包させたという報告はない。 Further, it has been reported that iron oxide is encapsulated with apoferritin (for example, Non-Patent Documents 1 to 3), but there is no report that a pharmaceutical compound is encapsulated with apoferritin.
しかしながら、上述したように、磁性体である担体をキャリアとして用いる場合、経口投与が困難なこと、担体分子が一般的に巨大であること、あるいは薬剤分子との結合強度、親和性に技術的な問題が指摘されており、実用化が困難であった。 However, as described above, when a carrier that is a magnetic substance is used as a carrier, it is difficult to administer orally, the carrier molecule is generally huge, or the binding strength and affinity with drug molecules are technical. Problems have been pointed out, making it difficult to put to practical use.
本発明は、上述した事情に鑑みてなされたものであり、従来の技術的問題を解決でき、実用化が容易なドラッグ・デリバリシステムを実現することを目的とする。 The present invention has been made in view of the above-described circumstances, and an object of the present invention is to realize a drug delivery system that can solve the conventional technical problems and can be easily put into practical use.
本発明は、(1)アポフェリチンにより医薬化合物を内包した、磁性を有する薬剤;
(2)前記医薬化合物は、下記式(I)で示される鉄サレン錯体又はその誘導体である、前記(1)記載の磁性を有する薬剤;
(4)前記個体外表面から前記組織又は患部に磁場を与えて、当該組織又は患部に誘導されるようにした、前記(3)に記載の磁性を有する薬剤;
(5)前記個体の前記組織内又は患部内に磁力発生手段を適用し、当該組織又は前記患部に誘導されるようにした、前記(4)に記載の磁性を有する薬剤;
(6)前記個体の前記組織内又は患部内に前記個体の体液を供給する血管等の経路の途中に磁力発生手段を配置して、下流の組織又は患部に誘導されるようにした、前記(3)に記載の磁性を有する薬剤;
(7)体内に投与した前記(1)又は(2)に記載の磁性を有する薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、個体の表面又は当該個体の組織又は患部に対して磁場を発生する手段を配置するようにした、薬剤の誘導システム;
(8)体内に投与した前記(1)又は(2)に記載の磁性を有する薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、個体に対して磁場を発生する手段と、当該磁場を前記固定の目的とする組織又は患部に誘導する手段と、を備える、薬剤の誘導システム;
(9)前記磁場を発生する手段は、2つの磁石を対にして当該二つの磁石の間に前記目的とする組織又は患部を置き、当該組織又は患部に磁束を集中させるように構成されてなる前記(7)又は(8)に記載の薬剤の誘導システム;
(10)前記目的とする組織又は患部はMRI又はCTによって同定されてなる前記(7)〜(9)の何れかに記載の薬剤の誘導システム;
(11)体内に投与した前記(1)又は(2)に記載の磁性を有する薬剤の磁性を検出することにより、当該薬剤の体内動態を検知することを特徴とする磁気検出装置;
(12)前記磁性を磁気共鳴誘導によって検出する前記(11)に記載の磁気検出装置;を提供する。
The present invention relates to (1) a magnetic drug encapsulating a pharmaceutical compound with apoferritin;
(2) The drug having magnetism according to (1), wherein the pharmaceutical compound is an iron-salen complex represented by the following formula (I) or a derivative thereof;
(4) The magnetic drug according to (3), wherein a magnetic field is applied to the tissue or affected area from the outer surface of the individual so as to be induced in the tissue or affected area;
(5) The magnetic agent according to (4), wherein a magnetic force generating means is applied in the tissue or the affected part of the individual so as to be guided to the tissue or the affected part;
(6) The magnetic force generating means is disposed in the middle of the path of a blood vessel or the like for supplying the body fluid of the individual into the tissue or the affected part of the individual so as to be guided to a downstream tissue or affected part. 3) a drug having magnetism according to 3);
(7) A guidance system for guiding the magnetic drug according to (1) or (2) administered into the body to a predetermined affected area using the magnetic property of the drug, the surface of the individual or the individual A drug induction system in which means for generating a magnetic field is arranged on the tissue or affected area of the patient;
(8) A guidance system for guiding the magnetic drug according to (1) or (2) administered into the body to a predetermined affected area using the magnetic property of the drug, wherein a magnetic field is applied to an individual. A drug induction system comprising: means for generating; and means for guiding the magnetic field to the target tissue or affected area for fixation;
(9) The means for generating the magnetic field is configured so that two magnets are paired and the target tissue or affected part is placed between the two magnets, and the magnetic flux is concentrated on the tissue or affected part. The drug induction system according to (7) or (8);
(10) The drug induction system according to any one of (7) to (9), wherein the target tissue or affected area is identified by MRI or CT;
(11) A magnetic detection device that detects the pharmacokinetics of the drug by detecting the magnetism of the drug having magnetism according to (1) or (2) administered into the body;
(12) The magnetic detection device according to (11), wherein the magnetism is detected by magnetic resonance induction.
本発明によれば、薬剤自体に磁性をもたせることができるため、従来のように磁性体からなる担体を用いることなく、薬剤自体が有する磁性を利用して体内の患部まで薬剤を誘導することができる。
薬剤自体に磁性をもたせることにより、高い磁化率を得ることができるため、体表面に存在する患部に限られず広範囲へのドラッグ・デリバリへ適用することができる。
また、薬剤を患部へ誘導後、交流磁場を印加することにより温度を上昇させがん細胞を殺傷することも可能である。
その結果、従来における、経口投与が困難なこと、担体分子が一般的に巨大であること、あるいは薬剤分子との結合強度、親和性に技術的な問題があることを解決することができ、実用化が容易なドラッグ・デリバリ・システムを実現することが出来る。
According to the present invention, since the drug itself can be magnetized, the drug can be guided to the affected part in the body by using the magnetic property of the drug itself without using a carrier made of a magnetic material as in the prior art. it can.
By providing the drug itself with magnetism, a high magnetic susceptibility can be obtained, so that it can be applied to drug delivery over a wide range without being limited to the affected area existing on the body surface.
It is also possible to kill cancer cells by increasing the temperature by applying an alternating magnetic field after guiding the drug to the affected area.
As a result, it can be solved that conventional oral administration is difficult, the carrier molecule is generally huge, or there are technical problems in binding strength and affinity with drug molecules. It is possible to realize a drug delivery system that can be easily realized.
次に、本発明の実施の形態について説明する。以下の実施形態は、本発明を説明するための例示であり、本発明をこの実施形態にのみ限定する趣旨ではない。本発明は、その要旨を逸脱しない限り、さまざまな形態で実施することができる。 Next, an embodiment of the present invention will be described. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.
(薬剤)
本発明の薬剤は、アポフェリチンにより医薬化合物を内包した、磁性を有する薬剤である。
(Drug)
The drug of the present invention is a magnetic drug encapsulating a pharmaceutical compound with apoferritin.
フェリチンは鉄貯蔵タンパク質として知られ、分子量は450kDである。フェリチンは、外側の直径が約12nmであり、24のサブユニットからなり、直径8nmの中空に3価の鉄を内包する。この内包された3価の鉄を除去することにより、アポフェリチンを得ることができる。
また、アポフェリチンは、フェリチンを窒素雰囲気の下、酢酸ナトリウム溶液に入れ濾過することによりアポフェリチンに変換することができる。
Ferritin is known as an iron storage protein and has a molecular weight of 450 kD. Ferritin has an outer diameter of about 12 nm, consists of 24 subunits, and encloses trivalent iron in a hollow of 8 nm in diameter. Apoferritin can be obtained by removing the encapsulated trivalent iron.
Apoferritin can be converted to apoferritin by filtering ferritin in a sodium acetate solution under a nitrogen atmosphere.
内包される前記医薬化合物としては、任意の薬剤を用いることができ、例えば、磁性をもたない市販の薬剤や有機磁性体を用いることができる。内包される医薬化合物として有機磁性体を用いた場合には、運び屋としてのアポフェリチンが医薬化合物から離れた後も医薬化合物自体の磁性を利用することができる。
内包される前記医薬化合物は、下記式(I)で示される鉄サレン錯体又はその誘導体であることが好ましい。
Any drug can be used as the pharmaceutical compound to be encapsulated, and for example, a commercially available drug or organic magnetic substance having no magnetism can be used. When an organic magnetic substance is used as the encapsulated pharmaceutical compound, the magnetic properties of the pharmaceutical compound itself can be utilized even after apoferritin as a carrier is separated from the pharmaceutical compound.
The pharmaceutical compound to be encapsulated is preferably an iron-salen complex represented by the following formula (I) or a derivative thereof.
本発明の磁性を有する薬剤は、生体内マーカーであってもよい。
本発明の薬剤の使用例としては、薬剤自体が磁性を有するため、個体に投与した後、当該個体に磁界を加えて、薬剤を目的とする組織又は患部に誘導させることができる。
別の使用例としては、前記個体外表面から前記組織又は患部に磁場を与えて、薬剤を当該組織又は患部に誘導させることができる。
別の使用例としては、前記個体の組織内又は患部内に磁力発生手段を適用し、薬剤を当該組織又は患部に誘導させることができる。
別の使用例としては、前記個体の組織内又は患部内に当該個体の体液を供給する血管等の経路の途中に磁力発生手段を配置して、薬剤を下流の組織又は患部に誘導させることができる。
The magnetic drug of the present invention may be an in vivo marker.
As an example of use of the drug of the present invention, since the drug itself has magnetism, after administration to an individual, a magnetic field can be applied to the individual to induce the drug to the target tissue or affected area.
As another use example, a magnetic field can be applied to the tissue or affected area from the outer surface of the individual to induce the drug to the tissue or affected area.
As another use example, a magnetic force generating means can be applied to the tissue or affected area of the individual to induce the drug to the tissue or affected area.
As another example of use, magnetic force generating means may be disposed in the path of a blood vessel or the like for supplying body fluid of the individual into the tissue or affected part of the individual to induce the drug to a downstream tissue or affected part. it can.
(薬剤誘導システム)
本発明の磁性を有する薬剤は、体内に投与した当該薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、個体の表面、組織、又は患部に対して磁場を発生する手段を配置するようにした、薬剤の誘導システム、に適用することができる。
本発明の磁性を有する薬剤は、体内に投与した当該薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、個体に対して磁場を発生する手段と、当該磁場を前記個体の目的とする組織又は患部に誘導する手段と、を備える薬剤の誘導システム、に適用することができる。
前記磁場を発生する手段は、2つの磁石を対にして当該二つの磁石の間に前記目的とする組織又は患部を置き、当該組織又は患部に磁束を集中させるように構成されてなることが好ましい。
前記目的とする組織又は患部は、MRI又はCTによって同定されることが好ましい。
(Drug guidance system)
The magnetic drug of the present invention is a guidance system that guides the drug administered into the body to a predetermined affected area using the magnetic property of the drug, and applies a magnetic field to the surface, tissue, or affected area of an individual. The present invention can be applied to a drug guidance system in which a generating means is arranged.
The magnetic drug of the present invention is a guidance system for guiding the drug administered into the body to a predetermined affected area using the magnetism of the drug, the means for generating a magnetic field for an individual, and the magnetic field And a means for guiding the target to the target tissue or affected area of the individual.
It is preferable that the means for generating the magnetic field is configured so that two magnets are paired and the target tissue or affected part is placed between the two magnets, and the magnetic flux is concentrated on the tissue or affected part. .
The target tissue or affected area is preferably identified by MRI or CT.
(磁気検出装置)
本発明の磁性を有する薬剤は、体内に投与した当該薬剤の磁性を検出することにより、当該薬剤の体内動態を検知する磁気検出装置に適用することができる。
本発明の磁性を有する薬剤は、体内に投与した当該薬剤の磁性を検出することにより、当該薬剤の体内分布を検知し、当該薬剤が示す生体機能(脳機能など)を定量する磁気検出装置に適用することができる。
前記薬剤の磁性は、磁気共鳴誘導によって検出することが好ましい。
(Magnetic detection device)
The magnetic drug of the present invention can be applied to a magnetic detection device that detects the pharmacokinetics of the drug by detecting the magnetism of the drug administered into the body.
The magnetic drug of the present invention is a magnetic detection device that detects the distribution of the drug in the body by detecting the magnetism of the drug administered into the body and quantifies the biological function (such as brain function) exhibited by the drug. Can be applied.
The magnetism of the drug is preferably detected by magnetic resonance induction.
(機能診断、がん化学療法)
本発明の磁性を有する薬剤の別の使用例として、がん組織に誘導された薬剤に電磁波を当てることにより、局所的に温度を上昇させ、がん細胞を特異的に殺傷することができる。
このように、本発明の薬剤を用いれば、一つの薬剤で機能診断及びがん化学療法を同時に行うことができる。例えば、がん化学療法が可能なMRI診断装置、磁場誘導ドラッグ・デリバリ・システムを提供することができる。
(Functional diagnosis, cancer chemotherapy)
As another example of use of the magnetic drug of the present invention, by applying electromagnetic waves to a drug induced in cancer tissue, the temperature can be locally increased and cancer cells can be specifically killed.
Thus, when the drug of the present invention is used, functional diagnosis and cancer chemotherapy can be performed simultaneously with one drug. For example, an MRI diagnostic apparatus capable of cancer chemotherapy and a magnetic field induction drug delivery system can be provided.
以下、本発明を実施例によりさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
(実施例1)
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
Example 1
アポフェリチンの合成:
馬の脾臓フェリチンを用いたアポフェリチンの合成を説明する。アポフェリンは窒素雰囲気の下、pH5.5で調整された酢酸ナトリウム溶液(0.2M)で濾過し、その後、トリグリコール酸を使用し還元キレート法を用いて内包されている3価の鉄を除去した。続いて、塩化ナトリウム溶液(0.15M)で繰り返し濾過することにより完全に内包されている3価の鉄を除去した。
Apoferritin synthesis:
The synthesis of apoferritin using horse spleen ferritin will be described. Apoferrin was filtered through a sodium acetate solution (0.2 M) adjusted to pH 5.5 under a nitrogen atmosphere, and then trivalent iron contained in the solution was removed using triglycolic acid using a reducing chelate method. . Subsequently, trivalent iron completely contained was removed by repeated filtration with a sodium chloride solution (0.15M).
アポフェリチンに化学式(I)の化合物を内包させる合成:
アポフェリンを0.05Mの4-(2-ヒドロキシエチル)-1-ピペラジンエタン-スルホン酸(HEPES)を用いたpH 7.5-8.5の溶液、または0.25MのAMPSOの何れかに分散させた。ついで、0.1Mの化学式(I)の鉄錯体酢酸水溶液を添加し、35〜50℃の温度で攪拌した。ついで水素化ホウ酸ナトリウムを使用して還元をおこなったところ、化学式(I)の鉄錯体がアポフェリチンのコアに内包されている化合物が合成された。
Synthesis in which apoferritin encapsulates a compound of formula (I):
Apoferrin was dispersed in either a solution of pH 7.5-8.5 using 0.05 M 4- (2-hydroxyethyl) -1-piperazineethane-sulfonic acid (HEPES) or 0.25 M AMPSO. Subsequently, 0.1 M iron complex acetic acid aqueous solution of chemical formula (I) was added and stirred at a temperature of 35-50 ° C. Subsequently, reduction was performed using sodium borohydride. As a result, a compound in which the iron complex of the formula (I) was encapsulated in the core of apoferritin was synthesized.
(実施例2)
ラットL6細胞が30%のコンフルエントの状態の時に上記式(I)で示される鉄錯体粉末を磁石に引き寄せられるのが目視できる程度の量を培地にふりかけて48時間後に培地の状態を写真撮影した。
図1はラットL6細胞の培地がある角型フラスコに棒磁石を接触させた状態を示している。次いで、48時間後角型フラスコ底面の一端から他端までを撮影し、細胞数を算出した結果を図2に示す。図2において磁石から近位とは、角型フラスコ底面における磁石端面の投影面積内を示し、磁石から遠位とは、角型フラスコ底面において磁石端面と反対側にある領域を示す。
(Example 2)
When the rat L6 cells were in a 30% confluent state, the medium was photographed after 48 hours after sprinkling the medium with an amount so that the iron complex powder represented by the above formula (I) could be visually attracted to the magnet. .
FIG. 1 shows a state in which a bar magnet is brought into contact with a rectangular flask having a culture medium of rat L6 cells. Then, 48 hours later, the results were obtained by photographing the bottom of the square flask from one end to the other end and calculating the number of cells. In FIG. 2, “proximal to magnet” means within the projected area of the magnet end face on the bottom of the square flask, and “distal from magnet” means a region on the bottom face of the square flask opposite to the magnet end face.
図2に示すように、磁石から近位では鉄サレン錯体が引き寄せられて鉄サレン錯体の濃度が増し鉄サレン錯体のDNA抑制作用によって細胞数が遠位よりも極端に低いことが分かる。この結果、本発明による、磁性を持った薬剤と、磁気発生手段とを備えたシステムによって、個体の目的とする患部や組織に薬剤を集中して存在させることが可能となる。
次に本発明に係る誘導装置の他の例について説明する。この誘導装置は、図3に示すように重力方向に互いに向き合う一対の磁石230,232がスタンド234とクランプ235によって支持されており、磁石の間には金属板236が置かれている。一対の磁石間に金属板、特に鉄板をおくことにより、局所的に一様で強力な磁界を作り出すことができる。
As shown in FIG. 2, it can be seen that the iron-salen complex is attracted near the magnet, the concentration of the iron-salen complex increases, and the number of cells is extremely lower than that of the distal due to the DNA-suppressing action of the iron-salen complex. As a result, the system including the magnetic drug and the magnetism generating means according to the present invention enables the drug to be concentrated on the target affected area or tissue of the individual.
Next, another example of the guidance device according to the present invention will be described. As shown in FIG. 3, in this guidance device, a pair of magnets 230 and 232 facing each other in the direction of gravity are supported by a stand 234 and a clamp 235, and a metal plate 236 is placed between the magnets. By placing a metal plate, particularly an iron plate, between a pair of magnets, a locally uniform and strong magnetic field can be created.
この誘導装置は磁石の代わりに電磁石を用いて発生磁力を可変にすることができる。また、XYZ方向に一対の磁力発生手段を移動できるようにして、テーブル上の固体の目的とする位置に磁力発生手段を移動させることができる。
この磁界の領域に固体の組織を置くことにより、この組織に薬剤を集中させることができる。体重約30グラムのマウスに既述の金属錯体(薬剤濃度5mg/ml(15mM))を静注して開腹し、右の腎臓を前記一対の磁石の間に来るようにマウスを鉄板の上に置く。
使用した磁石は、信越化学工業株式会社製 品番:N50(ネオジウム系永久磁石) 残留磁束密度:1.39-1.44 Tである。このとき、右側の腎臓に与えられた磁場は約0.3(T)で左側の腎臓に与えられる磁場はその約1/10である。左の腎臓及び磁界を適用しない腎臓(コントロール)と共に、マウスの右腎に磁界を加えて10分後MRIでSNRをT1モード及びT2モードで測定した。その結果、図4に示すように、磁界を加えた右腎(RT)が左腎(LT)及びコントロールに比較して薬剤を組織内に留め置くことができることが確認された。
This induction device can change the generated magnetic force by using an electromagnet instead of a magnet. Further, the pair of magnetic force generating means can be moved in the XYZ directions, and the magnetic force generating means can be moved to the target position of the solid on the table.
By placing solid tissue in the area of this magnetic field, the drug can be concentrated in this tissue. A mouse having a body weight of about 30 grams was intravenously injected with the aforementioned metal complex (drug concentration 5 mg / ml (15 mM)), and the mouse was placed on an iron plate so that the right kidney was between the pair of magnets. Put.
The magnet used was Shin-Etsu Chemical Co., Ltd., product number: N50 (neodymium permanent magnet), residual magnetic flux density: 1.39-1.44 T. At this time, the magnetic field applied to the right kidney is about 0.3 (T), and the magnetic field applied to the left kidney is about 1/10. Together with the left kidney and the kidney to which no magnetic field was applied (control), a magnetic field was applied to the right kidney of the mouse, and 10 minutes later, SNR was measured by MRI in T1 mode and T2 mode. As a result, as shown in FIG. 4, it was confirmed that the right kidney (RT) to which a magnetic field was applied can retain the drug in the tissue as compared with the left kidney (LT) and the control.
また、薬剤に磁場強度200Oe(エルステッド)、周波数50kHzから200KHzの交流磁場を印加したところ2℃から10℃薬剤の温度が上昇した(図5)。これは、体内投与時の温度に換算したところ39℃から47℃に相当しがん細胞を殺傷することが可能な温度域であることを確認した。 Further, when an alternating magnetic field having a magnetic field strength of 200 Oe (Oersted) and a frequency of 50 kHz to 200 KHz was applied to the drug, the temperature of the drug rose from 2 ° C. to 10 ° C. (FIG. 5). This was equivalent to 39 ° C to 47 ° C when converted into the temperature at the time of in vivo administration, and was confirmed to be a temperature range in which cancer cells can be killed.
Claims (5)
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