JP2009040770A - Release control method of carbon nanohorn inclusion material and carbon nanohorn inclusion material - Google Patents
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Abstract
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本発明は、カーボンナノホーンに内包させた物質の放出制御のための方法と、この放出が制御可能とされた物質内包カーボンナノホーンに関するものである。 The present invention relates to a method for controlling the release of a substance encapsulated in carbon nanohorns, and a substance-encapsulated carbon nanohorn in which the release can be controlled.
集合組織構造を有するカーボンナノホーン（ＮＨｓ）の単層内にシスプラティン（ＣＤＤＰ）等の薬剤やその他物質を内包させて、開孔部からこれを外部に放出可能とすることや、この放出によって、たとえばＣＤＤＰ抗ガン剤によるガン細胞への作用を可能とすることが本発明者らによって報告されている（たとえば非特許文献１、特許文献１）。 By encapsulating drugs and other substances such as cisplatin (CDDP) in a single layer of carbon nanohorn (NHs) having a textured structure, it can be released to the outside from the opening, For example, it has been reported by the present inventors that a CDDP anticancer agent can act on cancer cells (for example, Non-Patent Document 1 and Patent Document 1).
しかしながら、ナノホーンに内包している物質を放出させる際には、短時間に放出が完了してしまうことが多く、ナノホーンをＤＤＳに応用するには問題があった。これを解決するためには、開孔部にフタをしてプラグ効果を発現させることが有効であって、本発明者らによって、このようなプラグ効果として、開孔部にある水酸基やカルボキシル基の水素をＮａで置換する手法や、酢酸Ｇｄを反応させる手法などが開発されている（たとえば特許文献２）。 However, when the substance contained in the nanohorn is released, the release is often completed in a short time, and there is a problem in applying the nanohorn to DDS. In order to solve this problem, it is effective to cover the hole portion to develop a plug effect. A method of substituting hydrogen with Na and a method of reacting acetic acid Gd have been developed (for example, Patent Document 2).
しかし、このようなプラグ効果の発現はその着想と展望において注目されてよいものであるが、歩留まりの問題やプラグ付加時に内包有機物が出てしまうといった問題に対しての更なる改善策の実現が望まれていた。
本発明は、以上のとおりの背景から、更に有効なプラグ効果を実現し、歩留りの向上や、プラグ付加時の内包物質の漏出の抑制を図ることのできる、カーボンナノホーン内包物質の放出抑制のための新しい技術手段を提供することを課題としている。 From the background as described above, the present invention achieves a more effective plug effect, can improve the yield, and can suppress the leakage of the inclusion material when the plug is added, to suppress the release of the inclusion material of the carbon nanohorn. The challenge is to provide new technical means.
本発明は、上記の課題を解決するために、以下のことを特徴としている。 The present invention is characterized by the following in order to solve the above problems.
第１：カーボンナノホーン集合体（ＮＨｓ）の単層カーボンナノホーン（ＮＨ）内に内包させた物質の外部への放出を制御する方法であって、単層カーボンナノホーンの開孔部もしくは開孔部とその近傍外周に、嵩高な分子もしくは高分子を物理吸着させて開孔部を覆うことを特徴とするカーボンナノホーン内包物質の放出制御方法。 First: A method for controlling the release of a substance encapsulated in a single-walled carbon nanohorn (NH) of a carbon nanohorn aggregate (NHs), wherein the single-walled carbon nanohorn has an opening portion or an opening portion; A carbon nanohorn-encapsulating substance release control method characterized in that a bulky molecule or polymer is physically adsorbed on the outer periphery in the vicinity to cover an opening.
第２：嵩高な分子と高分子は、その分子量が１００〜５００，０００の範囲内であることを特徴とする上記第１のカーボンナノホーン内包物質の放出制御方法。 Second: The method for controlling release of the first carbon nanohorn-containing substance, wherein the bulky molecule and the polymer have a molecular weight in the range of 100 to 500,000.
第３：嵩高な分子と高分子は、グラファイトと親和性の高い置換基と親水性基の両方を有していることを特徴とする上記第１または第２のカーボンナノホーン内包物質の放出制御方法。 Third: The bulky molecule and the polymer have both a substituent having a high affinity for graphite and a hydrophilic group, and the method for controlling the release of the first or second carbon nanohorn-encapsulating material described above .
第４：カーボンナノホーン開孔部の置換基もしくは開孔部に付加した分子に、嵩高な分子もしくは高分子を物理吸着させることを特徴とする上記第１から第３のいずれかのカーボンナノホーン内包物質の放出制御方法。 Fourth: The carbon nanohorn inclusion material according to any one of the first to third aspects, wherein a bulky molecule or polymer is physically adsorbed to a substituent of the carbon nanohorn opening or a molecule added to the opening. Release control method.
第５：内包物質が薬剤であって、ＰＢＳ中において５分以内の初期バースト放出を抑え、１時間以上にわたって内包薬剤を徐放させることを特徴とする上記第１から第４のいずれかのカーボンナノホーン内包物質の放出制御方法。 5th: The carbon according to any one of the first to fourth, wherein the encapsulated substance is a drug, and the initial burst release within 5 minutes is suppressed in PBS, and the encapsulated drug is gradually released over 1 hour or more. Method for controlling release of nanohorn inclusion material.
第６：カーボンナノホーン集合体（ＮＨｓ）の単層カーボンナノホーン（ＮＨ）内に物質を内包させた物質内包カーボンナノホーンにおいて、単層カーボンナノホーンの開孔部もしくは開孔部とその近傍外周に、嵩高な分子もしくは高分子が物理吸着され開孔部が覆われて、内包物質の放出が制御可能とされていることを特徴とする物質内包カーボンナノホーン。 Sixth: In the substance-encapsulated carbon nanohorn in which the substance is encapsulated in the single-walled carbon nanohorn (NH) of the carbon nanohorn aggregate (NHs), the single-walled carbon nanohorn has a bulky portion at the perforated portion or the perforated portion and its peripheral periphery. A substance-encapsulated carbon nanohorn characterized in that the release of the encapsulated substance can be controlled by physically adsorbing a molecule or polymer and covering the opening.
第７：嵩高な分子と高分子は、その分子量が１００〜５００，０００の範囲内であることを特徴とする上記第６の物質内包カーボンナノホーン。 Seventh: The sixth substance-encapsulating carbon nanohorn, wherein the bulky molecule and the polymer have a molecular weight in the range of 100 to 500,000.
第８：嵩高な分子と高分子は、グラファイトと親和性の高い置換基と親水性基の両方を有していることを特徴とする上記第６または第７の物質内包カーボンナノホーン。 Eighth: The sixth or seventh substance-encapsulating carbon nanohorn, wherein the bulky molecule and the polymer have both a substituent and a hydrophilic group having high affinity with graphite.
第９：嵩高な分子もしくは高分子が、カーボンナノホーン開孔部の置換基もしくは開孔部に付加した分子に物理吸着されていることを特徴とする上記第６から第８のいずれかの物質内包カーボンナノホーン。 Ninth: The substance inclusion according to any one of the sixth to eighth aspects, wherein the bulky molecule or polymer is physically adsorbed to a substituent of the carbon nanohorn opening or a molecule added to the opening. Carbon nanohorn.
第１０：内包物質が薬剤であり、ＰＢＳ中において５分以内の初期バースト放出が抑えられ、１時間以内にわたって内包薬剤が徐放可能とされていることを特徴とする上記第６から第９のいずれかの物質内包カーボンナノホーン。 Tenth: The above-mentioned sixth to ninth, wherein the encapsulated substance is a drug, the initial burst release within 5 minutes is suppressed in PBS, and the encapsulated drug can be gradually released within 1 hour. Either substance-encapsulated carbon nanohorn.
上記のとおりの本発明によれば、これまでよりも更に有効なプラグ効果が実現され、長期にわたる内包物質の徐放や、初期バースト放出の抑制等が可能とされ、歩留りの向上が図られ、プラグ付加時の内包物質の漏出という問題も解消される。 According to the present invention as described above, a more effective plug effect than before is realized, the sustained release of the encapsulated substance over a long period of time, the suppression of the initial burst release, etc. are possible, and the yield is improved, The problem of leakage of encapsulated material when adding a plug is also eliminated.
本発明におけるカーボンナノホーンは、本発明者らがすでに開発して数多くの報告を行っている各種形態での方法によって合成されたものであってよい。この場合のカーボンナノホーンは、通常は、集合体の組織構造を有するもの（ＮＨｓ）であって、たとえば、複数の単層カーボンナノホーン（ＮＨ）がその閉鎖端部を外方に向けて集合した構造を有している。 The carbon nanohorn in the present invention may be synthesized by various forms of methods that have already been developed and reported by the present inventors. The carbon nanohorn in this case is usually one having an aggregate structure (NHs), for example, a structure in which a plurality of single-walled carbon nanohorns (NH) are aggregated with their closed ends facing outward. have.
本発明においては、このような集合体カーボンナノホーン（ＮＨｓ）を構成する少なくとも一つの単層カーボンナノホーン（ＮＨ）における物質内包とその外部への放出を対象としている。 In the present invention, the inclusion of the substance in at least one single-walled carbon nanohorn (NH) constituting such an aggregate carbon nanohorn (NHs) and its release to the outside are targeted.
カーボンナノホーンに内包させる物質としては従来公知のものをはじめとして各種のものであってよく、たとえば、シスプラティン、デキサメタゾン、ヨウ素などの薬剤、フラーレン、銀、金、ＣｄＳｅ、ＣｄＳなどの無機物、フタロシアニン、ポルフィリン、安息香酸、アルコール、エステル、飽和脂肪酸、不飽和脂肪酸、芳香族化合物、その他であってよい。単層のカーボンナノホーン（ＮＨ）においては、これら物質の内包化とその放出のための開孔部を壁部や頂部の少なくとも一箇所に有している。このような開孔部については、本発明者らがすでに提案している酸化等の手段によって形成することができる。また、この開孔部には炭素原子以外の置換基、たとえばカルボキシル基や水酸基を設けるようにしてもよく、あるいは分子を結合させてもよい。 The substance to be encapsulated in the carbon nanohorn may be various substances including conventionally known substances, for example, drugs such as cisplatin, dexamethasone, iodine, fullerene, silver, gold, inorganic substances such as CdSe, CdS, phthalocyanine, It may be porphyrin, benzoic acid, alcohol, ester, saturated fatty acid, unsaturated fatty acid, aromatic compound, and others. Single-layer carbon nanohorns (NH) have an opening for encapsulating and releasing these substances at at least one of the wall and top. Such an opening can be formed by means such as oxidation that the inventors have already proposed. In addition, a substituent other than a carbon atom, for example, a carboxyl group or a hydroxyl group may be provided in the opening, or a molecule may be bonded.
カーボンナノホーン（ＮＨ）内への物質の内包については、本発明者がすでに提案しているようにシスプラティン（ＣＤＤＰ）等の物質の有機溶媒（ＤＭＦ、ＤＭＳＯ他）溶液や水溶液中に開孔部を有するカーボンナノホーンを分散し、好ましくはＮ２等の不活性ガス雰囲気下に溶媒や水を蒸発させることにより可能とされる。 Regarding the inclusion of a substance in carbon nanohorn (NH), as already proposed by the present inventor, an opening portion is formed in an organic solvent (DMF, DMSO, etc.) solution or an aqueous solution of a substance such as cisplatin (CDDP). It is possible to disperse carbon nanohorns having a solvent and to evaporate the solvent and water in an inert gas atmosphere such as N 2 .
たとえば、図１および図２は、後述の実施例のように水溶液を用いてＣＤＤＰを内包させた単層で開孔部を有するカーボンナノホーン（ＳＷＮＨＯＸ）の電子顕微鏡写真と、走査ＴＥＭ像およびＥＥＬＳ写真である。 For example, FIG. 1 and FIG. 2 show an electron micrograph of a carbon nanohorn (SWNH OX ) having a single layer in which CDDP is encapsulated using an aqueous solution as in Examples described later, a scanning TEM image, and an EELS. It is a photograph.
図２においては、ＣＤＤＰのＰｔ（白金）とＣｌ（塩素原子）とＣ（炭素原子）も観察されている。 In FIG. 2, Pt (platinum), Cl (chlorine atom) and C (carbon atom) of CDDP are also observed.
本発明においては、カーボンナノホーンからの内包物質の放出速度を制御するために、カーボンナノホーンの開孔部に、嵩高な分子やポリマーによるプラグを付加する。 In the present invention, in order to control the release rate of the inclusion substance from the carbon nanohorn, a plug made of a bulky molecule or polymer is added to the opening of the carbon nanohorn.
このプラグは、カーボンナノホーンの外壁や開孔部に化学結合させたものではなく、物理的に吸着させたものである。 This plug is not physically bonded to the outer wall or aperture of the carbon nanohorn, but is physically adsorbed.
プラグは上記の嵩高な分子や高分子といったバルキーな分子であって、開孔部を覆って閉鎖するだけのサイズとナノホーン外壁に対する充分な付着力を有しているものとする。これらの嵩高な分子や高分子は、その分子量が、１００〜５００，０００の範囲であることが好ましい。 The plug is a bulky molecule such as the above-described bulky molecule or polymer, and has a size sufficient to cover and close the aperture and sufficient adhesion to the outer wall of the nanohorn. These bulky molecules and polymers preferably have a molecular weight in the range of 100 to 500,000.
嵩高な分子あるいは高分子は、カーボンナノホーンを形成するグラファイトと親和性の高い置換基を有するものであることが好ましく、その具体例としては、ピレン、フタロシアニン、ドキソルビシン、ドセタキシル等の芳香族分子のようにπ電子に富むもの、あるいは、デキストランなどの糖類、脂肪族基含有の有機分子などが挙げられる。この置換基は、グラファイト壁に強く吸着し、アンカーとなる。 The bulky molecule or polymer preferably has a substituent having a high affinity with graphite forming carbon nanohorn, and specific examples thereof include aromatic molecules such as pyrene, phthalocyanine, doxorubicin, and docetaxyl. Examples thereof include those rich in π electrons, sugars such as dextran, and organic molecules containing aliphatic groups. This substituent is strongly adsorbed on the graphite wall and becomes an anchor.
また、これら嵩高な分子あるいは高分子は、それ自身が親水性であるか、あるいは親水性基を有していることが有効でもある。たとえば、ポリエチレングリコールなど水酸基を持つもの、たんぱく質などアミノ基を持つもの、カルボン酸基をもつもの等があるが、これ以外でもよい。この嵩高な分子あるいは高分子は、カーボンナノホーンの開孔部を覆うことで、内包物質の初期漏洩をおさえ、長期間の徐放を可能とする。 Further, it is also effective that these bulky molecules or polymers are hydrophilic per se or have a hydrophilic group. For example, there are those having a hydroxyl group such as polyethylene glycol, those having an amino group such as protein, those having a carboxylic acid group, and the like. This bulky molecule or polymer covers the pores of the carbon nanohorn, thereby suppressing the initial leakage of the encapsulated substance and enabling sustained release over a long period of time.
本発明に用いられる嵩高な分子あるいは高分子の好適な例としては、ポリエチレングリコール付加ドキソルビシン（ＰＥＧ−ＤＸＲ）を挙げることができる。ＰＥＧ−ＤＸＲにおけるポリエチレングリコールの分子量は、プラグ効果を有効に発揮させる点からは、好ましくは５００〜５００００である。 Preferable examples of the bulky molecule or polymer used in the present invention include polyethylene glycol-added doxorubicin (PEG-DXR). The molecular weight of polyethylene glycol in PEG-DXR is preferably 500 to 50,000 from the viewpoint of effectively exhibiting the plug effect.
なお、プラグ効果を発現するバルキーな分子である嵩高な分子あるいは高分子は、開孔部にある置換基、または開孔部に付加した分子に物理吸着させてもよい。 Note that a bulky molecule or polymer that is a bulky molecule that exhibits a plug effect may be physically adsorbed to a substituent in the opening or a molecule added to the opening.
本発明においては、たとえば以下の実施例にも示すように、カーボンナノホーンに内包する物質のナノホーンからの初期（５分以内）バースト放出が抑えられ、長時間（１時間以上）にわたって、徐々に放出される。 In the present invention, for example, as shown in the following examples, the initial (within 5 minutes) burst release of the substance contained in the carbon nanohorn from the nanohorn is suppressed, and the release is gradually performed over a long time (1 hour or more). Is done.
そこで以下に実施例を示し、さらに詳しく説明する。もちろん、本発明は以下の例によって限定されることはない。 Therefore, an example will be shown below and will be described in more detail. Of course, the present invention is not limited by the following examples.
＜実施例１＞
シスプラティン（ＣＤＤＰ）水溶液（５０ｍｇ／５０ｍｌ）に単層で開孔部を有するＳＷＮＨ（ＳＷＮＨｏｘ）５０ｍｇを分散させ、大気圧窒素気流中で水を蒸発させ、シスプラティン内包ＳＷＮＨｏｘ（ＣＤＤＰ＠ＳＷＮＨｏｘ：内包ＣＤＤＰとＳＷＮＨｏｘの重量比＝１：１）を作製した（ＨＲＴＥＭ像：図１、ＥＥＬＳ像：図２）。別途、ポリエチレングリコール付加ドキソルビシン（ＰＥＧ−ＤＸＲ：ＰＥＧ分子量５０００）の水溶液（１０ｍｇ／１０ｍｌ）を用意し、その１２．５μｌをＣＤＤＰ＠ＳＷＮＨｏｘ（５ｍｇ）に加え、ＣＤＤＰ＠ＳＷＮＨｏｘとＰＥＧ−ＤＸＲと水からなるペースト状にして、ＰＥＧ−ＤＸＲをＣＤＤＰ＠ＳＷＮＨｏｘに付着させた。このペーストをＰＢＳ（６００ｍｌ）中に浸漬させたメンブレン（Ｍ.Ｗ.C.O.：１００ ｋＤａ、ｐｏｒｅ ｓｉｚｅ：１０ｎｍ）に入れて、そのままＣＤＤＰのＳＷＮＨからの放出を調べた。その結果を図３に示す。
<Example 1>
Disperse 50 mg of SWNH (SWNHox) having a single layer and an opening in a cisplatin (CDDP) aqueous solution (50 mg / 50 ml), evaporate water in an atmospheric pressure nitrogen stream, and cisplatin inclusion SWNHox (CDDP @ SWNHox: inclusion A weight ratio of CDDP to SWNHox = 1: 1) was prepared (HRTEM image: FIG. 1, EELS image: FIG. 2). Separately, an aqueous solution (10 mg / 10 ml) of polyethylene glycol-added doxorubicin (PEG-DXR: PEG molecular weight 5000) is prepared, and 12.5 μl thereof is added to CDDP @ SWNHox (5 mg), and from CDDP @ SWNHox, PEG-DXR and water PEG-DXR was attached to CDDP @ SWNHox. This paste was put in a membrane (MW CO: 100 kDa, pore size: 10 nm) immersed in PBS (600 ml), and the release of CDDP from SWNH was examined as it was. The result is shown in FIG.
図３に示すように、ＣＤＤＰ＠ＳＷＮＨｏｘ−（ＰＥＧ−ＤＸＲ）からのＣＤＤＰ放出は初期バースト量約２０％、半減期約１８時間であった。ＰＥＧ−ＤＸＲによるプラグ効果が無い場合、初期バースト量約４０％、半減期約４時間であった。放出飽和量は、ＰＥＧ−ＤＸＲを付加した場合もそうで無い場合も１８０時間程度経過して、約９０％に到達していた。参考のために、ＣＤＤＰのＰＢＳ溶液をメンブレンに入れて、同様に放出実験を行った場合の結果も図３に示した。
＜実施例２＞
ＣＤＤＰ＠ＳＷＮＨ−（ＰＥＧ−ＤＸＲ）、ＣＤＤＰ＠ＳＷＮＨ、ＣＤＤＰを培地に加えてHuman Lung Cancer Cell（H460）を２４時間と４８時間培養し、ＷＳＴ−１アッセイ法により細胞のviabilityのＣＤＤＰ濃度依存性を調べた。
As shown in FIG. 3, CDDP release from CDDP @ SWNHox- (PEG-DXR) had an initial burst amount of about 20% and a half-life of about 18 hours. When there was no plug effect by PEG-DXR, the initial burst amount was about 40% and the half-life was about 4 hours. The amount of saturated release reached about 90% after about 180 hours whether or not PEG-DXR was added. For reference, FIG. 3 also shows the results of a similar release experiment in which a PBS solution of CDDP was placed in a membrane.
<Example 2>
CDDP @ SWNH- (PEG-DXR), CDDP @ SWNH, and CDDP were added to the medium, and the human Lung Cancer Cell (H460) was cultured for 24 and 48 hours. I investigated.
その結果を図４Ａ、図４Ｂに示す。ＣＤＤＰ＠ＳＷＮＨはＣＤＤＰより強い毒性を持つため、少量で細胞死が顕著となるというこれまでの効果を確認することができた。さらに、ＣＤＤＰ＠ＳＷＮＨ−（ＰＥＧ−ＤＸＲ）を加えた場合、実施例１に示したＣＤＤＰ徐放性を反映して、細胞死誘発に遅延効果がみられることが確認された。 The results are shown in FIGS. 4A and 4B. Since CDDP @ SWNH has a stronger toxicity than CDDP, it was possible to confirm the effect so far that cell death becomes remarkable even in a small amount. Furthermore, when CDDP @ SWNH- (PEG-DXR) was added, it was confirmed that a delayed effect was observed in cell death induction reflecting the CDDP sustained release property shown in Example 1.
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| JP2015147718A (en) * | 2014-01-10 | 2015-08-20 | 国立研究開発法人産業技術総合研究所 | Method for producing nanocarbon polymer composite and nanocarbon polymer composite produced by the method |
| JP2018002789A (en) * | 2016-06-29 | 2018-01-11 | 株式会社東芝 | Composite material and curable resin composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2005343885A (en) * | 2004-05-07 | 2005-12-15 | Japan Science & Technology Agency | Drug carbon nanohorn complex and method for producing the same |
| WO2007004545A1 (en) * | 2005-07-01 | 2007-01-11 | Japan Science And Technology Agency | Nanocarbon-supported object, process for producing the same, and drug for dds comprising the same |
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| JP2005343885A (en) * | 2004-05-07 | 2005-12-15 | Japan Science & Technology Agency | Drug carbon nanohorn complex and method for producing the same |
| WO2007004545A1 (en) * | 2005-07-01 | 2007-01-11 | Japan Science And Technology Agency | Nanocarbon-supported object, process for producing the same, and drug for dds comprising the same |
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| JPN6013006564; 松村幸子 他: 'ＤＤＳキャリアとしての単層カーボンナノホーンの分散化と薬剤担持' 日本化学会講演予稿集 Ｖｏｌ． ８７ｔｈ， Ｎｏ． ２, 20070312, １４３６ * |
Cited By (2)
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| JP2015147718A (en) * | 2014-01-10 | 2015-08-20 | 国立研究開発法人産業技術総合研究所 | Method for producing nanocarbon polymer composite and nanocarbon polymer composite produced by the method |
| JP2018002789A (en) * | 2016-06-29 | 2018-01-11 | 株式会社東芝 | Composite material and curable resin composition |
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