JP5138954B2 - Amphiphilic polymer composite - Google Patents
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- JP5138954B2 JP5138954B2 JP2007058271A JP2007058271A JP5138954B2 JP 5138954 B2 JP5138954 B2 JP 5138954B2 JP 2007058271 A JP2007058271 A JP 2007058271A JP 2007058271 A JP2007058271 A JP 2007058271A JP 5138954 B2 JP5138954 B2 JP 5138954B2
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- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 9
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- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、両親媒性ポリマーを利用して薬物をデリバリーするなどの有用材料を作製する技術に関する。 The present invention relates to a technique for producing useful materials such as drug delivery using an amphiphilic polymer.
両親媒性ポリマーには種々の物質が知られているが、エーテル、ケトン、エステル、アミド、イミン等の水溶性を与えるドメインから成る親水性ポリマーとアルキル、アルケニル、アルキニル、芳香族炭化水素等の水不溶性ドメインから成る疎水性ポリマーとを共有結合で連結したブロックコポリマーが一般的である。適切に設計された両親媒性ポリマーは水中で自己組織的にミセルもしくはベシクル状の構造体を形成する。そして疎水性の液体や固体を内包することができるため、薬物や情報記録材料等の機能性物質のデリバリーなどに効果的に使用される。 Various substances are known as amphiphilic polymers. Hydrophilic polymers composed of water-soluble domains such as ethers, ketones, esters, amides, and imines, and alkyl, alkenyl, alkynyl, aromatic hydrocarbons, etc. A block copolymer in which a hydrophobic polymer composed of a water-insoluble domain is covalently linked is generally used. Properly designed amphiphilic polymers form micelles or vesicle-like structures in a self-organized manner in water. And since it can enclose a hydrophobic liquid or solid, it is effectively used for delivery of functional substances such as drugs and information recording materials.
薬物のデリバリーシステムへの応用例を挙げると、（１）水混和性の両親媒性ポリマー内に水不溶性薬物もしくは診断用剤をパッケージングする方法（特許文献１）、（２）内部に無機ナノ粒子が安定して均一に分布している疎水性ポリマーマトリックス部分と親水性部分を含む両親媒性共重合体から成り、治療用組成物として有用な複合体粒子（特許文献２）、（３）中性疎水性αヒドロキシカルボン酸ポリマーブロックとイオン化されたペプチドα鎖を有する直鎖親水性ポリアミノ酸ブロックとで構成されるジブロックコポリマーによるタンパク質送達用粒子のコロイド懸濁液（特許文献３）、（４）ポリ（アルキレンオキシド）を含むＡポリマーブロックおよびポリ（ヒドロキシアルカノエート）を含むＢポリマーブロックを含み、かつ治療剤が、ヒドロゲルの内心に含まれるシクロデキストリンおよび両親媒性コポリマーから形成されるヒドロゲルを含む薬物送達システム（特許文献４）などの特許が公開されている。
情報記録材料への応用例を挙げると、（１）光学材料として有用なミセル粒子含有組成物に使われる両親媒性ブロックポリマー（特許文献５）、（２）インクジェット用のインク組成物に使われる非イオン性の両親媒性ブロックポリマー、イオン性ポリマー、色材からなる機能性物質の溶剤含有物（特許文献６）などがある。
そのような両親媒性ブロックコポリマーにおける親水性ブロックに多糖類が使用される例も幾つか知られている。化粧品を水中油型ナノエマルション組成物に含有させて使用する場合の両親媒性脂質における親水性ブロックの一例に多糖類が挙げられている（特許文献７および８）。眼科用医薬のデリバリー用に使えるカプセル用ナノ粒子の素材として両親媒性ポリエステルコポリマーをグラフトした多糖類が知られている（特許文献９）。
上記の例に見られる両親媒性ブロックコポリマーは、いずれも親水性ブロックと疎水性ブロックとを特別の結合反応による共有結合を介して連結させているものであり、結合生成に労を要し、さらに、所望の目的を達成した後など、必要に応じて結合を解離することも容易でない。また、生体への安全性が確保されていない材料が用いられている場合も多い。 All of the amphiphilic block copolymers found in the above examples are those in which a hydrophilic block and a hydrophobic block are linked via a covalent bond by a special bonding reaction, and labor is required for bond formation. Furthermore, it is not easy to dissociate bonds as necessary, for example, after achieving a desired purpose. In addition, there are many cases where a material whose safety to a living body is not secured is used.
本発明の目的は、生体に安全であり、結合生成と解離も容易な両親媒性ポリマーを創製し、各種機能性物質のデリバリーなどに利用できる技術を提供することにある。 An object of the present invention is to create an amphiphilic polymer that is safe for the living body and easy to generate and dissociate, and to provide a technique that can be used for delivery of various functional substances.
本発明者は、β-1,3-グルカンに代表される多糖類を用いることにより、共有結合によらない両親媒性ポリマーが形成され得ることを見出し本発明を導き出した。
すなわち、本発明は、多糖、疎水性ポリマーおよび疎水性物質から成り、多糖と疎水性ポリマー間の結合が非共有結合性であることを特徴とする複合体を提供するものである。
さらに、本発明に従えば、このような複合体を製造する方法であって、多糖、疎水性ポリマーおよび疎水性物質を非プロトン性極性溶媒またはアルカリ性水溶液中で混合した後、中性の状態で水を混合させる工程を含むことを特徴とする方法が提供される。
The present inventor has found that an amphiphilic polymer not based on a covalent bond can be formed by using a polysaccharide represented by β-1,3-glucan, and has derived the present invention.
That is, the present invention provides a complex comprising a polysaccharide, a hydrophobic polymer, and a hydrophobic substance, wherein the bond between the polysaccharide and the hydrophobic polymer is non-covalent.
Furthermore, according to the present invention, there is provided a method for producing such a complex, in which a polysaccharide, a hydrophobic polymer and a hydrophobic substance are mixed in an aprotic polar solvent or an alkaline aqueous solution, and then in a neutral state. A method is provided comprising the step of mixing water.
本発明の複合体は、疎水性物質として各種の機能性物質や有機溶剤を使用することにより、薬物のデリバリーやナノ粒子、ナノエマルション、薄膜等の製造に利用することができる。特に、生体に安全な多糖類を使用するので薬物のデリバリーシステム用などに有効である。中間に（in situ）生成すると考えられる両親媒性ポリマーの親水性ドメインと疎水性ドメイン間の結合が非共有結合性であるため、簡単な物理的操作だけで生成可能である。また、その非共有結合を解離し、複合体を崩壊させる必要が生じた場合も、酸を添加するなど簡単な操作で達成できる。 The composite of the present invention can be used for drug delivery and production of nanoparticles, nanoemulsions, thin films and the like by using various functional substances and organic solvents as hydrophobic substances. In particular, it is effective for drug delivery systems because it uses polysaccharides that are safe for living bodies. Since the bond between the hydrophilic domain and the hydrophobic domain of the amphiphilic polymer that is considered to be generated in situ is non-covalent, it can be generated by simple physical manipulation. Further, when it is necessary to dissociate the non-covalent bond and disrupt the complex, it can be achieved by a simple operation such as addition of an acid.
本発明は、基本的に、両親媒性ポリマーが水中で自己組織的に形成するミセル状構造体に疎水性の機能物質を内包させ、薬物のデリバリー等に活用する手法を、新規な両親媒性物質を使って行おうとするものである。通常使われる両親媒性ポリマーは、各種の親水性ポリマーと疎水性ポリマーとを共有結合によって共重合させたコポリマーである。本発明において疎水性ポリマーとしては、通常使われるアルカン、アルケン、アルキン、芳香族炭化水素等が骨格となっている疎水性ポリマーを使用し、親水性ポリマーに相当する部分には、好ましくはβ-1,3-グルカンである多糖類を用いる。 The present invention basically employs a novel amphiphilic method in which a hydrophobic functional substance is encapsulated in a micellar structure formed by self-organization of an amphiphilic polymer in water and used for drug delivery and the like. It is going to be done using a substance. A commonly used amphiphilic polymer is a copolymer obtained by copolymerizing various hydrophilic polymers and hydrophobic polymers by covalent bonds. As the hydrophobic polymer in the present invention, a commonly used hydrophobic polymer having a skeleton of alkane, alkene, alkyne, aromatic hydrocarbon or the like is used, and the portion corresponding to the hydrophilic polymer is preferably β- Polysaccharides that are 1,3-glucans are used.
β-1,3-グルカンは天然の状態で3重のらせん構造を形成しているが、非プロトン性極性溶剤中やアルカリ水溶液中においては1本鎖のランダムコイル状に解離している。その1本鎖のβ-1,3-グルカンに高分子物質を共存させた状態で中性の水と接触させると、共存高分子物質をヘリカル状に巻き込み、高分子物質がβ-1,3-グルカンでラッピングされること、そして、β-1,3-グルカンの外側表面は親水性であり、高分子物質はβ-1,3-グルカンの内側表面の疎水部分と疎水的相互作用をしてβ-1,3-グルカンの内部に取り込まれることを本発明者らが見出している。
本発明で使用する多糖類としては、上記のβ-1,3-グルカンが好適であり、その中でも水溶性の高いシゾフィラン（略称：SPG）、スクレログルカンおよびレンチナンから選ばれたものがより好適である。特に、天然のβ-1,3-グルカンの一つであるシゾフィランは筋肉内注射製剤の臨床薬として実際に使用されており、婦人科癌に対する免疫増強法の筋肉内注射薬として20年以上の使用実績があり、免疫系の抗原提示細胞への親和性も知られており、生体内での安全性が確認されている。β-1,3-グルカンの平均分子量は1本鎖の状態で25000以上のものであればよい。側鎖が官能基で置換されたβ-1,3-グルカンを用いることもできる。また、β-1,3-グルカン以外の多糖類ではアミロース、デキストラン、プルランも場合により使用可能である。 As the polysaccharide used in the present invention, the above β-1,3-glucan is preferable, and among them, one selected from schizophyllan (abbreviation: SPG), scleroglucan and lentinan having high water solubility is more preferable. It is. In particular, schizophyllan, one of the natural β-1,3-glucans, has been used as a clinical drug for intramuscular injections, and has been used as an intramuscular injection for immune enhancement for gynecological cancer for over 20 years. There is a track record of use, and the affinity of the immune system for antigen-presenting cells is also known, and safety in vivo has been confirmed. The average molecular weight of β-1,3-glucan may be 25,000 or more in a single chain state. Β-1,3-glucan having a side chain substituted with a functional group can also be used. As polysaccharides other than β-1,3-glucan, amylose, dextran, and pullulan can be used in some cases.
疎水性ポリマーに関しては特に制限はなく、アルカン、アルケン、アルキン、の芳香族炭化水素などを骨格とする多数の物質が使われる。例えば、本発明で用いられる疎水性ポリマーとしてポリスチレン（略称：ＰＳ）が挙げられるが、これに限られるものではない。多糖と疎水性ポリマーとの使用比率については、ポリマーの種類によっても異なるが、疎水性ポリマーの全部が多糖によるラッピングを受けないようにする必要がある。重量単位で等量付近では問題なく、一般にかなり広範囲の比率で実施可能である。 The hydrophobic polymer is not particularly limited, and a large number of substances having an alkane, alkene, alkyne, aromatic hydrocarbon or the like as a skeleton are used. For example, polystyrene (abbreviation: PS) can be given as an example of the hydrophobic polymer used in the present invention, but the invention is not limited thereto. The ratio of the polysaccharide to the hydrophobic polymer used varies depending on the type of polymer, but it is necessary to prevent the entire hydrophobic polymer from being wrapped by the polysaccharide. There is no problem in the vicinity of an equivalent amount by weight, and in general, it can be carried out in a fairly wide range of ratios.
本発明において疎水性物質とは、既述のように、所望の目的に応じて用いられる各種の機能性物質や有機溶剤であり、この疎水性物質に関しても特に制限はなく、水に不溶かつ有機溶剤に可溶または安定に分散できるものであれば、固体もしくは液体のいずれも適用可能である。本発明において用いられるのに特に好ましい疎水性物質は、疎水性薬物（薬剤）であり、これによって、後述するような両親媒性ポリマーに薬物が封入（内包）されドラックデリバリーシステムに使用されるのに好適な複合体が得られる（後述の実施例９、１０参照）。
本発明では、疎水性物質を多糖類および疎水性ポリマーと非プロトン性極性溶剤（ジメチルスルホキシド：DMSO,1-メチル-2-ピロリジノン：NMPなど）もしくはアルカリ水溶液（NaOH水溶液など）と混合し、中性の状態を保ちつつ水を混和し、熟成することにより、多糖、疎水性ポリマーおよび疎水性物質から成る複合体が形成される。熟成は、一般に、室温〜60℃付近の温度で数時間〜数日間行われる。
In the present invention, the hydrophobic substance is, as described above, various functional substances and organic solvents used according to a desired purpose. There is no particular limitation on the hydrophobic substance, and it is insoluble in water and organic. Any solid or liquid can be used as long as it is soluble or stably dispersible in the solvent. A particularly preferable hydrophobic substance to be used in the present invention is a hydrophobic drug (drug), which allows the drug to be encapsulated (encapsulated) in an amphiphilic polymer as described later and used in a drug delivery system. (See Examples 9 and 10 below).
In the present invention, a hydrophobic substance is mixed with a polysaccharide and a hydrophobic polymer with an aprotic polar solvent (dimethyl sulfoxide: DMSO, 1-methyl-2-pyrrolidinone: NMP, etc.) or an alkaline aqueous solution (NaOH aqueous solution, etc.). By mixing and aging water while maintaining the state of sex, a complex composed of a polysaccharide, a hydrophobic polymer and a hydrophobic substance is formed. The aging is generally carried out at room temperature to around 60 ° C. for several hours to several days.
以上の記述から明らかなように、本発明の複合体は、本質的に、複合体の構成成分を混合するだけの操作により調製され、共有結合を形成させるための格別の反応工程を要しない。多くの実験事実から、疎水性ポリマーはシゾフィランのような多糖にラッピングされて、親水性ドメインと疎水性ドメインから成る両親媒性ポリマーを形成し、これが従来から知られた両親媒性ポリマーと同様に自己集合してミセル状構造体を形成しているものと理解される。特に、疎水性ポリマーがエマルジョン化した疎水性溶媒中に分散していると考えられため、エマルジョンをテンプレートに容易にミセル状会合体を形成できると考えられる。図１はこのような様子を模式的に示すものである。多糖と疎水性ポリマー間の結合は非共有結合性、すなわち疎水性相互作用（疎水結合）による（後述の実施例１、２、３、６、７等参照）。
そして、多糖と疎水性ポリマーとともに、疎水性物質を加えて所定の混合を行った後も、このような構造体が保持され、疎水性物質は当該構造体内に取り込まれて三元複合体を形成することが示されている（後述の実施例４，５参照）。
As is apparent from the above description, the complex of the present invention is essentially prepared by simply mixing the components of the complex and does not require any special reaction step for forming a covalent bond. From many experimental facts, hydrophobic polymers are wrapped into polysaccharides such as schizophyllan to form amphiphilic polymers consisting of hydrophilic and hydrophobic domains, similar to previously known amphiphilic polymers. It is understood that they are self-assembled to form a micellar structure. In particular, since it is considered that the hydrophobic polymer is dispersed in the emulsified hydrophobic solvent, it is considered that micelle-like aggregates can be easily formed using the emulsion as a template. FIG. 1 schematically shows such a state. The bond between the polysaccharide and the hydrophobic polymer is non-covalent, that is, by hydrophobic interaction (hydrophobic bond) (see Examples 1, 2, 3, 6, 7, etc. described later).
And after adding a hydrophobic substance together with a polysaccharide and a hydrophobic polymer, the structure is retained, and the hydrophobic substance is incorporated into the structure to form a ternary complex. (See Examples 4 and 5 below).
このように本発明の複合体は、水性溶液中ではミセル状と理解される安定な構造体に疎水性物質が結合した構造を呈するとともに、ｐＨ変化や溶媒組成の変化などの条件によりその構造が崩壊され、当該疎水性物質を放出することができる（後述の実施例８参照）。
以下、実施例に沿って本発明の特徴を更に具体的に説明する。
As described above, the complex of the present invention exhibits a structure in which a hydrophobic substance is bound to a stable structure that is understood as a micelle in an aqueous solution, and the structure varies depending on conditions such as pH change and solvent composition change. When disintegrated, the hydrophobic substance can be released (see Example 8 below).
Hereinafter, the features of the present invention will be described more specifically with reference to examples.
多糖／疎水性ポリマー複合体サンプルの調製 まず、SPG（1本鎖でのMw＝35000）とPS（Mw＝1.09×106）のNMP（１−メチル−２−ピロリジノン）ストック溶液をそれぞれ500μlをサンプル管中で混合し、軽く攪拌した。この溶液にトルエン100μlを加え素早く攪拌を行った。この段階で溶液は均一であることが目視により確認できた。溶液に超音波照射を行いながら蒸留水4.0mlを加えた、さらに超音波照射を１分間行った。この段階で溶液は白濁しエマルジョンを形成しているのが確認できた。さらに溶液を60℃にて３日間インキュベートしたところ、溶液の白濁は次第に消失し均一溶液となった。得られた溶液から透析（MWCO＝8000）によりNMPを除去した。溶媒を水に置換した後も溶液は均一を保っているのが目視により確認できた。 Preparation of polysaccharide / hydrophobic polymer complex sample First, 500 μl each of NPG (1-methyl-2-pyrrolidinone) stock solution of SPG (Mw in single chain = 35000) and PS (Mw = 1.09 × 10 6 ) Mix in sample tube and mix gently. To this solution, 100 μl of toluene was added and stirred rapidly. At this stage, it was confirmed by visual observation that the solution was uniform. While the solution was subjected to ultrasonic irradiation, 4.0 ml of distilled water was added, and further ultrasonic irradiation was performed for 1 minute. At this stage, it was confirmed that the solution became cloudy and formed an emulsion. Furthermore, when the solution was incubated at 60 ° C. for 3 days, the cloudiness of the solution gradually disappeared and became a homogeneous solution. NMP was removed from the resulting solution by dialysis (MWCO = 8000). It was confirmed by visual observation that the solution remained uniform even after the solvent was replaced with water.
CDスペクトルを用いた相互作用の検証 SPGとPS が相互作用していることを確かめるためにCDスペクトルによる評価を行った。図２に示す結果より、ポリスチレンの吸収領域にCDが確認できたことから、SPGがPSをラッピングしているものと考えられる。 Verification of interaction using CD spectrum In order to confirm that SPG and PS are interacting, evaluation using CD spectrum was performed. From the results shown in FIG. 2, it was considered that SPG was wrapping PS because CD was confirmed in the polystyrene absorption region.
TEMを用いた構造評価（１） 得られた水溶液をグリッドにキャストしTEMによる観察を行った。図３に示す結果より直径約150nmの球状物が確認できる。その形状、大きさはほぼ均一であることが分かる。得られた球状物は親水性であることを考えると、疎水性のPSが核を形成し、表面はシゾフィランによって覆われているものと考えられる。もし、得られた構造体の内部に空孔が存在しミセル状の構造体を与えているとすると、その内部に様々な疎水性分子を取り込めることが期待される。 Structural evaluation using TEM (1) The obtained aqueous solution was cast on a grid and observed by TEM. From the result shown in FIG. 3, a spherical object having a diameter of about 150 nm can be confirmed. It can be seen that the shape and size are almost uniform. Considering that the obtained spheroids are hydrophilic, it is considered that hydrophobic PS forms nuclei and the surface is covered with schizophyllan. If pores exist inside the obtained structure to give a micellar structure, it is expected that various hydrophobic molecules can be taken into the structure.
C 60 の取り込み 実施例１のトルエンの代わりにC60のトルエン溶液を用いて、同様の操作でサンプル調製を行った。得られた溶液はC60が凝集したことを示す褐色を呈していたが、特に沈殿など不溶成分は確認出来なかった。溶液の均一性は溶媒を透析により水に置換した後も保たれていた。C60がミセルの疎水性内部に取り込まれることにより水溶化できたものと理解される。得られた水溶液の写真を図４に示した。また、この図にはSPGの代わりにアミロース、デキストラン、プルランを用いた参照溶液の写真も示してある。図４よりSPGを用いた場合は他の多糖を用いたものよりC60がより高濃度で溶解していることが解る。 Using a toluene solution of C 60 instead of toluene uptake Example 1 C 60, were samples prepared in the same manner. The resulting solution had exhibited a brown color to indicate that the C 60 are aggregated, but was not confirmed insoluble component, particularly precipitation. The homogeneity of the solution was maintained after the solvent was replaced with water by dialysis. It is understood that C 60 can be water-solubilized by incorporation into the hydrophobic interior of the micelle. A photograph of the resulting aqueous solution is shown in FIG. This figure also shows a photograph of a reference solution using amylose, dextran, or pullulan instead of SPG. It can be seen from FIG. 4 that when SPG is used, C 60 is dissolved at a higher concentration than those using other polysaccharides.
TEMを用いた構造評価（２） 実施例４で得られたサンプルのTEMによる観察を行った。結果を図５に示した。この図より疎水性のゲスト分子存在下においても図３同様の球状物が形成しているのが分かる。混合したC60が疎水性分子であるにも関わらず完全に水に溶解している事実を考え合わせると、C60は内部の疎水空間に取り込まれているものと考えられる。この結果は得られた構造体が巨大ミセル構造をとっていることを強く示唆するものである。 Structural evaluation using TEM (2) The sample obtained in Example 4 was observed by TEM. The results are shown in FIG. From this figure, it can be seen that spheres similar to those in FIG. 3 are formed even in the presence of hydrophobic guest molecules. Considering the fact that the mixed C 60 is completely dissolved in water even though it is a hydrophobic molecule, it is considered that C 60 is taken into the internal hydrophobic space. This result strongly suggests that the obtained structure has a giant micelle structure.
ビオチン修飾シゾフィランを用いたミセル表面の機能化 ミセル表面を様々な機能性分子で修飾するとミセル同士の会合制御、ミセル膜を介した内外の情報伝達が可能となる。この実施例では、SPGの側鎖にビオチンを修飾したSPG-Bio（図６）を用いて同様にミセルの形成を試みた。ミセルの表面がSPG-Bioによって被覆されているとすると、ビオチンに特異的に結合することが知られているタンパク質（アビジン）を表面に集積させることが可能と考えられる。サンプルは実施例１と同様の操作で調製した。得られた溶液は未修飾SPGを用いた場合と同様に、乳白色のエマルジョン溶液となった。 Functionalization of the micelle surface using biotin-modified schizophyllan When the micelle surface is modified with various functional molecules, it becomes possible to control the association of micelles and to transmit information inside and outside the micelle membrane. In this example, micelle formation was similarly attempted using SPG-Bio (FIG. 6) in which biotin was modified on the side chain of SPG. If the micelle surface is coated with SPG-Bio, it is considered possible to accumulate on the surface a protein (avidin) known to specifically bind to biotin. Samples were prepared in the same manner as in Example 1. The resulting solution became a milky white emulsion solution as in the case of using unmodified SPG.
CLSMによる評価 ミセル状の構造を呈すると表面は親水性のSPGで覆われていると考えられる。そこで次にビオチン修飾したシゾフィラン（SPG-Bio）を用いて形成されるミセル表面の機能化の可能性について検討を行った。サンプルは以下に示す表１の組成に従い、実施例１と同様の操作で調製した。最終的に得られた水溶液500μlにFITC修飾アビジン水溶液（5mgml-1）を5.0μl加え共焦点レーザー顕微鏡観察用のサンプルとした。測定結果を図７および図８にそれぞれ示す。図７よりミセルと考えられる構造体とFITC由来の蛍光が完全に一致しているのが解る。このことはミセルとアビジンが共存していることを示している。一方、ビオチン部位を持たないSPGを用い調製したミセルはアビジンに対する親和性は確認されていない（図８）。このことはミセル表面のビオチンによってアビジンが認識されていることを強く示唆する結果である。さらに、図６の蛍光像を拡大するとミセルからは円状の蛍光が確認できた（図９）。これは巨大ミセルの表面がビオチン修飾SPGで覆われていることを示す結果である。 It is thought that the surface is covered with hydrophilic SPG when it exhibits a micellar structure evaluated by CLSM . Next, we investigated the possibility of functionalizing the micelle surface formed using biotin-modified schizophyllan (SPG-Bio). Samples were prepared in the same manner as in Example 1 according to the composition shown in Table 1 below. 5.0 μl of FITC-modified avidin aqueous solution (5 mg ml −1 ) was added to 500 μl of the finally obtained aqueous solution to prepare a sample for confocal laser microscope observation. The measurement results are shown in FIGS. 7 and 8, respectively. It can be seen from FIG. 7 that the structure considered to be a micelle and the fluorescence derived from FITC completely match. This indicates that micelles and avidin coexist. On the other hand, micelles prepared using SPG having no biotin moiety have not been confirmed to have affinity for avidin (FIG. 8). This result strongly suggests that avidin is recognized by biotin on the micelle surface. Furthermore, when the fluorescence image of FIG. 6 was enlarged, circular fluorescence could be confirmed from the micelle (FIG. 9). This is a result showing that the surface of the giant micelle is covered with biotin-modified SPG.
SPGの加水分解によるミセル構造の崩壊 次に、内部にA.ポルフィリンおよびB.C60を内包させたミセルを調製し、得られた水溶液に塩酸を滴下することによりミセルの分解挙動を検討することにした。pHメータにてpHを2.2に調整し、UVスペクトルにて経時変化を追跡した。結果を図１０に示す。この図より時間の経過に伴い内包したゲストの吸光度が減少していく様子が解る。また、時間の経過に伴いセルの底には沈殿物が堆積していくのが目視で確認された。この結果はSPGが酸による加水分解を受けそれによりミセル構造が崩壊したことを示唆している。一方、酸を加えないサンプルは数週間放置しても沈殿物の生成は認められないことを別途確認している。以上の結果はミセル内部に包接したゲストが酸性条件下でのみ放出可能であることを示している。このことから本発明の複合体は、ドラッグキャリアーとしての応用が期待される。 Disruption of micelle structure by hydrolysis of SPG Next, we prepared micelles containing A. porphyrin and BC 60 inside, and decided to investigate the decomposition behavior of micelles by dropping hydrochloric acid into the obtained aqueous solution. . The pH was adjusted to 2.2 with a pH meter, and the change over time was followed with a UV spectrum. The results are shown in FIG. From this figure, it can be seen that the absorbance of the encapsulated guest decreases with time. Further, it was visually confirmed that precipitates accumulated on the bottom of the cell as time passed. This result suggests that SPG was hydrolyzed with acid, which caused the micelle structure to collapse. On the other hand, it was confirmed separately that no sample was added to the sample without addition of acid even if it was left for several weeks. The above results indicate that the guest included in the micelle can be released only under acidic conditions. From this, the complex of the present invention is expected to be applied as a drug carrier.
薬物のミセル封入 本系の特徴はまず疎水性ポリマーと疎水性薬物をあらかじめ混合させ安定なエマルジョンを形成し、その後SPG層を超分子化学的に構築できる点である。これにより、より効果的な薬物封入が達成できるものと期待される。また、様々な官能基を予めSPGに導入しておくおことにより、ミセル表面の機能デザインも可能である。今回細胞系での利用を考慮して生分解性のポリ乳酸(PLA)を用いた。また薬物としては抗がん剤であるカンプトテシン(CPT)を用いた。ポリ乳酸はAldrich社のpoly(DL-lactide)(Mw = 75,000-120,000)[CAS番号：51063-13-9]を用いた。 Drug micelle encapsulation This system is characterized in that a hydrophobic polymer and a hydrophobic drug are mixed in advance to form a stable emulsion, and then an SPG layer can be constructed supramolecularly. Thereby, it is expected that more effective drug encapsulation can be achieved. In addition, the functional design of the micelle surface can be achieved by introducing various functional groups into SPG in advance. This time, biodegradable polylactic acid (PLA) was used in consideration of its use in cell systems. In addition, camptothecin (CPT), an anticancer drug, was used as a drug. As polylactic acid, poly (DL-lactide) (Mw = 75,000-120,000) [CAS number: 51063-13-9] manufactured by Aldrich was used.
サンプルの調製は表２に示す配合で行った。基本的な操作を以下に示す。PLAの塩化メチレン溶液(5mg/mL)とCPTの塩化メチレン溶液(1mg/mL)を混合した後、水2.0mLを加え、プローブ型ソニケーターを10秒照射した。混合溶液は乳白色を示し、エマルジョンが形成されているのが目視により確認できた。この段階で、特に不溶物の形成なども認められていない。このエマルジョンの塩化メチレン層を濃縮する目的で、室温にて3.5時間撹拌を行った。撹拌30分後にはPLAの混在量を1/5としたサンプル2において、エマルジョンが完全に消失し、2層に分離しているのが目視で確認された。その他のサンプルについては特に2層に分離する事は無く、溶液の乳白色は次第に消えながらわずかに濁りを示す溶液となった。この溶液にSPGのDMSO溶液を加え、エマルジョンの表面をSPGにて被覆した。得られた溶液をさらに室温にて1日撹拌し、塩化メチレン層の濃縮とSPGの巻き戻りを促進させた。得られた溶液にはわずかに不溶物が存在する程度でCPTは効率的にミセル内に封入されているものと考えられる。得られた溶液のDLS測定を行ったところサンプル1, 3, 4について直径250nm程度のミセルの形成が確認されている。 Samples were prepared with the formulation shown in Table 2. The basic operation is shown below. After mixing a methylene chloride solution of PLA (5 mg / mL) and a methylene chloride solution of CPT (1 mg / mL), 2.0 mL of water was added and the probe-type sonicator was irradiated for 10 seconds. The mixed solution was milky white, and it was confirmed visually that an emulsion was formed. At this stage, insoluble matter formation is not particularly recognized. Stirring was performed at room temperature for 3.5 hours for the purpose of concentrating the methylene chloride layer of the emulsion. After 30 minutes of stirring, it was visually confirmed that the emulsion completely disappeared and was separated into two layers in Sample 2 in which the amount of PLA mixed was 1/5. The other samples were not separated into two layers, and the milky white color of the solution gradually disappeared and became slightly turbid. A DMSO solution of SPG was added to this solution, and the surface of the emulsion was coated with SPG. The resulting solution was further stirred at room temperature for 1 day to promote concentration of the methylene chloride layer and unwinding of SPG. It is considered that CPT is efficiently enclosed in the micelle to the extent that there is a slight insoluble matter in the obtained solution. When DLS measurement was performed on the obtained solution, formation of micelles with a diameter of about 250 nm was confirmed for samples 1, 3, and 4.
UVスペクトルによる内包量の評価：得られた溶液を200mL分取し、ここに1800mLのDMSOを加えUVスペクトルによりCPTの含有量を評価した。結果を表３にまとめて示す。内包量にばらつきはあるもののCPTがミセル内に内包され水溶化できていた事が表３の結果より示された。特に少量のCPTを用いてミセルを形成させたサンプル３については高い回収率が達成されている。 Evaluation of inclusion amount by UV spectrum : 200 mL of the resulting solution was taken, 1800 mL of DMSO was added thereto, and the content of CPT was evaluated by UV spectrum. The results are summarized in Table 3. The results shown in Table 3 showed that CPT was contained in micelles and water-solubilized although there was variation in the amount of inclusion. In particular, a high recovery rate is achieved for sample 3 in which micelles are formed using a small amount of CPT.
本発明により自己組織的に形成される巨大複合体の内部に様々な疎水性分子を内包できるため、薬物のデリバリー等の医療分野への応用や、情報記録材料分野への応用などが期待できる。 Since various hydrophobic molecules can be encapsulated inside the giant complex formed in a self-organized manner according to the present invention, application to the medical field such as drug delivery and application to the field of information recording materials can be expected.
Claims (6)
該ミセル状構造体の内部の前記疎水空間に、前記疎水性ポリマーとは異なる疎水性物質が取り込まれて構成されている複合体であって、
前記多糖がβ−１，３−グルカンであることを特徴とする複合体。 A hydrophilic polymer polysaccharide and a hydrophobic polymer are combined by a hydrophobic interaction, and the hydrophobic polymer is wrapped on the polysaccharide, and is composed of an amphiphilic polymer composed of a hydrophilic domain and a hydrophobic domain, Including a micellar structure having a hydrophobic space inside and having a hydrophobic surface covered with the hydrophilic polysaccharide,
A complex formed by incorporating a hydrophobic substance different from the hydrophobic polymer into the hydrophobic space inside the micellar structure,
A complex wherein the polysaccharide is β-1,3-glucan.
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