JP4919496B2 - Method for producing anisotropic polymer fine particles having plural kinds of functional groups - Google Patents
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本発明は、生体・化学物質を共有結合によってラテックス微粒子へ固定化するに際して、生体・化学物質と段階的に反応する複数種の官能基を持つ異方性高分子微粒子の製造方法に関する。 The present invention relates to a method for producing anisotropic polymer fine particles having a plurality of types of functional groups that react stepwise with biological / chemical substances when the biological / chemical substances are immobilized to latex fine particles by covalent bonds.
近年、数十nm〜数mmまでの粒子径を持つ機能性高分子微粒子はラテックス診断薬、アフィニティー生体物質分離及びドラッグまたは酵素のキャリアーなど生化学へ幅広く応用されてきた。生体分子、例えばタンパク質は通常物理的吸着或いは共有結合によってラテックス微粒子へ固定化される。このような技術はナノバイオテクノロジーの基盤的要素技術のひとつとして重要である。
ラテックス微粒子の表面へ生体分子を共有結合するために、特有な官能基を持つラテックス微粒子が用いられる。これまでに、エポキシド、アセタール、カルボン酸、アルデヒド、クロロメチル、ヒドロキシなど官能基を持つラテックス微粒子が生体分子の共有結合による固定化のために開発された。
機能性ラテックス微粒子のサイズ（粒子径）は通常重合方法によって違ってくる。数μm以上のラテックス微粒子は懸濁重合法を用い、μm〜数μmまでの微粒子は分散重合によって製造され、乳化重合では100 nmからμmまでの微粒子が作られ、数十nmの微粒子はミニ及びマイクロ乳化重合により合成される。これまでに、懸濁重合及び分散重合法によって作られた微粒子はアフィニティークロマトグラフィー、ドラッグデリバリーシステム（DDS）などに応用されてきた。乳化重合法の中の一つの重合法、ソープフリー乳化重合（界面活性剤を用いない重合法）によって作られた微粒子は主として、ラテックス診断薬、アフィニティー生体物質分離に応用されている。
In recent years, functional polymer fine particles having a particle size of several tens of nanometers to several millimeters have been widely applied to biochemistry such as latex diagnostic agents, affinity biomaterial separation, and drug or enzyme carriers. Biomolecules such as proteins are usually immobilized on latex microparticles by physical adsorption or covalent bonding. Such technology is important as one of the fundamental elemental technologies of nanobiotechnology.
In order to covalently bond biomolecules to the surface of the latex particulates, latex particulates having a specific functional group are used. So far, latex microparticles with functional groups such as epoxide, acetal, carboxylic acid, aldehyde, chloromethyl, and hydroxy have been developed for the immobilization of biomolecules by covalent bonds.
The size (particle diameter) of functional latex particles usually varies depending on the polymerization method. Latex fine particles of several μm or more are produced by suspension polymerization, fine particles from μm to several μm are produced by dispersion polymerization, fine particles from 100 nm to μm are made by emulsion polymerization, and fine particles of several tens of nm are mini and Synthesized by microemulsion polymerization. So far, fine particles produced by suspension polymerization and dispersion polymerization methods have been applied to affinity chromatography, drug delivery systems (DDS) and the like. Fine particles produced by one of the emulsion polymerization methods, soap-free emulsion polymerization (polymerization method not using a surfactant), are mainly applied to latex diagnostic agents and affinity biomaterial separation.
しかし、バイオテクノロジーへの応用を目指した従来のラテックス微粒子は主に均一組成、多孔質またはコアーシェルタイプ構造であり、微粒子表面は一種類の官能基しか持たない。従って、微粒子表面は均一、画一的であり、より高度な機能を制御することはできない。例えば、生体物質と微粒子を組み合わせたナノマシンを構築するためには、微粒子の両側に異なる官能基を持たせて方向性を付与する必要があり、このような微粒子はナノバイオテクノロジーにおける新たな要素技術として期待されるところである。
しかし、親水性の官能基を持つモノマーから微粒子を作ることは難しく（特にソープフリー乳化重合の場合）、高固形分（ラテックス中の含有量が高いポリマー成分）を持つ親水性微粒子の調製は未だに高分子微粒子研究の一つの重要な課題である。
また、官能基を有するモノマーは殆ど親水性であり、親水性ポリマー間の相分離も難しいので、２つ以上の官能基を持つ異方性高分子微粒子、すなわち、エポキシ環及び水酸基をそれぞれ微粒子の異なるドメインに持たせたラテックス微粒子及びその製造方法についてはまだ報告されていなかった。
However, conventional latex fine particles aiming at application to biotechnology mainly have a uniform composition, a porous or core-shell type structure, and the fine particle surface has only one type of functional group. Therefore, the surface of the fine particles is uniform and uniform, and it is impossible to control more advanced functions. For example, in order to construct a nanomachine that combines biological materials and fine particles, it is necessary to provide different functional groups on both sides of the fine particles to provide directionality, and such fine particles are a new elemental technology in nanobiotechnology. This is what is expected.
However, it is difficult to make fine particles from monomers having hydrophilic functional groups (especially in the case of soap-free emulsion polymerization), and preparation of hydrophilic fine particles having a high solid content (polymer component having a high content in latex) is still in progress. This is one important issue for the research on polymer fine particles.
In addition, since monomers having functional groups are almost hydrophilic and phase separation between hydrophilic polymers is difficult, anisotropic polymer fine particles having two or more functional groups, that is, epoxy rings and hydroxyl groups, respectively, Latex fine particles imparted to different domains and the production method thereof have not yet been reported.
上記目的を達成するために本発明は、今回の発明で開発した二つの官能性を有する異方性複合高分子微粒子はソープフリー乳化重合によって合成され、約200 nmのサイズを持つ。また、本法では、種々の組み合わせの官能基を持つ微粒子の製造が可能である。
すなわち本発明は、第１段目は、グリシジルメタクリレート（ＧＭＡ）とジビニルベンゼンを用いて、中性を保って、ソープフリー乳化重合によるシードポリマー粒子を合成し、シードポリマー粒子から未反応のモノマーと開始剤、オリゴマーを除去したのち、第２段目は、このシードポリマー粒子とスチレンモノマーとを、２−メルカプトエタノール及び溶剤を加えて、水中でソープフリーシード乳化重合を行い、官能基としてエポキシ環及び水酸基をそれぞれ微粒子の異なるドメインに持たせた異方性高分子の製造方法に関する。
In order to achieve the above object, according to the present invention, anisotropic composite polymer fine particles having two functionalities developed in the present invention are synthesized by soap-free emulsion polymerization and have a size of about 200 nm. Moreover, in this method, it is possible to produce fine particles having various combinations of functional groups.
That is, according to the present invention, in the first stage, glycidyl methacrylate (GMA) and divinylbenzene are used to synthesize seed polymer particles by soap-free emulsion polymerization while maintaining neutrality, and from the seed polymer particles, unreacted monomers and After removing the initiator and oligomer , the second stage is the addition of 2-mercaptoethanol and solvent to the seed polymer particles and styrene monomer, and soap-free seed emulsion polymerization in water, and epoxy ring as a functional group. And a method for producing an anisotropic polymer having hydroxyl groups in different domains of fine particles.
本発明において官能基Aとしては、エポキシ基が挙げられる。
本発明において官能基Bとしては、水酸基、カルボキシル基を挙げることができる。
本発明で用いるビニルモノマーXとしては、グリシジルメタクリレートがある。
本発明で用いるビニルモノマーYとしては、メチルメタクリレートが挙げられる。
本発明で用いるビニル架橋剤Zとしては、ジビニルベンゼン、エチレングリコールジメタクリレートが挙げられる。
本発明で用いるビニルモノマーPとしては、スチレン、メチルスチレンやエチルスチレン等のアルキルスチレン、α-メチルスチレン、β-メチルスチレン等が挙げられる。
本発明で用いる官能基Bを生じる化合物Sとしては、2-メルカプトエタノール、3-メルカプトプロピロン酸が挙げられる。
本発明で用いる添加溶媒は、トルエン、酢酸エチル等が挙げられる。
In the present invention, examples of the functional group A include an epoxy group.
In the present invention, examples of the functional group B include a hydroxyl group and a carboxyl group.
The vinyl monomer X used in the present invention includes glycidyl methacrylate.
Examples of the vinyl monomer Y used in the present invention include methyl methacrylate.
Examples of the vinyl crosslinking agent Z used in the present invention include divinylbenzene and ethylene glycol dimethacrylate.
Examples of the vinyl monomer P used in the present invention include styrene, alkyl styrene such as methyl styrene and ethyl styrene, α-methyl styrene, β-methyl styrene and the like.
Examples of the compound S generating the functional group B used in the present invention include 2-mercaptoethanol and 3-mercaptopropionic acid.
Examples of the additive solvent used in the present invention include toluene and ethyl acetate.
本発明の概要について説明する。
本発明で開発した種々の官能基を持つ異方性高分子微粒子はソープフリー乳化重合によって合成される。ソープフリー乳化重合法とは、モノマーと水の混合物に重合開始剤を導入し、ラテックス微粒子を作る方法であり、通常の乳化重合との違いは界面活性剤を使用しない。したがって、粒子表面の電荷が通常の乳化重合によって合成された微粒子の表面電荷よりも低く、また適度なサイズを持つので遠心分離で簡単に分離できる。ラテックス微粒子の特徴は、得られた微粒子の単分散性（サイズの均一性）が高いことである。
本発明で開発した微粒子は、２つの異なるドメインを持ち、各ドメインはそれぞれ異なるエポキシ環、Bを持ち、エポキシ環、Bそれぞれに異なる機能分子を結合させることができる。官能基数はモノマーの添加量によって制御できる。
その製造方法は２段階より成る。第１段目は、モノマーXあるいは２種類のモノマーX、Yと架橋剤Zを用いたソープフリー乳化重合によるシード粒子の合成であり、第２段目は、このシード粒子を用いたモノマーPあるいは２種類のモノマーP、Qのソープフリーシード乳化重合過程である。モノマーXは目的とするエポキシ環を有し、官能基Ｂは、微粒子製造中にポリマーＰに導入することができた。
本発明のエポキシ環及び水酸基をそれぞれ微粒子の異なるドメインに持たせた異方性高分子微粒子の典型的な製造方法を図１に示す。
The outline of the present invention will be described.
The anisotropic polymer fine particles having various functional groups developed in the present invention are synthesized by soap-free emulsion polymerization. The soap-free emulsion polymerization method is a method in which a polymerization initiator is introduced into a mixture of a monomer and water to form latex fine particles, and a difference from normal emulsion polymerization is that a surfactant is not used. Accordingly, the surface charge of the particles is lower than the surface charge of the fine particles synthesized by ordinary emulsion polymerization and has an appropriate size, so that the particles can be easily separated by centrifugation. The feature of latex fine particles is that the obtained fine particles have high monodispersity (size uniformity).
The fine particles developed in the present invention have two different domains, and each domain has a different epoxy ring and B, and different functional molecules can be bonded to the epoxy ring and B, respectively. The number of functional groups can be controlled by the amount of monomer added.
The manufacturing method consists of two stages. The first stage is synthesis of seed particles by soap-free emulsion polymerization using monomer X or two kinds of monomers X and Y and a crosslinking agent Z, and the second stage is monomer P or the monomer P using these seed particles. This is a soap-free seed emulsion polymerization process of two types of monomers P and Q. Monomer X had the desired epoxy ring, and functional group B could be introduced into polymer P during microparticle production.
FIG. 1 shows a typical method for producing anisotropic polymer fine particles having an epoxy ring and a hydroxyl group in different domains of the fine particles according to the present invention.
本願について実施例を用いてさらに詳しく説明するが、本発明はこれら実施例に限定されるものではない。
（実施例１）官能基Ａがエポキシ基、官能基Ｂが水酸基、モノマーＸがグリシジルメタクリレート（ＧＭＡ）、架橋剤Ｚがジビニルベンゼン（ＤＶＢ）、モノマーＰがスチレンの場合の実施例について示す。
（安定でより親水的なポリ（グリシジルメタクリレート−ジビニルベンゼン）シード粒子[Ｐ（ＧＭＡ−ＤＶＢ）]の調製）
グリシジルメタクリレート（ＧＭＡ）モノマーは水よりも密度が高く（１．０８ｇ／ｍｌ）、親水性も高いので、ＧＭＡの単独ソープフリー乳化重合では安定なラテックスを得ることは難しい。
安定なポリマーラテックスはジビニルベンゼン（ＤＢＶ）の添加により合成できた。その方法は以下の通りである。
ＧＭＡ １４ｇ／ＤＶＢ１ｇ／重合開始剤Ｖ−５０ ０．４５ｇ／水約２８５ｇを用い、２００ｒｐｍの回転速度、７０℃で１５時間重合を行った。モノマー変化率、粒子径はそれぞれ１００ｗｔ％、約１８０ｎｍである。開始剤Ｖ−５０の使用は重合中に反応液のｐＨを中性に保ち、ＧＭＡのエポキシド基の開環反応を防ぐために有効である。一方、過硫酸系の開始剤を用いると、重合反応に連れて反応液が酸性となり、７０℃でエポキシドが開環してしまう。
Although this application is demonstrated in more detail using an Example, this invention is not limited to these Examples.
(Example 1) An example in which the functional group A is an epoxy group, the functional group B is a hydroxyl group, the monomer X is glycidyl methacrylate (GMA), the crosslinking agent Z is divinylbenzene (DVB), and the monomer P is styrene is shown.
(Preparation of stable and more hydrophilic poly (glycidyl methacrylate-divinylbenzene) seed particles [P (GMA-DVB)])
Since glycidyl methacrylate (GMA) monomer has a higher density than water (1.08 g / ml) and high hydrophilicity, it is difficult to obtain a stable latex in GMA's single soap-free emulsion polymerization.
A stable polymer latex could be synthesized by the addition of divinylbenzene (DBV). The method is as follows.
Polymerization was carried out at a rotational speed of 200 rpm and 70 ° C. for 15 hours using 14 g of GMA / 1 g of DVB / 0.45 g of polymerization initiator V-50 / about 285 g of water. The monomer change rate and particle size are 100 wt% and about 180 nm, respectively. Use of the initiator V-50 is effective for keeping the pH of the reaction solution neutral during polymerization and preventing ring-opening reaction of the epoxide group of GMA. On the other hand, when a persulfuric acid-based initiator is used, the reaction solution becomes acidic along with the polymerization reaction, and the epoxide is ring-opened at 70 ° C.
（ソープフリーシード乳化重合による半球型ポリ（グリシジルメタクリレートｃジビニルベンゼン）とポリ（スチレン）複合微粒子［P(GMA-DVB)/P(St)］の調製）
上記で調製した親水性のポリ（グリシジルメタクリレート−ジビニルベンゼン）［P(GMA-DVB)］をシード粒子(seed particle)とし、スチレンモノマー、2-メルカプトエタノール、重合開始剤V-50、溶媒（トルエンあるいは酢酸エチル）及び水を添加し、ソープフリーシード乳化重合により二官能性のポリ（グリシジルメタクリレート−ジビニルベンゼン）とポリ（スチレン）複合微粒子［P(GMA-DVB)/P(St)］の調製を行った。P(GMA-DVB)シードは、使用する前にセルロース膜を用いて水道水及び純水でそれぞれ24時間の透析を行い、未反応のモノマーと開始剤、オリゴマーなどを除去した。P(GMA-DVB)/P(St)複合微粒子の調製方法を下表に示す。
P(GMA-DVB)シード粒子(seed particle)に、スチレンモノマー2 g/2-メルカプトエタノール0.02 g/重合開始剤(V-50) 0.04 g/トルエン2 g/純水 約130 gを添加し、70 ℃、200 rpmで24時間重合を行うことにより、目的とする微粒子が得られた。得られた複合微粒子の形態は透過型電子顕微鏡により観察した。その結果を図２に示す。試料は四酸化ルテニウムにより染色した。明るい部分は親水性のポリ（グリシジルメタクリレート−ジビニルベンゼン）、暗い部分はポリスチレンを示す。
(Preparation of hemispherical poly (glycidyl methacrylate c divinylbenzene) and poly (styrene) composite fine particles [P (GMA-DVB) / P (St)] by soap-free seed emulsion polymerization)
The hydrophilic poly (glycidyl methacrylate-divinylbenzene) [P (GMA-DVB)] prepared above was used as seed particles, and styrene monomer, 2-mercaptoethanol, polymerization initiator V-50, solvent (toluene) Or ethyl acetate) and water, and preparation of bifunctional poly (glycidyl methacrylate-divinylbenzene) and poly (styrene) composite fine particles [P (GMA-DVB) / P (St)] by soap-free seed emulsion polymerization Went. Before use, P (GMA-DVB) seeds were dialyzed for 24 hours with tap water and pure water using a cellulose membrane to remove unreacted monomers, initiators, oligomers, and the like. The preparation method of P (GMA-DVB) / P (St) composite fine particles is shown in the table below.
To P (GMA-DVB) seed particles, add styrene monomer 2 g / 2-mercaptoethanol 0.02 g / polymerization initiator (V-50) 0.04 g / toluene 2 g / pure water about 130 g, Polymerization was performed at 70 ° C. and 200 rpm for 24 hours to obtain the desired fine particles. The morphology of the obtained composite fine particles was observed with a transmission electron microscope. The result is shown in FIG. Samples were stained with ruthenium tetroxide. The bright part indicates hydrophilic poly (glycidyl methacrylate-divinylbenzene), and the dark part indicates polystyrene.
本発明は、二つの官能性を有する異方性複合高分子微粒子をソープフリー乳化重合によって合成され、約200 nmのサイズを持つ。また、本発明の方法を用いれば、エポキシ環及び水酸基について、種々の組み合わせの官能基を持つ微粒子の製造が可能である。
また、本発明のエポキシ環及び水酸基をそれぞれ微粒子の異なるドメインに持たせた異方性高分子微粒子は、例えば、生体物質と微粒子を組み合わせたナノマシンを構築するためには、微粒子の両側に異なる官能基を持たせて方向性を付与する必要があり、本微粒子はナノバイオテクノロジーにおける新たな要素技術として期待される。
In the present invention, anisotropic composite polymer fine particles having two functionalities are synthesized by soap-free emulsion polymerization and have a size of about 200 nm. Moreover, if the method of this invention is used, the microparticles | fine-particles which have a functional group of various combinations about an epoxy ring and a hydroxyl group are possible.
In addition, the anisotropic polymer fine particles having the epoxy ring and the hydroxyl group in different domains of the fine particles of the present invention, for example, have different functionalities on both sides of the fine particles in order to construct a nanomachine combining a biological material and fine particles. It is necessary to give directionality by providing a group, and this fine particle is expected as a new elemental technology in nanobiotechnology.
Claims (1)
In the first stage, glycidyl methacrylate (GMA) and divinylbenzene are used to synthesize seed polymer particles by soap-free emulsion polymerization while maintaining neutrality. Unreacted monomers, initiators and oligomers are synthesized from the seed polymer particles. After removal , the second stage is the seed polymer particles and styrene monomer, and 2-mercaptoethanol and solvent are added to perform soap-free seed emulsion polymerization in water. Of anisotropic polymer having different domains.
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