JP2019507730A - 生体適合性ナノ粒子及びその使用 - Google Patents
生体適合性ナノ粒子及びその使用 Download PDFInfo
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- JP2019507730A JP2019507730A JP2018537622A JP2018537622A JP2019507730A JP 2019507730 A JP2019507730 A JP 2019507730A JP 2018537622 A JP2018537622 A JP 2018537622A JP 2018537622 A JP2018537622 A JP 2018537622A JP 2019507730 A JP2019507730 A JP 2019507730A
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- nanoparticles
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Abstract
本発明の生体適合性ナノ粒子は、有機溶媒又は架橋剤の混入による人体内の毒性問題が発生する心配が全くなく、その製造工程の中で、別の精製工程が不要なため、短時間の電子ビーム照射だけで大量生産が可能であり、生産性の面でも極めて優れている。また、本発明のナノ粒子は、薬剤伝達体、薬学的組成物、造影剤組成物、腸癒着防止剤等、多方面で活用きるという点で極めて有用である。
Description
前記本発明の目的を達成するために、本発明は多糖、その誘導体及びポリエチレングリコールからなる群から選ばれたいずれか一つ以上の分子間架橋結合又は分子内架橋結合だけで形成されたことを特徴とする、生体適合性ナノ粒子を提供する。
(i)多糖又はその誘導体の分子間又は分子内架橋結合のみからなるナノ粒子、
(ii)多糖又はその誘導体がポリエチレングリコールと分子間架橋結合を形成して生成されたナノ粒子。
(a)水に多糖、その誘導体及びポリエチレングリコールからなる群から選ばれたいずれか一つ以上の物質を添加して溶液を製造する段階;及び(b)前記(a)段階で生成された溶液に電子ビームを照射して、前記物質を架橋結合させる段階。
治療用タンパク質や薬剤を生体内に伝達するために使用される殆どのナノ粒子は、有機溶媒を使用する乳剤蒸発法を介して製造されるので、製造から乾燥時までの製造工程が複雑で時間がかかり、有機溶媒の使用に伴うコストも増加し、また、有機溶媒の使用に伴う生体内問題を引き起こす可能性がある(TG Park、et al.、Biomacromolecules 8(2007)650-656; TG Park、et al.、Biomacromolecules 7(2006)1864-1870; DT Birnbaum、et al.、J. Control. Rel. 65(2000)375-387)。
(1)ヒアルロン酸の場合、0.5乃至7%、最も好ましくは1乃至5%;
(2)マンナンの場合、0.5乃至7%、最も好ましくは0.5乃至3%;
(3)β-シクロデキストリンの場合、0.5乃至3%、最も好ましくは1乃至3%;
(4)アルギン酸塩の場合、0.5乃至10%、最も好ましくは0.5乃至7%;
(5)フルクトオリゴ糖の場合、0.5乃至10%、最も好ましくは0.5乃至3%;
(6)イソマルトオリゴ糖の場合、3乃至10%、最も好ましくは3乃至7%;
(7)キトサンの場合、0.1乃至3%、最も好ましくは0.3乃至1%;
(8)フコイダンの場合、0.5乃至3%;及び
(9)カルボキシメチルデキストランの場合、3 乃至10%、最も好ましくは5乃至10%であってもよい。
(1)ヒアルロン酸の場合、30乃至230kGy;
(2)マンナンの場合、30乃至230kGy:
(3)β-シクロデキストリンの場合、10乃至100kGy、最も好ましくは30乃至70kGy
(4)アルギン酸塩の場合、10乃至230kGy
(5)フルクトオリゴ糖の場合、10乃至230kGy最も好ましくは150乃至230kGy;
(6)イソマルトオリゴ糖の場合、10乃至230kGy、最も好ましくは30乃至70kGy;
(7)フコイダンの場合、100乃至230kGy、最も好ましくは150乃至230kGy;
(8)キトサンの場合、10乃至230kGy、最も好ましくは150乃至230kGy;及び
(7)カルボキシメチル-デキストランの場合、100乃至230kGy、最も好ましくは150乃至230kGyであってもよい。
本発明の生体適合性ナノ粒子は、電子ビームを通じて多糖又はその誘導体分子間又は分子内架橋結合を誘導することにより製造されるので、有機溶媒又は架橋剤の混入による人体における毒性の問題が発生する心配が全くなく、その製造工程の中で、別の精製工程が不要な短時間の電子ビーム照射だけで大量生産が可能なため、生産性の面でも極めて優れている。また、本発明のナノ粒子は、薬剤伝達体、薬学的組成物、造影剤組成物又は腸癒着防止剤等、多方面で活用することができる点で極めて有用である。
電子ビーム加速器を用いた電子ビーム照射条件及び準備
電子ビームを照射する溶液について、多様な条件の電子ビーム線量を調査して実験を進めた。実験には、線形電子ビーム加速器を使用し、一定の速度で移動するコンベア上のサンプルにビーム電流及び照射時間を調節する形式で電子ビームを照射することにより、5kGy、10kGy、50kGy、100kGy、200kGy線量で電子ビームを照射した。電子ビームを照射する時間と照射量は電子ビーム照射時の温度条件、サンプルの濃度、照射される電子ビームのエネルギー強度等を考慮して、製造しようとするナノ粒子の大きさに応じて、当業者が適切に調節して選択することができる。
電子ビーム照射によるナノ粒子の製造
<2−1>カルボキシメチルデキストラン溶液及び電子ビーム照射条件
カルボキシメチル-デキストランを使用してナノ粒子を合成する実験を進めて、直流型電子ビーム加速器を使用して調査サンプルに電子ビームを照射するが、ビーム電流及び照射時間を調節する形式で電子ビーム照射条件が異なるようにした。
多様な濃度と多様な電子ビーム線量条件で実験を進め、製造されたナノゲルの粒子サイズをDLS(Dynamic light scattering)で確認した結果、10%の濃度のカルボキシメチルデキストラン溶液に200kGyの電子ビームを照射したときにのみ10nm程度の均一な大きさのナノ粒子が合成されるのを確認することができた(図2)。
前記カルボキシメチルデキストランナノ粒子以外に、他の多糖類又はオリゴ糖類を利用してナノ粒子を製造した。
1%、5%、10%(w/v%)濃度のヒアルロン酸溶液に、10kGy、50kGy、200kGyの電子ビームを照射して実験を行った。
1%、5%、10%(w/v%)濃度のマンナン溶液に、10kGy、50kGy、200kGyの電子ビームを照射して、実験を行った。
0.1%、1%、5%(w/v%)濃度のβ-シクロデキストリン溶液に、10kGy、50kGy、200kGyの電子ビームを照射して実験を行った。
1%、5%、10%(w/v%)濃度のアルギン酸塩溶液に、10kGy、50kGy、200kGyの電子ビームを照射して実験を行った。
1%、5%、10%、20%、30%、40%(w/v%)濃度のフルクトオリゴ糖溶液で、10kGy、50kGy、200kGyの電子ビームを照射して実験を行った。
その結果、図8に示した通り、1%、200kGyの条件で501nmの粒子の大きさを有するナノゲルが形成されることを確認した。一方、10%、10kGY条件及び10%、200kGY条件でも、粒子の大きさが均一ではなかったが、ナノ粒子が形成されることを確認した。それ以外の条件では粒子の大きさが極めて大きいか、又は複数個のピークが現れ、ナノ粒子が正常に生成されなかった。
1%、5%、10%、20%、30%、40%(w/v%)濃度のイソマルトオリゴ糖溶液で、10kGy、50kGy、200kGyの電子ビームを照射して、実験を行った。
その結果、図9に示した通り、5%で50kGyの条件で542nmの粒子の大きさを有するナノゲルが形成されることを確認した。一方、5%、10kGy条件及び10%、200kGy条件でも、粒子の大きさが均一ではなかったが、ナノ粒子が形成されることを確認した。それ以外の条件では粒子の大きさが極めて大きいか、又は複数個のピークが現れ、ナノ粒子が正常に生成されなかった。
0.5%、1%、5%(w/v%)濃度のフコイダン溶液で、10kGy、50kGy、200kGyの電子ビームを照射して、実験を行った。
0.5%、1%、5%(w/v%)濃度のキトサン溶液で、10kGy、50kGy、200kGyの電子ビームを照射して、実験を行った。
カルボキシメチルデキストランナノ粒子(CM-DNP)の物性評価-ゲル(gel)の特性
電子ビームを照射した試料は、3.5kDa-6kDaサイズの透析メンブレンチューブを使用して、5日間、1日に2回ずつ、NaClが含まれた水を交換しながら透析を行い、粒子の大きさに変化が発生するか否かをDSLで確認したが、透析工程中には粒子の大きさに変化がないことを確認した。以降、サンプルを凍結乾燥して照射された電子ビームによる架橋形成を通じて作られたナノ粒子収率を計算したところ、43%程度の収率を示し、合計8.2gのナノ粒子を得ることができた。
電子ビームを通じたポリエチレングリコール(PEG)が混合されたカルボキシメチルデキストランナノ粒子(CM-DNP)の合成
デキストラン以外に、既に臨床で使用されている有機分子を一緒に添加して、有機分子がデキストランナノ粒子形成及び物性に及ぼす影響を研究することを計画して、添加する有機分子として、既に臨床で広く使用されるPEGを使用して研究を進めた(図13)。
まず、PEG自体で、電子ビーム照射時に架橋形成を起こすか否かを確認するための実験を進め、PEGの濃度を変えて、複数のエネルギー強度で電子ビームを照射する実験を行った。実験には、6kDaのPEGを使用し、水に溶解して1%、5%、10%(w/v)濃度の溶液を調製し、電子ビームのエネルギーの強度は10kGy、30kGy、50kGy、100kGy、200kGyで照射した。エネルギーの強度が増加して30kGy以上になると、サンプルの色が濁り、バルクゲル(bulkgel)が作られる傾向を確認することができ、PEGの濃度が低いとき、より大きいナノゲルが作られる傾向性を確認できた(図14)。
PEG溶液に電子ビームを照射する際に架橋を形成する事実を直接確認することができ、PEGとカルボキシメチルデキストランを一緒に混合して電子ビームを照射し、架橋がよく形成されたか、また、カルボキシメチルデキストランだけを利用して製作したナノ粒子とは異なる大きさ及び物性を有するナノ粒子が作られるかを確認する実験を行った。
前記の通り、1%のPEGを10%のカルボキシメチルデキストランと一緒に混合して、10、50、200kGyのエネルギー強度において電子ビームを照射した場合にも、ナノ粒子がよく作られる結果を得た。その後、どの程度の収率でナノ粒子が形成されたかを確認するために、サンプルを3.5kDa-5kDaサイズの透析メンブレンチューブを使用して、5日間、一日に2回ずつNaClが含まれた水を交換しながら透析を進め、その後、それぞれのサンプルを凍結乾燥して、照射された電子ビームによる架橋形成を介して作られたナノ粒子の収率を計算した結果、各エネルギー条件でのサンプルは全て24〜36%程度の収率を示した。
電子ビーム照射によるPEG及びCM-DNP混合ナノ粒子の製造が、電子ビーム照射によるPEGだけの架橋によるナノ粒子の形成の結果でであるかを確認するために(つまり、生成されたナノ粒子がPEGとカルボキシメチルデキストランの分子間架橋結合によって形成されたかどうかを確認するために)、前記実施例4-3で得られたCM-DNPに対するNMR分析を行うことにより、作られたナノ粒子にPEGとデキストランが全て存在するか、そしてPEG又はデキストランに対するピークは確認できないかを確認する実験を行った。
カルボキシメチルデキストランナノ粒子のキレートコンジュゲーション及びCu-64放射性標識
合成したCM-DNPを使用して多様なキレートをコンジュゲーションさせて、Cu-64で放射性標識する実験を行った。ナノ粒子にCu-64を利用した標識実験を進めるために、まず、ナノ粒子にキレートをコンジュゲーションさせ、DOTA-Bn-p-NH2、DOTA-GA-NH2、TE2A-NH2の3つのキレートを使用して行った。
放射性ヨウ素を利用したカルボキシメチルデキストランナノ粒子の標識
放射性核種標識を通じたCM-DNP基盤核医学映像造影剤の開発は、Cu-64以外に放射性ヨウ素を利用しても進行しており、放射線ヨウ素標識法として広く活用されている補欠分子族(prosthetic group)であるBolton-Hunter試薬を使用して行い、放射性ヨウ素では、半減期が8日と長く、価格も比較的安いI-131を購入して実験を行った(図21)。
ドキソルビシンが結合されたカルボキシメチルデキストラン基盤のナノ粒子の合成
<7-1>ナノ粒子へのドキソルビシンの結合
デキストランナノ粒子の抗癌剤として広く使用されているドキソルビシン(doxorubicin)を結合させる実験を行った。まず、CM-DNPを使用して実験を進め、10nmサイズのCM-DNP 15mgを3mLの蒸留水(D.W.)に溶解した後、NaOHを使用してpHを8に合わせ、ドキソルビシン(1mg/mL)を入れて光を遮断し、常温で一日攪拌させる方法で反応を行った。反応後、16000×gで90分間遠心分離を行うと、ドキソルビシンが結合されたデキストランナノ粒子は、底に沈殿を形成するようになり、上澄み液と沈殿を分離した(図23)。
ドキソルビシンが結合されたカルボキシメチルデキストランナノ粒子(CM-DNP)とPEG及びカルボキシメチルデキストランの混合ナノ粒子(PEG-DNP)を使用して薬剤が放出される速度はどうであるかを確認する流出実験を行った。10mgの同じ量のナノ粒子を使用して、pHが7.4のPBSでドキソルビシンが放出される速度を確認するために、複数の時点に合わせてサンプルを得て遠心分離を行い、上澄み液に存在するドキソルビシンの量を確認することにより、ナノ粒子から放出されたドキソルビシンの量を確認した。その結果、6日間にわたって、CM-DNPの場合には9.16%でドキソルビシンが抜け出て、PEG-DNPの場合には18.4%でナノ粒子に結合されたドキソルビシンが、かなり徐々に連続的に抜け出ることを確認することができた(図24)。
ドキソルビシンが結合されたデキストラン基盤のナノ粒子が、腫瘍の成長を阻害することができる治療剤として使用できるのか、その能力を比較確認する実験を行った。実験に使用された腫瘍モデルには、大腸癌マウスの腫瘍モデル(CT26 tumor model)を使用し、5x106個の細胞を、マウスの脇腹に注射した後、10日後に腫瘍が発生することを確認した後、実験に使用した。PBSを処理するブランク(Blank)グループ、遊離ドキソルビシンを処理するグループ(free DOX)、ドキソルビシンが結合されたPEG-DNPを処理するグループ(DOX@PEG-DNP)に区分した後、実験を始めた。各グループに該当するマウスの数は3匹であり、それぞれの投与物質を二日間隔で、計3回、静脈注射を通じてマウスの腫瘍モデルに処理し、この時、遊離ドキソルビシンを処理するグループ、ドキソルビシンが結合されたPEG-DNP(DOX@PEG-DNP)グループに処理されるドキソルビシンの量は200μgであった。
Claims (13)
- 多糖、その誘導体及びポリエチレングリコールからなる群から選ばれたいずれか一つ以上の分子間架橋結合又は分子内架橋結合だけで形成されたことを特徴とする生体適合性ナノ粒子。
- 前記生体適合性ナノ粒子は、多糖又はその誘導体の分子間架橋結合又は分子内架橋結合だけで形成されたことを特徴とする請求項1記載のナノ粒子。
- 前記生体適合性ナノ粒子は、多糖又はその誘導体がポリエチレングリコールと分子間架橋結合によって形成されたことを特徴とする請求項1記載のナノ粒子。
- 前記多糖は、キトサン、ゼラチン、コラーゲン、マンナン、デキストラン硫酸、α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリン、フルクトオリゴ糖、イソマルトオリゴ糖、イヌリン、ヒアルロン酸、アルギン酸、グリコーゲン、アミロース、カルボキシメチルデキストラン、ベータグルカン、ヒドロキシエチルセルロース、カルボキシメチルセルロース、フコイダン及びコンドロイチンからなる群から選ばれた一つ以上であることを特徴とする請求項1記載のナノ粒子。
- 前記ナノ粒子は、(a)水に多糖、その誘導体及びポリエチレングリコールからなる群から選ばれたいずれか一つ以上の物質を添加して溶液を製造する段階;及び(b)前記(a)段階で生成された溶液に電子ビームを照射して、前記の物質を架橋結合させる段階を含む方法によって製造されたことを特徴とする請求項1記載のナノ粒子。
- 前記方法は、架橋剤及び有機溶媒を使用しないことを特徴とする請求項5記載のナノ粒子。
- 前記電子ビームの強度は、5乃至250kGyの照射量で照射されることを特徴とする請求項3記載のナノ粒子。
- 請求項1乃至請求項7のいずれか一つの項のナノ粒子に核酸、タンパク質、多糖類及び薬剤からなる群から選ばれたいずれか一つ以上が結合されたことを特徴とする薬剤伝達体。
- 前記薬剤は、抗生剤、抗癌剤、鎮痛剤、消炎剤、鎮咳剤、去痰剤、鎮静剤、筋肉弛緩剤、癲癇治療剤、潰瘍治療剤、抗うつ剤、抗アレルギー剤、強心剤、抗不整脈剤、血管拡張剤、降圧利尿剤、糖尿病治療薬、凝固防止剤、止血剤、抗結節剤、ホルモン剤、及びこれらの組み合わせからなる群から選ばれた一つ以上であることを特徴とする請求項8記載の薬剤伝達体。
- 前記薬剤伝達体に放射性同位元素、有機蛍光物質、無機物質の量子ドット、磁気共鳴画像造影剤、コンピュータ断層撮影造影剤、陽電子断層撮影造影剤、超音波造影剤及び蛍光造影剤からなる群から選ばれた一つ以上の標識物質が標識されていることを特徴とする請求項8記載の薬剤伝達体。
- 請求項8の薬剤伝達体を有効成分として含む薬学的組成物。
- 請求項1乃至請求項7のいずれか一つの項のナノ粒子に放射性同位元素、有機蛍光物質、無機物質の量子ドット、磁気共鳴画像造影剤、コンピュータ断層撮影造影剤、陽電子断層撮影造影剤、超音波造影剤及び蛍光造影剤からなる群から選ばれた一つ以上の標識物質を標識したナノ粒子及び薬学的に許容される担体又は添加剤を含む造影剤組成物。
- (a)水に多糖、その誘導体及びポリエチレングリコールからなる群から選ばれたいずれか一つ以上の物質を添加して溶液を製造する段階;及び(b)前記(a)段階で生成された溶液に電子ビームを照射して、前記物質を架橋結合させる段階を含む、生体適合性ナノ粒子の製造方法。
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