JP2019163229A - ホウ素同位体を含有するナノシリカ粒子のホウ素中性子捕捉剤 - Google Patents
ホウ素同位体を含有するナノシリカ粒子のホウ素中性子捕捉剤 Download PDFInfo
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Abstract
【課題】腫瘍細胞、癌細胞への特異的な結合性に優れ、簡便、簡易に製造できるオリゴ糖、オリゴペプチドをホウ素同位体ナノシリカ粒子に化学結合することで、腫瘍細胞、癌細胞への特異的な集積性に優れた薬物輸送（送達）を材料として中性子捕捉療法（ＢＮＣＴ）に提供する。【解決手段】ナノシリカ粒子に先ずホウ素同位体を化学結合させ、又種々の腫瘍細胞、癌細胞への選択性、集積性を考慮しオリゴ糖、オリゴペプチド更に結合させＢＮＣＴができる。【選択図】図１
Description
本発明はアミノ酸、アミノ糖、オリゴペプチドを用いて細胞へ特位的に高集積せるホウ素中性子捕捉療法（ＢＮＣＴ）用薬物を安定ナノシリカに化学結合し、薬物（送達）システム（Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ：（ＤＤＳ）に特化したＢＮＣＴ薬剤材料に関るものである。
ホウ素中性子捕捉療法（ＢＮＣＴ）は、ホウ素同位体化合物を癌細胞、悪性腫瘍細へ取り込ませ、熱中性子線を照射して細胞内でアルファ線により正常細胞を障害せず選択的に癌細胞を破壊する療法である。
この方法ではホウ素同位体化合物を癌細胞、悪性腫瘍細胞へより選択的に送達且つ集積させる事が、治療効果上最も重要である。
この方法ではホウ素同位体化合物を癌細胞、悪性腫瘍細胞へより選択的に送達且つ集積させる事が、治療効果上最も重要である。
理論上ＢＮＣＴではホウ素同位体化合物を癌細胞に選択的に集積できれば正常細胞に影響を与えることなく、癌細胞、悪性腫瘍細胞を殺すことができる。しかしながら現在使用されているメルカプトウンデカハロデカボレート（ＢＳＨ）は細胞膜透過性がなく、細胞と細胞間の細胞組織間局在しても腫瘍殺傷が充分でない、またｐ−ボロノフェニルアラニン（ｐ−ＢＰＡ）剤は生体内での可溶性が極めて乏しい為、溶解度を向上させるのに過剰のフルクトースを加えあるいはポリオールを添加するという方法が成されているが、溶解性向上には難が有り、現状では一度の治療に点滴静注で２０〜３０ｇ／６０ｋｇ注入されており、患者に大きな負担になっている。
より癌細胞に集積させる試みとして、体内に送達（ＤＤＳできる材料としてポリエチレングリコールにエンペロープベクターと組み合わせホウ素化合物を内包させ、使用することが報告されているが（特許文献１）、実用的には難がある。他方、ホウ素化合物を含む細胞膜透過性型ホウ素ペプチド類の方法も報告されているが、（特許文献２）ＤＤＳの賦形剤担体に従来のカプセル、ゲル、エマルジョンの形で注射による投与が記されているが、治療に有効な腫瘍細胞内蓄積量である１０−２５ｐｐｍを確保する投与量は０．０５−１．０ｇ／ｋｇであり、従来から使用されている投与量であり、患者に対する身体的、経済的負担は軽減されていない。この現状からｐ−ボロノフェニルアラニン（ｐ−ＢＰＡ）とＢＳＨの薬剤で全ての癌細に対しホウ素中性子捕捉療法（ＢＮＣＴ）に適応するには困難である。
本発明は癌のアミノ酸トランスポーター（非特許文献３）についての鋭意研究により癌、腫瘍細胞に高発現すアミ酸トランスポーター（輸送体）で、タンパク質ＬＡＣＴ１，ＬＡＴ３，ＡＴＢ０．＋，ＡＳＣＴ２は腫瘍選択的な発現と広い基質選性を示すことから、これら４種のタンパク質に着目し、輸送基質アミノ酸と関連性の高いオリゴペプチド（請求項５）を合成し、ホウ素同位体（１０Ｂ）が結合可能ナノシリカ粒子にオリゴペプチド配列を導入し、オリゴペプチドホウ素同位体（１０Ｂ）化合物を得ることができる。
他方、癌細胞、腫瘍細胞では、Ｗａｒｂｕｒｇ効果により好気的解糖が増加し、さらにグルコースの量が増加する、グルコ−ストランスポーターの発現が高度に増加するこれを利用してＮａ＋グルコーストランスポーターの基質であるグルコ−ス類以のグルコサミン、マノサミン、ガラクトサミン、ノイラミン酸などを含有するアミノオリゴ糖ホウ素同位（１０Ｂ）とし、癌細胞、腫瘍細胞に送達される。
即ち、癌細胞、悪性腫瘍細胞深部へ集積選択性、集積濃度及び患者への投与に於いて選択的に利用能での集積選択、薬物輸送性（送達）を持つホウ素同位体化合物は見受けられない。
Ａｍ Ｊ Ｃａｎｃｅｒ Ｒｅｓ．２０１５，５（４）：１２８１−１２９４
（１９７６）Ｐｒｏｃ．Ｎａｔｌ．Ａｃａｄ．Ｓｃｉ．ＵＳＡ，７３，３９６−４００
Ｐｈａｒｍａｃｏｌ Ｔｈｅｒ．２００９；１２１：２９−４０
本発明は前記の課題を解決するためになされたもので、アミノオリゴ糖、基質アミノ酸、オリゴペプチドからなるホウ素同位体化合物をナノシリカ粒子に化学結合し、癌細胞、腫瘍細胞への特異的な集積性に特化した薬物送達（ＤＤＳ）材料が、安定ナノシリカを母体とする薬剤をホウ素中性子捕捉療法（ＢＮＣＴ）に提供することを目的とする。
本発明に使用される多孔性球状シリカ粒子径が５ｎｍ−２０００ｎｍで、その表面積は１００−３００２／ｇの球状ナノシリカ粒子を呈する、この大きい表面積に反応性官能基を化学修飾し、この修飾基にホウ素同位体（１０Ｂ）を導入したナノシリカ粒子にオリゴ糖、基質アミノ酸、オリゴペプチドを化学結合し、ホウ素同位体（１０Ｂ）化合物を製造することを提供する。一つ様態では、本発明の基本骨格であるホウ素同位体結合ナノシリカ粒子は次なるものを提供する。
一般式
一般式
別の様態では、本発明は次なるものを提供する。
一般式
一般式
本発明のナノシリカ粒子を ＤＤＳ オリゴペプチドホウ素同位体は癌細胞悪性腫細胞深部へ集積選択的に且つ高濃度、効率的に細胞内に局在させることができる。オリゴ糖結合型ホウ素同位体は細胞膜周辺に選択的に輸送され、極めて高い腫瘍殺傷効果がより促進される。
本発明の薬物輸送（送達）（Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ，ＤＤＳ材料の多孔性球状ナシリカで、この粒子径は５ｎｍ−２０００ｎｍのシリカを使用するが特に限定されるもではないが粒子径は５ｎｍ−５０ｎｍが好ましい、静脈内投与する癌、腫瘍組織内で新生血管は壁が粗いので、血管壁を通過するに従って粒子が高濃度に腫瘍内に集積る。更に、本発明に使用されるナノシリカの表面積は１００〜３００ｍ２／ｇの大きい比表面積を持つため高濃度にオリゴ糖、アミノ酸、オリゴペプチドを化学結合することができ、その代表例を実施例に示す。
基本骨格アミノフェニルホウ素酸同位体結合コハク酸無水物修飾ナノシリカ粒子の合成。図１〔化１〕。コハク酸無水物修飾ナノシリカ粒子合成は、ナノシリカＳｉＯ２：１０．０ｇ（粒径１０ｎｍこの粒子径には限定されない）を採り１００ｍＬアセトンで洗浄し、次に１００ｍＬのイソプロパノールで洗浄し更に脱イオン水で最終洗浄をしてマイクロウェーブ処理をして、窒素気流下で乾燥する。このナノリカ粒子に、２−［３−（トリエトキシシリル）プロピル］コハク酸無水物（３−ｔｒｉｅｔｈｏｘｙｓｉｌｙｌｐｒｏｐｙｌ ｓｕｃｃｉｎｉｃ ａｎｈｙｄｒｉｄｅ）の０．３−０．９ｍｏｌをエタノール溶液１００ｍＬ（ｍｏｌ濃度には特に限定されない）を添加し１２０℃、１．５時間反応させ反応後イソプロパノール１００−１５０ｍＬで洗浄し減圧乾燥して化学修飾ナノシリカ粒子を得た。化学修飾ナノシリカ粒子２．０ｇを採り、水溶液１０ｍＬにホウ素同位体（１０Ｂ）４−アミノフェニルホウ素酸２−２００ｍｇを添加することが好ましく、更に４０−１２０ｍｇであることが好ましい。反応は０−６０℃で良いが好ましくは２０−３０℃が好ましいが限定されるものではない。得られた収率は７０−８０％である。構造式は図１に示した。
アミノフェニルホウ素同位体結合オリゴ糖ナノシカ粒子の合成。（代表例）
１０ｍＬの水にオリゴグルコサミンが５−１００ｍｍｏｌになるように調製し、実施例１で得られた化合物１．０ｇを添加する。反応は５−４０℃、時間は０．５−１２０分であるが温度、時間は特に限定されない。反応ろ過後、ＨＥＰＥＳ緩衝液（４−（２−ｈｙｄｒｏｘｙｅｔｈｙｌ）−１−ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｓｕｌｕｆｏｎｎｉｃ ａｃｉｄ）１０ｍＬを加え５−１２０分撹拌し、ろ過後エタノールで洗浄して目的物質が得られた。
１０ｍＬの水にオリゴグルコサミンが５−１００ｍｍｏｌになるように調製し、実施例１で得られた化合物１．０ｇを添加する。反応は５−４０℃、時間は０．５−１２０分であるが温度、時間は特に限定されない。反応ろ過後、ＨＥＰＥＳ緩衝液（４−（２−ｈｙｄｒｏｘｙｅｔｈｙｌ）−１−ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｓｕｌｕｆｏｎｎｉｃ ａｃｉｄ）１０ｍＬを加え５−１２０分撹拌し、ろ過後エタノールで洗浄して目的物質が得られた。
アミノフェニルホウ素体（１０Ｂ）オリゴペプチドナノシリカ粒子の合成。
代表例。
Ｓｅｒ−Ｔｒｐ−Ｌｙｓ−Ｐｒｏ−Ｌｅｕ−Ａｒｇのオリゴペプチド３−１０ｍｇを採り、ＭＥＳ緩衝液１０ｍＬを添加し撹拌しながら実施例１で得られた化合物１．０ｇを更に添加し、０．５−１２０分反応する、好ましくは１−３０分で行うが特に限定されない、温度は３−６０℃で反応後過剰の水で洗浄し更に過剰のアセトン洗浄後真空下で乾燥させアミノフェニルホウ素同位体結合オリゴペプチドシリカ粒子を得た。
代表例。
Ｓｅｒ−Ｔｒｐ−Ｌｙｓ−Ｐｒｏ−Ｌｅｕ−Ａｒｇのオリゴペプチド３−１０ｍｇを採り、ＭＥＳ緩衝液１０ｍＬを添加し撹拌しながら実施例１で得られた化合物１．０ｇを更に添加し、０．５−１２０分反応する、好ましくは１−３０分で行うが特に限定されない、温度は３−６０℃で反応後過剰の水で洗浄し更に過剰のアセトン洗浄後真空下で乾燥させアミノフェニルホウ素同位体結合オリゴペプチドシリカ粒子を得た。
Claims (6)
- 多孔性ナノシリカ粒子で粒子径が５〜２０００ナノメータの多孔性球状ナノシリカ粒子に化学修飾させた反性官能基利用してホウ素同位体を持つ化合物を合成し、ホウ素中性子捕捉療法（ＢＮＣＴ）に利用し、薬物輸送（送達）：［Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ，（ＤＤＳ）］に特化した材料。
- 癌細胞で発現上昇するアミノ酸トランスポーターの輸送基質類を請求項１のナノシリカ粒子にアミノ酸ホウ素同位体としＤＤＳ化したＢＮＣＴに利用する基質アミノ酸ホウ素同位体化合物。
- フェニルホウ素酸ホウ素同位体を含有するアミノ酸、オリゴペプド構成ナノシリカ粒子の合成、上記請求項１のＢＮＣＴ，ＤＤＳに利する。
- フェニルホウ素酸ホウ素同位体を含有するオリゴ糖構成シリカ粒子の合成。
- 請求項１、３に関する構成オリゴペプチドとしては膜透過性ペプチド下記オリゴペプチド配列が
Ｓｅｒ−Ｌｅｕ−Ｉｌｅ−Ｖａｌ−Ｍｅｔ−Ｔｈｒ−Ｃｙｓ−Ａｒｇ，
Ｓｅｒ−Ｌｅｓ−Ｐｒｏ−Ｔｈｒ，
Ｔｙｒ−Ｔｙｒ−Ａｒｇ−Ａｌａ−Ｔｙｒ，
Ｔｙｒ−Ｔｙｒ−Ｐｒｏ−Ａｒｇ−Ａｌａ−Ｔｙｒ，
Ｓｅｒ−Ｔｒｐ−Ｌｙｓ−Ｐｒｏ−Ｌｕｅ−Ａｒｇ、
Ｔｙｒ−Ｓｅｒ−Ｌｙｓ−Ｃｙｓ−Ｈｉｓであることを特徴とするオリゴペプチド。 - 請求項４に記載のオリゴ糖は構成するアミノ糖としてグルコサミン、マンオサミン、ガラクトサミン、ノイラミン酸を含有するホウ素同位体ナノシリカ粒子である。
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| CN113144205B (zh) * | 2021-04-22 | 2022-05-20 | 浙江大学 | 聚合物混合介孔二氧化硅的葡萄糖响应材料及其制备方法 |
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