JP6548060B2 - ホウ素中性子捕捉療法のための新規bsh複合体 - Google Patents
ホウ素中性子捕捉療法のための新規bsh複合体 Download PDFInfo
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- JP6548060B2 JP6548060B2 JP2018553029A JP2018553029A JP6548060B2 JP 6548060 B2 JP6548060 B2 JP 6548060B2 JP 2018553029 A JP2018553029 A JP 2018553029A JP 2018553029 A JP2018553029 A JP 2018553029A JP 6548060 B2 JP6548060 B2 JP 6548060B2
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Description
(1)水溶液中で疎水性アミノ酸残基と塩基性アミノ酸残基を含むペプチドとメルカプトウンデカハイドロデカボレート(BSH)を混合することを特徴とする、上記ペプチドとBSHを含む複合体の製造方法;
(2)上記ペプチド1モルに対してBSH1モル〜1000モルの割合で混合する、(1)記載の方法;
(3)複合体の直径を調節することをさらに特徴とする、(1)または(2)記載の方法;
(4)複合体が直径約20nm〜約200nmの球状である(1)〜(3)のいずれかに記載の方法;
(5)上記ペプチドが下式(1):
(6)Xがアラニンであり、mが6であり、Zがリジン、アルギニン、ホモアルギニン、オルニチン、2,7−ジアミノヘプタン酸、2,4−ジアミノブタン酸、または2−アミノ−4−グアニジノブタン酸であり、nが1である、(5)記載の方法;
(7)Xがアラニンであり、mが6であり、Zがリジンまたはアルギニンであり、nが1である、(6)記載の方法;
(8)疎水性アミノ酸残基と塩基性アミノ酸残基を含むペプチドとBSHを含む複合体;
(9)直径が約20nm〜約200nmの球形である(8)記載の複合体;
(10)上記ペプチドが下式(1):
(11)Xがアラニンであり、mが6であり、Zがリジン、アルギニン、ホモアルギニン、オルニチン、2,7−ジアミノヘプタン酸、2,4−ジアミノブタン酸、または2−アミノ−4−グアニジノブタン酸であり、nが1である、(10)記載の複合体;
(12)Xがアラニンであり、mが6であり、Zがリジンまたはアルギニンであり、nが1である、(11)記載の複合体;
(13)(8)〜(12)のいずれかに記載の複合体を含む、がんのホウ素中性子捕捉療法のための薬剤。
(14)(8)〜(12)のいずれかに記載の複合体をがん患者に投与し、該がん患者に中性子線を照射することを含む、がんの治療方法。
(15)がんのホウ素中性子捕捉療法に用いられる、(8)〜(12)のいずれかに記載の複合体。
(16)がんのホウ素中性子捕捉療法のための薬剤を製造するための、(8)〜(12)のいずれかに記載の複合体の使用。
常法により合成したA6K(TFA塩)の凍結乾燥品をMilli−Q水に溶解し(濃度1000μM)、HClにてpHを4に調節した。10分間超音波処理を行い、NaOHにてpHを7とした。得られた溶液をポアサイズ100nmのエクストルーダーに通し、Milli−Q水で濃度50μMに希釈した。そのうち1.2μLを試料として分取し、走査型電子顕微鏡で観察した。電子顕微鏡像を図1に示す。A6K(TFA塩)はチューブ状の形態を有していた。上と同様にして調製した濃度200μMのA6K(TFA塩)溶液をDLS試験に供した。そのチャートを図2に示す。このチャートにおいて2峰性のピークが観察され、A6K(TFA塩)がチューブ状であることが示された。
上記(1)と同様にしてA6K(TFA塩)のMilli−Q水溶液(10μM)を得た。BSHを添加し(濃度1000μM)、室温で3分間撹拌混合し、得られた複合体を走査型電子顕微鏡にて観察した。結果を図3に示す。複合体は角状突起を有する球形(金平糖状)であり、大部分のものが直径約20nm〜約150nmの範囲であった。上と同様にしてA6K(TFA塩)(200μM)とBSH(2000μM)を混合して得られた複合体をDLS試験に供した。結果を図4に示す。近接する2峰性のピークが観察され、複合体がほぼ球形であることが示された。これらの結果は、得られた複合体の形状やサイズが、BSHをがん細胞内に送達するのに最適なものであることを示す。
A6K(TFA塩)およびBSHを上記(2)に記載した方法と同様の方法で撹拌混合して複合体を調製した。混合時間を10分、30分、180分とした。得られた複合体をPBS(pH7.1−7.3)にて希釈し、シャーレ中のグリオーマセルラインU87ΔEGFRに添加した。複合体の添加量は、A6K(TFA塩)の最終濃度が50μM、BSHの最終濃度が5000μMとなるようにした。複合体とともに37℃で3時間、12時間、24時間培養して得られた各細胞試料をICP−AESに供して細胞中のホウ素濃度を測定した。結果を図5に示す。いずれの条件下でも、複合体は細胞に取り込まれた。12時間および24時間の培養で、多量の複合体ががん細胞内に取り込まれることがわかった。培養時間は12時間で十分であった。撹拌混合時間はがん細胞内への複合体の送達量に対してあまり影響しなかった。撹拌混合時間は10分で十分であった。培養時間の延長により、細胞内BSH量の増加が示された。これにより、本複合体にはがん細胞内滞留性があることが確認された。
常法により合成したA6R(TFA塩)の凍結乾燥品をMilli−Q水に溶解し(濃度1000μM)、HClにてpHを4に調節した。10分間超音波処理を行い、NaOHにてpHを7とした。得られた溶液をMilli−Q水で濃度10μMに希釈した。このようにして得られたA6R(TFA塩)のMilli−Q水溶液(10μM)にBSHを添加し(濃度1000μM)、室温で3分間撹拌混合および10分超音波処理した後、ポアサイズ50nmのエクストルーダーに通して複合体を得た。得られた複合体を走査型電子顕微鏡にて観察した。結果を図6に示す。複合体は球形であり、大部分のものが直径約100nm〜約200nmの範囲であった。また、A6R(TFA塩)とBSHのモル比を1:1(20μM:20μM)として上記と同様にして複合体を調製した場合は、複合体のサイズが小さくなり、直径約50nm〜約150nmのものが多く、直径20nm前後のものも見られた。
A6R(TFA塩)およびBSHを上記(1)に記載した方法と同様の方法で撹拌混合して複合体を調製した。得られた複合体をPBS(pH7.1−7.3)にて希釈し、シャーレ中のグリオーマセルラインU87ΔEGFRに添加した。複合体の添加量は、図7および図8に示すA6R(TFA塩)とBSHの最終濃度となるようにした。複合体とともに37℃で6時間、12時間、24時間培養して得られた各細胞試料をICP−AESに供して細胞中のホウ素濃度を測定した。結果を図7および図8に示す。図7に示すように、A6R(TFA塩)とBSHの複合体は濃度依存的に細胞内に導入されることが確認された。また図8に示すように、培養は6時間で十分であった。12時間培養後、24時間培養後にもかなりの複合体が細胞に残存しており、本複合体にはがん細胞内滞留性があることが確認された。
(1)実験方法
U87ΔEFGR細胞を24ウェルプレート(Falcon製)内、ガラスプレート(PLLコート、12mm:IWAKI製)に播種し(3000個/ウェル、各ウェルに1ml)、CO2インキュベータ内、37℃で24時間培養後、実施例1の(2)と同様の方法で調製したA6K(TFA塩)とBSHを含む複合体を添加した。複合体の添加量は、A6K(TFA塩)の最終濃度が20μM、BSHの最終濃度が2000μMとなるようにした。複合体を添加して90分培養した後、細胞培養液を除去して、室温下PBS(Phosphate Buffered Saline)を1ml加え5分間静置後除去し、3回(各1ml、5分間)洗浄した。次いで、パラフォルムアルデヒド(PFA)溶液(4%、1ml)を加え、30分間インキュベートして固定した。これをPBSで3回洗浄(同上)した。次いで、Triton(0.25%)を含むPBS溶液(1ml)を加えて、37℃で15分間インキュベートした。PBSで3回洗浄(同上)した。ついで、BSA(牛血清アルブミン、1%)を含むPBS溶液(1ml)を加え、室温下1時間インキュベートした。その後、PBSで3回洗浄(同上)した。
染色画像を図9に示す。細胞質のみならず、核内にも染色が見られたことから、本発明の複合体は、細胞内だけでなく核内にまで移行することが示された。これらの結果から、本発明の複合体を含む細胞に中性子線を照射することで、当該細胞を選択的に破壊することができ、効率的ながん治療が可能であるといえる。
常法により合成したA6K(塩酸塩)の凍結乾燥品をMilli−Q水に溶解し、10分間超音波処理を行った。得られたA6K(塩酸塩)のMilli−Q水溶液の一部を分取し、走査型電子顕微鏡および透過型電子顕微鏡にて観察した。A6K(塩酸塩)はチューブ状の形態を有していた。A6K(塩酸塩)のMilli−Q水溶液にBSHを添加し、室温で3分間撹拌混合および10分超音波処理した。A6K(塩酸塩)とBSHのモル比を1:10(166μM:1.66mM)および1:25(166μM:4.15mM)とした場合に、球形の複合体が得られた。得られた複合体の大部分のものは直径100nm前後であった。A6K(塩酸塩)とBSHのモル比を1対10とした場合の複合体の走査型電子顕微鏡写真を図10に示す。
実施例2(2)に記載したのと同様の手順にて、上記(1)で得られたA6K(塩酸塩)とBSHを含む複合体(A6K(塩酸塩):BSHのモル比1:10)をグリオーマセルラインU87ΔEGFRに添加した。複合体の添加量は、図11に示すA6K(塩酸塩)とBSHの最終濃度となるようにした。複合体とともに37℃で24時間培養後、ICP−AESにて細胞中のホウ素濃度を測定した。図11に示すように、BSH(2mM)のみを添加した群では細胞内ホウ素濃度が595.2±105.1ng/細胞106個であったのに対し、A6K(塩酸塩)(200μM)とBSH(2mM)の複合体を添加した群では細胞内ホウ素濃度は11262±3890ng/細胞106個であった。これらの結果から、本複合体はがん細胞内に特異的に取り込まれ、24時間培養後にも高濃度の複合体が細胞内に滞留していることがわかった。
実施例3(1)に記載したのと同様の手順にて、細胞内に送達されたA6K(塩酸塩)とBSHの複合体の細胞内分布について調べた。BSH特異抗体で染色したがん細胞の顕微鏡像を図12に示す。これらの結果から、A6K(塩酸塩)/BSH複合体 40μM/400μM投与群および200μM/400μM投与群の両方においてホウ素薬剤BSHの細胞内導入が確認された。本発明の複合体を含む細胞に中性子線を照射することで、当該細胞を選択的に破壊することができ、効率的ながん治療が可能であるといえる。
これらの脳腫瘍モデル動物に対し実施例4(1)記載の化合物(A6K/BSH)を尾静脈から1回投与し、12時間後にこの脳腫瘍組織を摘出して抗BSHマウスモノクローン抗体で免疫組織染色し、緑色蛍光によってBSHの存在を検出した。対照実験としてBSH単独を同量投与した。結果を図14にまとめ示す。
Claims (10)
- 水溶液中で疎水性アミノ酸残基と塩基性アミノ酸残基を含むペプチドとメルカプトウンデカハイドロデカボレート(BSH)を混合することを特徴とする、上記ペプチドとBSHを含む複合体の製造方法であって、上記ペプチドがA6KまたはA6Rであり、上記ペプチド1モルに対してBSH1モル〜1000モルの割合で混合するものである方法。
- 複合体の直径を調節することをさらに特徴とする、請求項1記載の方法。
- 複合体が直径約20nm〜約200nmの球状である請求項1または2記載の方法。
- 疎水性アミノ酸残基と塩基性アミノ酸残基を含むペプチドとBSHを含む複合体であって、上記ペプチドがA6KまたはA6Rであり、直径が約20nm〜約200nmの球形であり、がん細胞中に送達され滞留する複合体。
- 請求項4記載の複合体を含む、がんのホウ素中性子捕捉療法のための薬剤。
- がんのホウ素中性子捕捉療法に用いられる、請求項4記載の複合体。
- がんのホウ素中性子捕捉療法のための薬剤を製造するための、請求項4記載の複合体の使用。
- 静脈注射剤または輸液剤である請求項5記載の薬剤。
- 静脈注射または輸液により投与される請求項6記載の複合体。
- 薬剤が静脈注射または輸液により投与される請求項7記載の使用。
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