JP2008308440A - 癌治療用薬剤送達ビヒクルおよびその製造方法ならびにそれを用いた製剤 - Google Patents
癌治療用薬剤送達ビヒクルおよびその製造方法ならびにそれを用いた製剤 Download PDFInfo
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- JP2008308440A JP2008308440A JP2007157701A JP2007157701A JP2008308440A JP 2008308440 A JP2008308440 A JP 2008308440A JP 2007157701 A JP2007157701 A JP 2007157701A JP 2007157701 A JP2007157701 A JP 2007157701A JP 2008308440 A JP2008308440 A JP 2008308440A
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
【解決手段】 カチオン化ウイルスエンベロープベクターからなる癌治療用薬剤送達ビヒクルおよびそのビヒクル内に薬剤が封入されてなる製剤を提供する。ウイルスエンベロープベクターは、例えば、センダイウイルス由来のHVJ−Eであり、カチオン化は、ヒアルロン酸導入カチオン化ゼラチン、またはポリエチレングリコール導入カチオン化ゼラチンを、ウイルスエンベロープベクターに結合させてなされ得る。封入される薬剤は、核酸、核酸配列を含むベクター、タンパク質医薬、または低分子化合物の医薬などである。
【選択図】 なし
Description
(a)ウイルスを不活性化する工程、および
(b)不活性化された該ウイルスから得られるウイルスエンベロープベクターを、ヒアルロン酸および/またはポリエチレングリコール、カチオン化剤、およびゼラチンによってカチオン化する工程、を包含する方法を提供する。
(a)ウイルスを不活性化する工程、および
(b)不活性化された該ウイルスから得られるウイルスエンベロープベクターに、ヒアルロン酸および/またはポリエチレングリコールが結合したカチオン化ゼラチンを結合させる工程、を包含する方法を提供する。
HVJの種ウイルスを、SPF(Specific pathogen free)の受精卵を使って増殖させ分離・精製したHVJ(Z種)を細胞保存用チューブに分注し、10%DMSOを加えて液体窒素中に保存し、調製した。受精直後のニワトリ卵を入荷し、インキュベーター(SHOWA−FURANKI P−03型;約300鶏卵収容)に入れ、36.5℃、湿度40%以上の条件で10〜14日飼育した。暗室内で、検卵器を用いて、胚の生存および気室と漿尿膜を確認した。ポリペプトン溶液(1%ポリペプトン、0.2%NaClを混合し、1MNaOHでpH7.2に調整してオートクレーブ滅菌し、2℃〜6℃保存したもの)で種ウイルス(液体窒素から取り出したもの)を500倍に希釈し、2℃〜6℃に置いた。卵をイソジンおよびアルコールで消毒し、ウイルス注入箇所に千枚通しで小孔をあけ、希釈した種ウイルス0.1mlを26ゲージの針付き1mlシリンジを用いて、漿尿腔内に入るように注入した。溶かしたパラフィン(融点50〜52℃)をパスツールピペットを用いて孔の上に置きこれをふさいだ。卵をインキュベーターに入れ、34〜36.5℃、湿度40%以上の条件で3日飼育した。次に、接種卵を一晩2℃〜6℃に置いた。翌日、卵の気室部分をピンセットで割り、18ゲージの針を付けた10mlシリンジを漿尿膜の中に入れて、漿尿液を吸引し、滅菌ボトルに集め、2℃〜6℃に保存した。
(2)HVJの濃縮
上記(1)で得られたHVJ含有漿尿液(HVJ含有のニワトリ卵の漿尿液を集め2℃〜6℃にて保存)の約100mlを広口の駒込ピペットで約50mlの遠心チューブ2本に入れ、低速遠心機で3,000rpm、10分、2℃〜6℃で遠心し(ブレーキはオフ)、卵の組織片を除去した。遠心後、上清を35ml遠心チューブ4本(高速遠心用)に分注し、アングルローターで27,000g、30分遠心した。上清を除き、沈殿にBSS(10mM Tris−HCl(pH7.5)、137mM NaCl、5.4mM KCl;オートクレーブし、2℃〜6℃保存)(BSSのかわりにPBSでも可能)をチューブ当たり約5ml加え、そのまま2℃〜6℃で一晩静置した。広口の駒込ピペットでゆるやかにピペッティングして沈殿をほぐし、1本のチューブに集め、同様にアングルローターで27,000g、30分遠心した。上清を除き、沈殿にBSSを約10ml加え、同様に2℃〜6℃で一晩静置した。広口の駒込ピペットでゆるやかにピペッティングして沈殿をほぐし、低速遠心機で3,000rpm、10分、2℃〜6℃で遠心し(ブレーキはオフ)、除ききれなかった組織片やウイルスの凝集塊をのぞいた。上清を新しい滅菌済みチューブに入れ、HVJ濃縮液として2℃〜6℃で保存した。このHVJ濃縮液0.1mlにBSSを0.9ml加え、分光光度計で540nmの吸光度を測定し、ウイルス力価を赤血球凝集活性(HAU)に換算した。540nmの吸光度1がほぼ15,000HAUに相当した。HAUは融合活性とほぼ比例すると考えられる。
さらにショ糖密度勾配を用いたHVJの精製も必要に応じて行い得る。具体的には、実施例1で得られたHVJ懸濁液を60%、30%のショ糖溶液(滅菌済み)を重層した遠心チューブにのせ、62,800×gで120分間密度勾配遠心を行う。遠心後、60%ショ糖溶液層上に見られるバンドを回収する。回収したHVJ懸濁液をBSSもしくはPBSを外液として2℃〜6℃で透析を一晩行い、ショ糖を除去する。すぐに使用しない場合はHVJ懸濁液にグリセロール(オートクレーブ滅菌)と0.5M EDTA液(オートクレーブ滅菌)をそれぞれ最終濃度が10%と2〜10mMになるように加えて−80℃で穏やかに凍結し、最終的に液体窒素中で保存する(凍結保存はグリセロールと0.5M EDTA液の代わりに10mM DMSOでも可能)。
精製、濃縮したHVJに、99mJ/cm2で、紫外線照射を行った。エッペンドルフチューブにチューブあたり10,000HAU分ずつ分注し、15,000rpm、15分遠心し、沈殿を−20℃で保存した。
(1)カラムクロマトグラフィーによる精製
予め15Lの緩衝液1(20mM Tris−HCl(pH7.5)、150mM NaCl)で平衡化したQ−Sepharose FFカラム(直径20cm、ベッド高さ15cm、ベッド容量4710ml)に実施例2で得られた不活性化HVJ液を50mL/分の流速でフィードした。次に10Lの緩衝液1(20mM Tris−HCl(pH7.5)、150mM NaCl)、25Lの緩衝液2(20mM Tris−HCl(pH7.5)、350mM NaCl)を順にカラムに通じた。不活性化HVJは濃縮液フィード時にカラム樹脂に吸着し、一方、不活性化HVJ濃縮液中の不純物の大部分は緩衝液1,2によって樹脂から洗い出される。25Lの緩衝液3(20mM Tris−HCl(pH7.5)、650mM NaCl)を通じるとほぼ同時にHVJが樹脂から溶出するので、カラム画分の採取を始めた。UV吸収チャート(λ=280nm)上に不活性化HVJのピークが現れ、ベースラインに復帰するまでの間に7829mLの画分を得た。この画分に抗生物質を添加した。画分の分取完了後も緩衝液の通液を継続し、最後に20Lの緩衝液4(20mM Tris−HCl(pH7.5)、1M NaCl)をカラムに通じた。
上記実施例3(1)の工程で得られたカラム画分を10Lボトルに入れ、給液用チューブと循環用チューブを取り付けたキャップを締めた。給液用チューブはペリスタポンプを経由してA/G Technology Corporation製 UFP−500−E−5A限外濾過モジュール入口へ、循環用チューブは循環量調整バルブ経由でモジュール出口へ、それぞれ接続した。ポンプを運転し、モジュールの出口側圧力を40〜80kPaに保ちながら循環量調整バルブを絞って濃縮を行い、60〜70mL/分の排液を排出した。循環液量約600mLとなった後、ボトルを500mLボトルに、モジュールをA/G Technology Corporation製 UFP−500−E−4Aに交換して濃縮を継続した。上記と同様に約10mL/分の排液を排出して循環液量約60mLとなった後で60mLの緩衝液5(20mM Tris−HCl(pH7.5)、50mM NaCl、1mM MgCl2、2% マンニトール)を添加し、更に濃縮を継続して循環液量を約60mLとした(Buffer交換)。更にBuffer交換を2回行った後、循環液量は79mLであった。5mLディスポシリンジに循環液を採り、シリンジ先端にディスクフィルタ(CORNING製Sterile Syringe Filter、φ=26mm、0.45μm)を取付け、手動にて滅菌濾過を実施した。
分子量5,000の低分子量ゼラチンと、ゼラチン中のカルボキシル基に対して50モル当量のエチレンジアミンを加え、0.1 M pH5のリン酸バッファー溶液に添加し、EDC存在下37度一晩反応させた。透析後乾燥し、カチオン化ゼラチンを作製した。
実施例4にて作製したカチオン化ゼラチンと各種分子量のヒアルロン酸とを0.2MpH9.7炭酸バッファー溶液に添加し、NaCNBH3存在下37度3日間保存することで、糖還元末端とカチオン化ゼラチンのアミノ基を反応させた。透析後乾燥し、ヒアルロン酸結合(導入)カチオン化ゼラチンを作製した。作製したカチオン化ゼラチンと各種分子量のヒアルロン酸とを0.2M pH9.7炭酸バッファー溶液に添加し、NaCNBH3存在下37度3日間保存することで、糖還元末端とカチオン化ゼラチンのアミノ基を反応させた。透析後乾燥し、ヒアルロン酸結合(導入)カチオン化ゼラチンを作製した。各種分子量のヒアルロン酸は、分子量約180万程度のヒアルロン酸を、オートクレーブで熱分解し、透析して精製することにより、得られた。ここでは、分子量が5,000のヒアルロン酸と3,100のカチオン化ゼラチンを1:1の割合で配合した。
実施例4で作製したカチオン化ゼラチンと各種分子量のポリエチレングリコールとを0.2MpH9.7炭酸バッファー溶液に添加し、NaCNBH3存在下37度1時間保存することで、ポリエチレングリコール末端のアルデヒド基とカチオン化ゼラチンのアミノ基を反応させた。透析後乾燥し、ポリエチレングリコール結合(導入)カチオン化ゼラチンを作製した。ここで、各ポリエチレングリコールの分子量は約10kDa(キロダルトン)から100kDaである。分子量ならびにポリエチレングリコールの封入率(1-20%)をパラメーターとして、各分子量のポリエチレングリコールを分離し、使用した。ここでは、初期設定として分子量が5,000のPEGと3,100のカチオン化ゼラチンを、1:1、5:1、10:1の割合で配合した。
実施例4、5、および6で得られた各種ポリマーと、実施例1で得られたHVJ-Eとの配合比を、それぞれ250 μg対500 HAUを基本とし、以下の工程を行った。各種ポリマー溶液(溶媒はPBS)を20 mg/ml, 50 μL作製し、HVJ-Eストック500 HAU/10μL4検体分40μLを加えピペッティングを行う (全量で90 μL)。さらにPBS 110μlを加え(total 200 μL)、30 min氷上静置することで、各種ポリマーが結合したHVJ−Eを調製した。
実施例1で得られたHVJ−Eと、実施例7で得られたポリマー結合−HVJ−Eを用いて、マウス毒性試験を行った。HVJ−Eと、各種ポリマー結合-HVJ-E製剤(CG 1,000 mg: 2,000 HAU)をPBSに溶かし、最終容量を200 mLとして、正常C57/BL6マウスにそれぞれ心腔内投与し、投与後1週間以上生存したマウスの個体数より、その生存率を算出した。その結果を表1に示す。
実施例1で得られたHVJ−Eと実施例7で得られたポリマー結合−HVJ−E懸濁液(CG 250 mg: 500 HAU)を、2倍ずつ段階希釈することでサンプルの希釈系列を作製し、150 mLをウェルプレートに添加した後、これの凝集反応の有無を検定した。試料20 μlを 96穴マイクロタイタープレートに加え、ヒトから採血して得た1mlの血液を生理食塩水49mlに懸濁した試験液90 μlを添加し、室温で2時間静置後、肉眼で赤血球凝集 活性がみられる最小濃度を判定した。凝集反応が失われるサンプル系列のサンプル量とそのウェルの希釈倍率の逆数からHA活性を求めた。この結果、実施例1で得られたHVJ−Eに比し、実施例7で得られたポリマー結合−HVJ−Eは、いずれもインビトロにおいて、約2倍の血球凝集抑制作用を認めた。
含有されるホウ素原子換算で、PBSを溶媒として、17,240μgB/mlのBSHを調製した。この溶液を使用し、実施例7で得られた各種ポリマー結合HVJ-EとBSHとの配合比を、1,500 HAU対BSH 1,000 μgBとして製剤を作製した。1本当たり10,000 HAUの各種ポリマー結合HVJ-Eに6666.7 μgB (386.7 μl)のBSHを加え、十分にピペッティングを行った。次に3%TritonX-100/TE バッファー溶液を40 μlを加え、Vortex後、5 min氷上静置し、遠心分離15000rpm/4degree/5minを行った。BSS溶液を1.0 mlを加え、ボルテックスし、遠心分離15000rpm/4degree/5min後、上清を除去し、精製した。
CD44を発現するLM8G5(マウス骨肉腫細胞株:RIKEN CELL BANKから購入したLM8をin vivo selectionし樹立した肝転移高発現株)を、1×104細胞/0.2mL/ウェル(24ウェルプラスチックプレート)となるよう10%牛胎仔血清含有RPMI1640培養液に懸濁し、37℃、5%炭酸ガスインキュベーター内で培養した。20〜24時間培養後、HVJ−Eによる遺伝子導入の測定に供した。同様に、CT26(ヒト大腸がん細胞株;ATCCから購入)を1×104細胞/0.2mL/ウェル(24ウェルプラスチックプレート)となるよう10%牛胎仔血清含有RPMI1640培養液に懸濁し、37℃、5%炭酸ガスインキュベーター内で培養した。20〜24時間培養後、HVJ−Eによる遺伝子導入の測定に供した。
実施例11と同様の方法により、LM8G5細胞を保持した。これとは別に実施例1で得られたHVJ−Eと、実施例7で得られた各種ポリマー結合HVJ−Eとに、それぞれ蛍光色素Qdot655(Qd)を封入した。封入は実施例10と同様の方法にて行った。LM8G5細胞とそれぞれのウイルスエンベロープベクターとを1時間常温で接触させ、洗浄した後、24時間培養し、細胞への結合を蛍光顕微鏡で観察することで、それぞれのウイルスエンベロープベクターの腫瘍細胞への親和性を検討した。その結果、特に、ヒアルロン酸導入化カチオン化HVJ−Eにおいて、腫瘍細胞との強い親和性が認められた。
実施例10で得られた各種BSH封入HVJ−Eベクターを、マウス骨肉腫細胞株LM8G5およびヒト悪性胸膜中皮腫細胞株MESO−1培養液にそれぞれ添加し、10分放置後、直接中性子を1時間照射後、細胞を1週間培養し、細胞増殖抑制効果の有無を調べた。その結果、図2に示すように、いずれの細胞においても、中性子照射により、ホウ素濃度依存的に、細胞増殖抑制効果があることがわかった。
実施例10で得られた各種BSH封入HVJ−Eベクターの抗腫瘍効果を、マウス骨肉腫細胞株肝転移モデルを使って調べた。まず、C3H/HeNマウスに、1×106個のLM8G5細胞を、第0日において上腸間膜静脈接種した。第8日目に、マウスに各種BSH封入HVJ−Eベクター、またはコントロールとしてBSHのみ(PBS溶解)を心腔内に導入した。導入されたBSHの量は、ホウ素10B換算で、それぞれ1,000であった。このマウスを1日飼育した後、それぞれ中性子を照射(条件)することで処理した。照射は、1日、60分ずつ行った。第11日目にマウスを犠牲死させ、処置後、それぞれのマウスから肝臓を取り出し、肝臓の重量を計測することで、本発明のBSH封入HVJ−Eベクターの治療効果を調べた。その結果、図3に示すように、いずれのBSH封入HVJ−Eベクターにおいても、中性子照射により、抗腫瘍効果があることがわかったが、特にPEG導入カチオン化HVJ−Eにおいて、強い抗腫瘍細胞効果が認められた。
Claims (13)
- ヒアルロン酸および/またはポリエチレングリコールが結合したカチオン化ゼラチンと、ウイルスエンベロープベクターとを含む、癌治療用薬剤送達ビヒクル。
- 前記ウイルスエンベロープベクターが、センダイウイルス由来のHVJ−Eである、請求項1記載の癌治療用薬剤送達ビヒクル。
- 請求項1または2に記載の癌治療用薬剤送達ビヒクル中に癌治療用薬剤が封入されてなる製剤。
- 前記癌治療用薬剤が、低分子化合物、核酸、核酸を含むプラスミドベクター、およびタンパク質医薬からなる群より選択される、請求項3に記載の製剤。
- 前記癌治療用薬剤が、抗腫瘍剤である請求項3または4に記載の製剤。
- 前記抗腫瘍剤が、シクロホスファミド、メクロレタミン、カルバジルキノン、メルファラン、チオテパ、ブスルファン、ニムスチン、カルムスチン、プロカルバジン、ダカルバジン、メトトレキサート、6−メルカプトプリン、6−チオグアニン、アザチオプリン、5−フルオロウラシル、フトラフール、フロクスウリジン、シタラビン、アンシタビン、テガフール、ドキシフルリジン、アクチノマイシンD、ブレオマイシン、マイトマイシン、クロモマイシンA3、シネルビンA、アクラシノマイシンA、アドリアマイシン、ペプロマイシン、シスプラチン、ミトキサントロン、エピルビシン、ピラルビシン、ビンブラスチン、ビンクリスチン、ビンデシン、エトポシド、シスプラチン、カルボプラチン、リン酸エストラムスチン、ミトタン、ポルフィリン、およびタキソールからなる群より選択される少なくとも1種である請求項5に記載の製剤。
- 前記癌治療用薬剤が、ホウ素含有化合物である請求項4に記載の製剤。
- 前記ホウ素含有化合物が、メルカプトウンデカハイドロドデカボレート(BSH)またはp−ボロノフェニルアラニン(BPA)である、請求項7に記載の製剤。
- ホウ素中性子捕捉療法(BNCT)に用いるための請求項7または8の製剤。
- 悪性胸膜中皮腫、または肝臓癌から選択される1種の治療に用いられる請求項9記載の製剤。
- 請求項1または2のいずれかに記載の癌治療用薬剤送達ビヒクルの製造方法であって、
(a)ウイルスを不活性化する工程、および
(b)不活性化された該ウイルスから得られるウイルスエンベロープベクターを、ヒアルロン酸および/またはポリエチレングリコール、カチオン化剤、およびゼラチンによってカチオン化する工程、
を包含する方法。 - 請求項1または2のいずれかに記載の癌治療用薬剤送達ビヒクルの製造方法であって、
(a)ウイルスを不活性化する工程、および
(b)不活性化された該ウイルスから得られるウイルスエンベロープベクターに、ヒアルロン酸および/またはポリエチレングリコールが結合したカチオン化ゼラチンを接触させる工程、
を包含する方法。 - 前記ウイルスエンベロープベクターが、センダイウイルス由来のHVJ−Eである、請求項11または12のいずれかに記載の方法。
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JP2007157701A JP2008308440A (ja) | 2007-06-14 | 2007-06-14 | 癌治療用薬剤送達ビヒクルおよびその製造方法ならびにそれを用いた製剤 |
US12/054,200 US20080312130A1 (en) | 2007-06-14 | 2008-03-24 | Drug delivery vehicle for cancer therapy, process for producing the same, and pharmaceutical preparation using the same |
US13/103,275 US20110268769A1 (en) | 2007-06-14 | 2011-05-09 | Drug delivery vehicle for cancer therapy, process for producing the same, and pharmaceutical preparation using the same |
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JP2007157701A JP2008308440A (ja) | 2007-06-14 | 2007-06-14 | 癌治療用薬剤送達ビヒクルおよびその製造方法ならびにそれを用いた製剤 |
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JP2008308440A true JP2008308440A (ja) | 2008-12-25 |
JP2008308440A5 JP2008308440A5 (ja) | 2010-07-29 |
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JP (1) | JP2008308440A (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013039098A (ja) * | 2011-08-19 | 2013-02-28 | National Institute For Materials Science | 被覆hvj−e及び被覆hvj−eの製造方法 |
JP2016510324A (ja) * | 2013-01-17 | 2016-04-07 | シット・ソフト・インテリジェント・セラピューティクス・ゲーエムベーハー・ウント・コー・カーゲー | 選択的細胞死誘発バイナリ−酵素系 |
WO2018105630A1 (ja) | 2016-12-06 | 2018-06-14 | 国立大学法人大阪大学 | 新規プリオノイド病用治療薬 |
JP2020510702A (ja) * | 2017-03-13 | 2020-04-09 | トゥーレル,シルヴァン | 選択的細胞死誘導酵素系 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017181790A1 (zh) * | 2016-04-19 | 2017-10-26 | 南京中硼联康医疗科技有限公司 | 用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统 |
JP6548060B2 (ja) * | 2016-11-25 | 2019-07-24 | 国立大学法人 岡山大学 | ホウ素中性子捕捉療法のための新規bsh複合体 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5599796A (en) * | 1993-12-02 | 1997-02-04 | Emory University | Treatment of urogenital cancer with boron neutron capture therapy |
CN101302536A (zh) * | 2000-02-02 | 2008-11-12 | 安增子摩祺株式会社 | 用于基因转移的病毒包膜载体 |
-
2007
- 2007-06-14 JP JP2007157701A patent/JP2008308440A/ja not_active Withdrawn
-
2008
- 2008-03-24 US US12/054,200 patent/US20080312130A1/en not_active Abandoned
-
2011
- 2011-05-09 US US13/103,275 patent/US20110268769A1/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013039098A (ja) * | 2011-08-19 | 2013-02-28 | National Institute For Materials Science | 被覆hvj−e及び被覆hvj−eの製造方法 |
JP2016510324A (ja) * | 2013-01-17 | 2016-04-07 | シット・ソフト・インテリジェント・セラピューティクス・ゲーエムベーハー・ウント・コー・カーゲー | 選択的細胞死誘発バイナリ−酵素系 |
WO2018105630A1 (ja) | 2016-12-06 | 2018-06-14 | 国立大学法人大阪大学 | 新規プリオノイド病用治療薬 |
JP2020510702A (ja) * | 2017-03-13 | 2020-04-09 | トゥーレル,シルヴァン | 選択的細胞死誘導酵素系 |
Also Published As
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US20080312130A1 (en) | 2008-12-18 |
US20110268769A1 (en) | 2011-11-03 |
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