JP5721140B2 - 新生血管に対する標的化剤 - Google Patents
新生血管に対する標的化剤 Download PDFInfo
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- JP5721140B2 JP5721140B2 JP2011518581A JP2011518581A JP5721140B2 JP 5721140 B2 JP5721140 B2 JP 5721140B2 JP 2011518581 A JP2011518581 A JP 2011518581A JP 2011518581 A JP2011518581 A JP 2011518581A JP 5721140 B2 JP5721140 B2 JP 5721140B2
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- gelatin
- targeting agent
- amino acid
- targeting
- genetically modified
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Description
好ましくは、本発明の標的化剤は、新生血管部位を標的としたイメージング剤である。
好ましくは、本発明の標的化剤は、新生血管部位を標的としたドラッグデリバリー剤である。
好ましくは、ゼラチン様タンパク質は、コラーゲンの部分アミノ酸配列に由来するアミノ酸配列を有する遺伝子組み換えゼラチンである。
好ましくは、遺伝子組み換えゼラチンは、コラーゲンに特徴的なGly-X-Yで示される配列(X及びYはそれぞれ独立にアミノ酸の何れかを示す)の繰り返しを有し(複数個のGly-X-Yはそれぞれ同一でも異なっていてもよい)、分子量が10 KDa以上90 KDa以下である。
好ましくは、細胞接着シグナルがArg-Gly-Aspで示されるアミノ酸配列である。
好ましくは、遺伝子組み換えゼラチンのアミノ酸配列が、セリン及びスレオニンを含まない。
好ましくは、遺伝子組み換えゼラチンのアミノ酸配列が、セリン、スレオニン、アスパラギン、チロシン、及びシステインを含まない。
好ましくは、遺伝子組み換えゼラチンのアミノ酸配列が、Asp-Arg-Gly-Aspで示されるアミノ酸配列を含まない。
式:A−[(Gly−X−Y)n]m−B
(式中、Aは任意のアミノ酸又はアミノ酸配列を示し、Bは任意のアミノ酸又はアミノ酸配列を示し、n個のXはそれぞれ独立にアミノ酸の何れかを示し、n個のYはそれぞれ独立にアミノ酸の何れかを示し、nは3〜100の整数を示し、mは2〜10の整数を示す。なお、n個のGly-X-Yはそれぞれ同一でも異なっていてもよい。)で示される。
式:Gly-Ala-Pro-[(Gly−X−Y)63]3−Gly
(式中、63個のXはそれぞれ独立にアミノ酸の何れかを示し、63個のYはそれぞれ独立にアミノ酸の何れかを示す。なお、n個のGly-X-Yはそれぞれ同一でも異なっていてもよい。)
で示される。
好ましくは、架橋がアルデヒド類、縮合剤、又は酵素により施される。
好ましくは、標識プローブが、蛍光色素、放射性同位体、PET用核種、SPECT用核種、MRI造影剤、CT造影剤、又は磁性体である。
好ましくは、該結合が、配位結合、共有結合、水素結合、疎水性相互作用、又は物理吸着である。
本発明で用いるゼラチン様タンパク質は本発明の効果を奏する限り特に限定されないが、好ましくはゼラチン、コラーゲン、フィブロネクチン、プロネクチン、ビトロネクチンの何れか、又はその組み合わせである。ゼラチン様タンパク質の由来は特に限定されない。ゼラチン様タンパク質は、好ましくはゼラチンであり、特に好ましくは遺伝子組み換えゼラチンである。
また、遺伝子組み換えゼラチンは部分的に加水分解されていてもよい。
好ましくは、遺伝子組み換えゼラチンはプロコラーゲンおよびプロコラーゲンを有さない。
好ましくは、遺伝子組み換えゼラチンはテロペプタイドを有さない。
好ましくは、遺伝子組み換えゼラチンは天然コラーゲンをコードする核酸により調製された実質的に純粋なコラーゲン用材料である。
(1)配列番号1に記載のアミノ酸配列;又は
(2)配列番号1に記載のアミノ酸配列と80%以上(さらに好ましくは90%以上、最も好ましくは95%以上)の相同性を有し、新生血管に集積する作用を有するアミノ酸配列;
を有する遺伝子組換えゼラチンである。
CBE3
分子量:51.6kD
構造: GAP[(GXY)63]3G
アミノ酸数:571個
RGD配列:12個
イミノ酸含量:33%
ほぼ100%のアミノ酸がGXYの繰り返し構造である。
CBE3のアミノ酸配列には、セリン、スレオニン、アスパラギン、チロシン及びシステインは含まれていない。
CBE3はERGD配列を有している。
等電点:9.34
GAP(GAPGLQGAPGLQGMPGERGAAGLPGPKGERGDAGPKGADGAPGAPGLQGMPGERGAAGLPGPKGERGDAGPKGADGAPGKDGVRGLAGPIGPPGERGAAGLPGPKGERGDAGPKGADGAPGKDGVRGLAGPIGPPGPAGAPGAPGLQGMPGERGAAGLPGPKGERGDAGPKGADGAPGKDGVRGLAGPP)3G
虚血部位に、自然治癒によって再生される新生血管、再生新生血管が作製される動物モデルを作製した。
C57BL6マウス(オス、6週令:日本SLC)に体重の1/10重量の10%ネンブタール(生理食塩水で希釈済み)を腹腔投与し、麻酔下で処置を行った。左右下肢を毛剃り、その後、右下肢のみ血管の除去・焼灼・止血を行った。
作製した下肢虚血モデルについて、レーザードップラー血流計を用い、処置肢(右肢)と未処置肢(左肢)の血流状態を測定することにより、下肢虚血処置が成功しているか、又その後の血管新生(血流回復)が進行しているかどうかの確認を行った。
R-GelをクロラミンT法により125I標識した。
1mgのR-Gelを1mLのbuffer.A(0.5M リン酸緩衝液, 0.5M NaCl, pH7.5)に溶解させた。内200μLに5μLのNaI / NaOH溶液を添加し、更に100μLの0.2mg/mLクロラミンT / buffer. Aを添加して(クロラミンT:ナカライテスク)、ボルテックスで2分間混合した。その後、100μLの4mg/mL SMS(二亜硫酸ナトリウム)水溶液を添加し、ボルテックスで2分間混合した(混合液B)。
DDYマウス(オス6週令:日本SLC)に、上記(2)で作製した125I-R-Gelを200μL尾静脈投与し、投与後、1時間、3時間、6時間、24時間の組織分布を、各臓器・組織毎のγ線放射能量、及び排泄された尿のγ線放射能量をオートウェルガンマシステム(ARC-380:Aloka社)で測定することで決定した。臓器・組織中のγ線放射能量は解剖によって直接に、又、血中γ線放射能量は心採血した200μL中のγ線放射能量から計算により、決定した。
上記(1)で作製した「下肢虚血→新生血管モデル」について、上記(2)で作製した125I-R-Gelを200μL尾静脈投与し、投与後、3時間、24時間の組織分布を、各臓器・組織毎のγ線放射能量、及び排泄された尿のγ線放射能量をオートウェルガンマシステムで測定することで決定した。臓器・組織中のγ線放射能量は解剖によって直接に、又、血中γ線放射能量は心採血した200μL中のγ線放射能量から計算により、決定した。
上記結果により、動物ゼラチン及びR-gelの新生血管部位への蓄積が確認された。
塩基性線維芽細胞増殖因子(bFGF)を含有したゼラチンゲルを、マウス背部皮下に埋め込み、皮下新生血管モデルを作製した。ゼラチンゲルはメドジェルpI5(メドジェル社)を使用し、EOG滅菌処理を施した2mgのメドジェルpI5に、50μgのbFGFを水溶液にして無菌化で添加、4℃で一晩膨潤したものをbFGFゲルとして用いた。
R-Gel、豚皮膚由来のゼラチン(以後、PSKと呼称する)、動物ゼラチン、及びcyclo-RGDfK(AnaSpec, Inc.)について、蛍光色素Cy7ラベルを施した物を作製した。
Cy7としては、GEヘルスケア社のCy7 mono-reactive NHS esterを使用した。Cy7 NHS esterは10mg/mL濃度でDMSO(ジメチルスルホキシド)に溶解した。 10μLのCy7 NHS ester / DMSOと、等モル量のR-Gelを0.1M Sodium Carbonate buffer, pH 9.3中で混合し、遮光状態、室温で1時間反応させた。又、10μLのCy7 NHS ester / DMSOと1mgのR-Gelを同様に反応させた物も作製した。得られた反応物は、予めPBS(リン酸緩衝液)で平衡化しておいたPD-10カラムにアプライし、十分量のPBSで溶出を行った。溶出液の蛍光量を測定しながら、Cy7ラベルしたR-Gel(以後、Cy7-R-Gelと記す)とCy7の未反応物を分離し、Cy7-R-Gelを得た。
上記(5)で作製したbFGF誘導皮下新生血管モデルに対し、Cy7-R-Gel、あるいはCy7-PSK、あるいはCy7-cyclo-RGDfKを投与し、マウス体外からの蛍光イメージング実験を行った。投与量は200μL、投与経路は尾静脈投与で行った。
R-Gelによる新生血管部位集積が環状RGDペプチドcyclo-RGDfKと同様のメカニズムによるターゲティングであるかを評価する為、cyclo-RGDfKの事前大量投与によりR-Gelの集積阻害が生じるか、検討を実施した。ラベル化していないcyclo-RGDfKを超純水に1mg/mL濃度で溶解し、それを尾静脈投与によって100μL投与した後、30分後にCy7-R-Gelを尾静脈投与によって100μL投与した。比較としてcyclo-RGDfKの代わりにPBS(リン酸緩衝液)を尾静脈投与によって100μL投与した後、30分後にCy7-R-Gelを尾静脈投与によって100μL投与した。
使用動物: BALB/cマウス メス 6週令
移植癌細胞: Colon-26(BALB/cマウス結腸癌由来細胞)
Homograftモデルである。
上記(6)で作製したCy7-R-Gel、又はCy7-動物ゼラチンを、上記(9)で作製した担癌動物へ、尾静脈投与により200μL投与し、その体外からの蛍光イメージング実験を行った。
R-Gelの新生血管集積メカニズムの詳細を得る為、R-Gelの血管内皮細胞への細胞接着性試験、及びαVβ3インテグリンとの相互作用を調べる為の実験を行った。
使用した血管内皮細胞としては、HUVEC(正常ヒト臍帯静脈内皮細胞:タカラバイオ社)を用いた。該細胞はその細胞表面に多数のαVβ3インテグリンを恒常的に発現していることが知られており、該細胞との細胞接着性を試験することは、新生血管で活性化される血管内皮細胞への結合性を明らかにするとともに、新生血管部位で高発現されることが報告されているαVβ3インテグリンへの結合性を明らかにすることにもなる。
R-GelとHUVECの結合が、αVβ3インテグリンを介した結合であることを確認するため、上記(7)で行ったR-Gelの細胞接着性試験について、αVβ3インテグリンを抗αV抗体によってブロックすることで、当該接着が抑制されるかの実験を行った。
Claims (18)
- 配列番号1に記載のアミノ酸配列を有する遺伝子組み換えゼラチンを含む、新生血管部位に対する標的化剤。
- 新生血管部位を標的としたイメージング剤である、請求項1に記載の標的化剤。
- 新生血管部位を標的としたドラッグデリバリー剤である、請求項1に記載の標的化剤。
- 細胞接着シグナルを一分子中に2配列以上含む、請求項1から3の何れか一項に記載の標的化剤。
- 細胞接着シグナルがArg-Gly-Aspで示されるアミノ酸配列である、請求項4に記載の標的化剤。
- 遺伝子組み換えゼラチンのアミノ酸配列が、セリン及びスレオニンを含まない、請求項1から5の何れかの何れか一項に記載の標的化剤。
- 遺伝子組み換えゼラチンのアミノ酸配列が、セリン、スレオニン、アスパラギン、チロシン、及びシステインを含まない、請求項1から6の何れかの何れか一項に記載の標的化剤。
- 遺伝子組み換えゼラチンのアミノ酸配列が、Asp-Arg-Gly-Aspで示されるアミノ酸配列を含まない、請求項1から7の何れかの何れか一項に記載の標的化剤。
- 遺伝子組み換えゼラチンが架橋されている、請求項1から8の何れかの何れか一項に記載の標的化剤。
- 架橋がアルデヒド類、縮合剤、又は酵素により施される、請求項9に記載の標的化剤。
- さらに標識プローブまたは薬剤を含有する、請求項1から10の何れかの何れか一項に記載の標的化剤。
- 標識プローブが、蛍光色素、放射性同位体、PET用核種、SPECT用核種、MRI造影剤、CT造影剤、又は磁性体である請求項11に記載の標的化剤。
- 蛍光色素が、量子ドット、インドシアニングリーン又は近赤外蛍光色素であり、放射性同位体、PET用核種及びSPECT用核種が、11C、13N、15O、18F、66Ga、 67Ga、68Ga、60Cu、61Cu、62Cu、67Cu、 64Cu、48V、Tc-99m、241Am、55Co、57Co、153Gd、111In、133Ba、82Rb、139Ce、Te-123m、137Cs、86Y、90Y、185/187Re、186/188Re、125I、又はそれらの錯体、あるいはそれらの組み合わせであり、MRI造影剤、CT造影剤及び磁性体が、ガドリニウム、Gd-DTPA、Gd-DTPA-BMA、Gd-HP-DO3A、ヨード、鉄、酸化鉄、クロム、マンガン、又はその錯体・キレート錯体、あるいは又はそれらの組み合せである、請求項12に記載の標的化剤。
- 遺伝子組み換えゼラチンと標識プローブとが、直接又はリンカーを介すことにより物理的又は化学的に結合されている、請求項11から13の何れか一項に記載の標的化剤。
- 該結合が、配位結合、共有結合、水素結合、疎水性相互作用、又は物理吸着である、請求項14に記載の標的化剤。
- 遺伝子組み換えゼラチンが、配列番号1に記載のアミノ酸配列からなる、請求項1から15の何れか一項に記載の標的化剤。
- 配列番号1に記載のアミノ酸配列を有する遺伝子組み換えゼラチンを対象(ヒトを除く)に投与することを含む、新生血管部位に対して物質を標的化する方法。
- 新生血管部位に対する標的化剤の製造のための、配列番号1に記載のアミノ酸配列を有する遺伝子組み換えゼラチンの使用。
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