JPWO2009145243A1 - 光線力学的治療に利用可能な脂質膜およびその利用 - Google Patents
光線力学的治療に利用可能な脂質膜およびその利用 Download PDFInfo
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- 229960002317 succinimide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 210000003812 trophozoite Anatomy 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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Abstract
Description
本発明は、光活性化物質および光感受性物質を含有している脂質膜を提供する。本発明において、光感受性物質は光活性化物質に光エネルギーを供与するドナー分子であり、光活性化物質はドナー分子からの光エネルギーを受容するアクセプター分子である。本明細書中で使用される場合、「光エネルギーの供与/受容」は、光の受容に直接的または間接的に起因して生成されるエネルギーおよび電子の少なくとも一方の移動が意図される。また、「光エネルギー」は、光の受容に起因して生成されるエネルギーおよび電子の少なくとも一方だけでなく、光エネルギーの供与/受容に起因して生成されるさらなるエネルギーおよび電子の少なくとも一方が意図される。本発明に係る脂質膜は、人工の脂質膜であることが好ましく、膜構造の安定性の観点から脂質二重膜であることがより好ましい。脂質二重膜は、極性脂質(特にリン脂質)が二層となった膜状の構造(脂質二重層)である。脂質二重層構造が二次元構造として安定化するのは球状であるが、末端を水分子から隔離すれば平面構造になり得る。本明細書中で使用される場合、人工的に作製される脂質二重層のうち球状のものをリポソーム、平面状のものを脂質平面膜という。なお、脂質一重層からなるミセルは一般に不安定であるが、特許文献9に記載されているような、ブロック共重合分子(ブロックコポリマー)が形成するミセルであれば安定性がよいことを、当業者は十分認識している。このようなミセルは薬物送達(DDS)の手段の一つとして研究されている。
本発明はまた、本発明に係る脂質膜を含んでいる組成物を提供する。本発明に係る組成物は、上述した脂質膜を含んでいればよく、その他の具体的な構成は特に限定されず、例えば、脂質膜が水性溶媒に溶解した溶液もまた本発明に係る組成物に含まれる。以下、本発明に係る組成物の一実施形態として、光線力学的治療剤および細胞増殖抑制剤について説明するが、本発明はこれらに限定されるものではない。
本実施形態に係る組成物は、光照射、好ましくは、波長範囲が500〜800nmの光照射、より好ましくは、波長範囲が600〜700nmの光照射により、活性酸素を生成する脂質膜を含んでいる。具体的には、上述した光活性化物質および光感受性物質を含有し、カチオン性脂質を含む脂質膜であることが好ましい。好ましいカチオン性脂質としては、例えば、上述したカチオン性脂質が挙げられるが、特に、上記式(1)で表される脂質が好ましい。また、その含有量は、全脂質量の1〜50モル%であることが好ましく、10モル%であることがより好ましい。
本実施形態に係る組成物は、光照射、好ましくは、波長範囲が500〜800nmの光照射、より好ましくは、波長範囲が600〜700nmの光照射により、活性酸素を生成する脂質膜を含んでいる。本実施形態に係る組成物における脂質膜の含有量は、特に限定されないが、光照射により脂質膜が生成する活性酸素により細胞の増殖を抑制することができる程度の量であればよい。適用対象の細胞としては特に限定されないが、微生物等であってもよく、この場合、本実施形態に係る組成物は、抗菌剤または殺菌剤であり得る。また、本実施形態に係る組成物の具体的な使用方法は、特に限定されるものではないが、例えば、本実施形態に係る組成物を散布し、散布した領域を自然太陽光に曝すか、もしくは人工光源によって一定時間光照射する。人工光源によって照射する場合は、紫外光をフィルター等でカットした光を照射することが好ましい。
〔1〕C60・γ−シクロデキストリン(γCD)錯体水溶液の調製
5.0mgのC60と35.8mgのγCDを、高速振動粉砕法(30Hz,20分間)によって混合した後、0.9%NaCl水溶液1.5mlを加えて抽出した。不溶なフラーレンを遠心分離(18000×g,20分間)により沈降させ、上清を回収した後、メンブランフィルタ(0.2μm)を用いて濾過した。濃度を、紫外−可視光吸収スペクトルにより決定し、0.2mMとなるように希釈した(ε332nm=4.27×104cm−1mol−1dm3)。
双極性脂質(DMPC)/CHCl3 3.6μmol、カチオン性脂質(N+C5Ala2C16)/CHCl3 0.4μmol、カルボシアニン色素(1,1’−ジオクタデシル−3,3,3’,3’−テトラメチルインドカルボシアニンパークロレート(「DiI」;DiIC18(3))、1,1’−ジオクタデシル−3,3,3’,3’−テトラメチルインドジカルボシアニンパークロレート(「DiD」 oil;DiIC18(5) oil)、または1,1’−ジオクタデシル−3,3,3’,3’−テトラメチルインドトリカルボシアニンアイオダイド(「DiR」;DiIC18(7))(いずれもInvitrogen社))/EtOH 0.1μmol(2.5%)を混合し、N2ガスで薄膜を形成した。この薄膜を、35℃で1時間減圧乾燥した後、0.9%NaCl水溶液 1mlを加え、ボルテックスミキサーで撹拌した。エクストルーダーを用いて、孔径50nmのメンブレンフィルターに11回通すことで、リポソーム溶液(脂質濃度4mM)を調製した。また、カルボシアニン色素を混合せずに、カチオン性リポソームを同様に調製した。なお、用いたカチオン性脂質は
上述したリポソーム溶液(カルボシアニン色素あり/なし)を、脂質濃度2mMとなるように希釈し、上述した0.2mM γCD−C60錯体水溶液とを等量ずつ混合し、80℃で1時間加熱攪拌することによって、C60フラーレンの交換反応を行った。
HeLa細胞を2.13×104cells/cm2の細胞密度で播種し、37℃、5%CO2条件下で一晩培養した。培養後の細胞に、各リポソーム溶液を、脂質の最終濃度が50μMとなるように添加し、24時間インキュベートして細胞にリポソームを取り込ませた。24時間後、PBSで細胞を3回洗浄し、培地を再度加えた後に25℃のインキュベータに細胞を移し、光照射(照射波長:500〜740nm)を行なった。光照射24時間後に顕微鏡下で観察し、位相差像を撮影した。細胞生存率は、シャーレ中の細胞をトリプシン処理により回収し、0.25%(W/V)トリパンブルーにより死細胞を染色した後、生存細胞数を血球計算盤上で算出する手法、またはCell Counting Kit−8を用いて算出した。
〔1〕C70・γ−シクロデキストリン(γCD)錯体水溶液の調製
5.0mgのC70と60mgのγCDを、高速振動粉砕法(30Hz,20分間)によって混合した後、0.9%NaCl水溶液1.5mlを加えて抽出した。不溶なフラーレンを遠心分離(18000×g,20分間)により沈降させ、上清を回収した後、メンブランフィルタ(0.2μm)を用いて濾過した。濃度を、紫外−可視光吸収スペクトルにより決定し、0.2mMとなるように希釈した(ε380nm=3.80×104cm−1mol−1dm3)。
双極性脂質(DMPC)/CHCl3 3.6μmol、カチオン性脂質(N+C5Ala2C16)/CHCl3 0.4μmol、カルボシアニン色素(1,1’−ジオクタデシル−3,3,3’,3’−テトラメチルインドジカルボシアニンパークロレート(「DiD」 oil;DiIC18(5) oil)、Invitrogen社)/EtOH 0.1μmol(2.5%)を混合し、N2ガスで薄膜を形成した。この薄膜を、35℃で1時間減圧乾燥した後、0.9%NaCl水溶液 1mlを加え、ボルテックスミキサーで撹拌した。エクストルーダーを用いて、孔径50nmのメンブレンフィルターに11回通すことで、リポソーム溶液(脂質濃度4mM)を調製した。
上述したリポソーム溶液を、脂質濃度2mMとなるように希釈し、上述した0.2mM γCD−C70錯体水溶液とを等量ずつ混合することで、C70フラーレンの交換反応を行った。
HeLa細胞を2.13×104cells/cm2の細胞密度で48 well plateに播種し、37℃、5%CO2条件下で一晩培養した。培養後の細胞に、各リポソーム溶液を、
C70の濃度が0.5〜20μM(DiD=0.125〜5μM)となるように添加し、24時間インキュベートして細胞にリポソームを取り込ませた。24時間後、PBSで細胞を洗浄し、培地を再度加えた後に25℃のインキュベータに細胞を移し、光照射(照射波長:610〜740nm、17mWcm−2、30分)を行なった。光照射24時間後、Cell Counting Kit−8を用いて細胞の生存率を算出した。結果を図5に示す(DiD−C70」参照)。
Claims (7)
- 波長範囲500〜800nmの光照射によって活性酸素を生成し得る脂質膜であって、
500〜800nmの範囲内の光を吸収し得る光感受性物質、および500〜800nmの範囲内の光を吸収し得ないかまたは500〜800nmの範囲内の光の吸収が非常に弱い光活性化物質を含有し、
該光活性化物質は、光照射によって該光感受性物質が生成する第1の光エネルギーを受容して、酸素に供与される第2の光エネルギーを生成し、
該光感受性物質は、炭素数8〜20の炭化水素基を2個含んでいることを特徴とする脂質膜。 - 上記炭化水素基が、直鎖であることを特徴とする請求項1に記載の脂質膜。
- 上記光活性化物質が、フラーレン、ポルフィリン、オリゴチオフェン、カロテノイドおよびピレンからなる群より選択されることを特徴とする請求項1に記載の脂質膜。
- 上記光感受性物質が、
として示される化合物であることを特徴とする請求項1に記載の脂質膜。 - リポソーム形態であることを特徴とする請求項1〜4のいずれか1項に記載の脂質膜。
- 請求項1〜5のいずれか1項に記載の脂質膜を含んでいることを特徴とする細胞増殖抑制剤。
- 請求項1〜5のいずれか1項に記載の脂質膜を含んでいることを特徴とする光線力学的治療剤。
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