JP2021508320A - Capeロードされた標的化微小胞抗がん剤およびその開発方法 - Google Patents
Capeロードされた標的化微小胞抗がん剤およびその開発方法 Download PDFInfo
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-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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Abstract
Description
・細胞および組織特異的ではない。
・高濃度での使用を必要とする。
・単核食細胞系の活性化。
・がん組織が薬剤用途で耐薬品性を示す。
本発明の目的は、組織細胞の培養およびその後の特殊化(分化)の結果として得られた微小胞にCAPEをロードすることにより、細胞特異的な標的化小胞の開発(development)を提供することである。
本発明の目的を達成するために開発された「SH-SY5Y神経芽腫がんを標的とするCAPEロードされた微小胞抗がん剤の開発」は、添付の図に示される。
「特殊化した」という用語は、図1に示されるように、SHSY5Y細胞を他の細胞と比較した結果として得られる。
培地に皮膚幹細胞を播種(培養)すること;
神経芽細胞腫認識の機能が細胞に提供され、それらを標的にすることができるようにするために、十分な密集度(70〜80%)に達した培養培地中の細胞が6ウェル細胞培養プレートに播種されるようにする特殊化プロトコルを実装すること;
CAPE(カフェイン酸フェネチルエステル)をDMSO(ジメチルスルホキシド)に溶解し、原液を調製すること(したがって、異なる濃度が、より高濃度の原液から得ることができる);
特殊化皮膚細胞からの微小胞の単離を行うこと;
微小胞にCAPEを加えること;
溶液中に遊離し、微小胞にロードされていないCAPEから、CAPEロードされた微小胞を分離すること;
最終生成物であるSH-SY5Y神経芽腫がんを標的とするCAPEロードされた微小胞抗がん剤を得ること。
より低い濃度(5μM)で使用する;
細胞の種類に特異的である;
血液脳関門を通過する;
炎症を起こさない;
身体への毒性がない;、
がん型の抵抗性を防止する;
使用後に細胞内で代謝される;
長時間循環内に留まる;
ことが可能になる。
ロードされるCAPEの量の測定
ローディングプロセスの後、分光測光法に基づいて、微小胞構造に移動したCAPEの量を測定した。ロードされたCAPEの量を測定する場合、波長323 nmにおける分子の固有放射線を利用した。異なる濃度(1-100 μM)のCAPEを323 nmの波長で測定し、標準曲線を作成した。ロードされたCAPEの量を、2つの相互に関連する方法を使用して決定した。第一に、ロードされたCAPEの量を、CAPEをロードされた微小胞の沈殿後に上清中に残っている量を測定することによって決定した。第二に、ロードされたCAPEの量を、沈殿した物質でロードされた微小胞の膜構造の分画、および小胞構造にロードされたCAPEの量の測定によって決定した。
培養液に10%ウシ胎児血清(Invitrogen)および1% PSA(Biological Industries、Beit Haemek、イスラエ)を含むダルベッコ改変イーグル培地(DMEM)中、96ウェル培養プレート(Corning Glasswork、Corning、NY)に細胞を5000細胞/ウェルにて播種した後、細胞の生存率レベルを1日目、2日目および3日目に測定した。細胞生存率は、3-(4,5-ジ-メチル-チアゾール-2-イル)-5-(3-カルボキシ-メトキシ-フェネチル)-2-(4-スルホ-フェネチル)-2H-テトラゾリウム(MTS)法を用いて決定した(CellTiter 96 Aqueous One Solution;Promega, Southampton, UK)。10 μlのMTS溶液を100 μlの培地中の細胞に添加し、37℃にて暗所で2時間インキュベートした。インキュベーション処理の後、ELISAプレートリーダー(Biotek、Winooski、VT)デバイスを介して490 nmの波長にて吸光度を測定することによって、細胞生存率を観察した。
[1]. Lin, H.P., Lin, C.Y., Liu, C.C., Su, L.C., Huo, C., Kuo, Y.Y., Tseng, J.C., Hsu, J.M., Chen, C.K., Chuu, C.P. 2013. "Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling", Int J Mol Sci., 6;14(3):5264-83. doi: 10.3390/ijms14035264。
[2]. Tolba, M.F., Omar, H.A., Azab, S.S., Khalifa, A.E., Abdel-Naim, A.B., Abdel-Rahman, S.Z. 2014. "Caffeic acid phenethyl ester: A review of its antioxidant activity, protective effects against ischemia-reperfusion injury and drug adverse reactions", Crit Rev Food Sci Nutr.,DOI: 10.1080/10408398.2013.821967。
[3]. Wu, J., Omene, C., Karkoszka, J., Bosland, M., Eckard, J., Klein, C.B., Frenkel, K. 2011. "Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer", Cancer Lett.,1;308(1):43-53. doi: 10.1016/j.canlet.2011.04.012.
[4]. Omene, C.O., Wu, J., Frenkel, K. 2012. "Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells", Invest New Drugs, 30(4):1279-88. doi: 10.1007/s10637-011-9667-8。
[5]. Chuu, C.P., Lin, H.P., Ciaccio, M.F., Kokontis, J.M., Hause, R.J. Jr, Hiipakka, R.A., Liao, S., Jones, R.B. 2012. "Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks", Cancer Prev Res (Phila)., 5(5):788-97. doi: 10.1158/1940-6207.CAPR-12-0004-T。
[6]. Hsu, T.H., Chu, C.C., Hung, M.W., Lee, H.J., Hsu, H.J., Chang, T.C. 2013. "Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells" FEBS J., 280(11):2581-93. doi: 10.1111/febs.12242.
[7]. Kuo, Y.Y., Lin, H.P., Huo, C., Su, L.C., Yang, J., Hsiao, P.H., Chiang, H.C., Chung, C.J., Wang, H.D., Chang, J.Y., Chen, Y.W., Chuu, C.P. 2013. "Caffeic Acid Phenethyl Ester Suppresses Proliferation and Survival of TW2.6 Human Oral Cancer Cells via Inhibition of Akt Signaling", Int J Mol Sci., 24;14(5):8801-17. doi: 10.3390/ijms14058801。
[8]. Kim, E.Y., Ryu, J.H., Kim, A.K. 2013. "CAPE promotes TRAIL-induced apoptosis through the upregulation of TRAIL receptors via activation of p38 and suppression of JNK in SK-Hep1 hepatocellular carcinoma cells", Int J Oncol., 43(4):1291-300. doi: 10.3892/ijo.2013.2018.
[9]. Yagmurca, M., Erdogan, H., Iraz, M., Songur, A., Ucar, M., Fadillioglu, E. 2004. "Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats", Clin Chim Acta, 348:27-34。
[10]. Fadillioglu, E., Oztas, E., Erdogan, H., Yagmurca, M., Sogut, S., Ucar, M., et al. 2004. "Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats", J Appl Toxicol, 24:47-52。
[11]. Irmak, M.K., Fadillioglu, E., Sogut, S., Erdogan, H., Gulec, M., Ozer, M., et al. 2003. "Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain", Cell Biochem Funct., 21:283-9.
[12]. Iraz, M., Ozerol, E., Gulec, M., Tasdemir, S., Idiz, N., Fadillioglu, E., et al. 2006. "Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat", Cell Biochem Funct, 24:357-61。
[13]. Akyol, S., Ginis, Z., Armutcu, F., Ozturk, G., Yigitoglu, M.R., Akyol, O. 2012. "The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity", Cell Biochem Funct., 30(5):438-43. doi: 10.1002/cbf.2817.
[14]. Yildiz, O.G., Soyuer, S., Saraymen, R., Eroglu, C. 2008. "Protective effects of caffeic acid phenethyl ester on radiation induced lung injury in rats", Clin Invest Med, 31: E242-7。
[15]. Izuta, H., Shimazawa, M., Tazawa, S., Araki, Y., Mishima, S., & Hara, H. 2008. "Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells", Journal of Agricultural and Food Chemistry, 56(19), 8944-8953。
[16]. Lee, H. Y., Jeong, Y. I., Kim, E. J., Lee, K. D., Choi, S. H., Kim, Y. J., ... & Choi, K. C. 2015. "Preparation of Caffeic Acid Phenethyl Ester‐Incorporated Nanoparticles and Their Biological Activity". Journal of pharmaceutical sciences, 104(1), 144-154。
Claims (17)
- 細胞(幹細胞、細胞株、プライマー細胞、がん細胞、組織から得られた細胞)自体の成長条件に加えて、細胞の成長を可能にする37℃の温度、pH、5%二酸化炭素およびDMEM、F12、RPMI培地などの因子を変化させることによって産生される細胞小胞に、薬物(CAPE(カフェイン酸フェネチルエステル)をローディングすることにより得られる抗がん剤。
- 細胞自体の成長条件に加えて、細胞(幹細胞、細胞株、プライマー細胞、がん細胞、組織から得られた細胞)を他の化学物質(bFGF、EGF、NGFなどの成長因子;メラトニン、インスリン、ラクトフェリンなどのホルモン;アスコルビン酸、葉酸などのビタミン;カルシウム、マグネシウム、ホウ素などのミネラル)で処理することによって産生される細胞小胞に、薬物(CAPE(カフェイン酸フェネチルエステル)をローディングすることにより得られる抗がん剤。
- がん細胞に対する細胞毒性作用を提供するために使用される、請求項1または2に記載の抗がん剤。
- 25〜30日よりもむしろ12〜14日に獲得される、前記腫瘍形成が観察される、細胞の組織細胞への分化によって、特定のがんタイプに特異的な細胞によって産生される微小胞が使用される、請求項3に記載の抗がん剤。
- 神経細胞分化に付された幹細胞の分化によって獲得されるSHSY5Y細胞の特異的特徴は、25〜30日よりもむしろ12〜14日での分化による神経分化の初期段階で行われるので、該細胞によって産生された微小胞が、非常に低濃度でCAPEをローディングするために使用される、請求項4に記載の抗がん剤。
- CAPEが、SH-SY5Y神経芽腫がんを標的とするCAPEロードされた微小胞抗がん剤を開発する目的で、神経細胞を介して産生された細胞微小胞に、5 μM〜100 μMの範囲でローディングされる、請求項5に記載の抗がん剤。
- 前記請求項のいずれか1つに記載のSH-SY5Y神経芽腫がんを標的とするCAPEロードされた微小胞抗がん剤の製造方法であって、以下のステップ:
培地に皮膚幹細胞を播種(培養)すること;
神経芽細胞腫認識の機能が細胞に提供され、それらを標的にすることができるようにするために、十分な密集度(70〜80%)に達した培養培地中の細胞が6ウェル細胞培養プレートに播種されるようにする特殊化プロトコルを実装すること;
CAPE(カフェイン酸フェネチルエステル)をDMSO(ジメチルスルホキシド)に溶解することによって原液を調製すること;
特殊化皮膚細胞からの微小胞の単離を行うこと;
微小胞にCAPEを加えること;
溶液中に遊離し、微小胞にロードされていないCAPEから、CAPEロードされた微小胞を分離すること;
最終生成物であるSH-SY5Y神経芽腫がんを標的とするCAPEロードされた微小胞抗がん剤を得ること;
を含む方法。 - 皮膚幹細胞、SH-SY5Y、PNT-1A、PC-3細胞が、好ましくは、37℃の温度および5% CO2の細胞培養インキュベーターにて、10%ウシ胎児血清および1% PSAを含むDMEM(ダルベッコ改変イーグル培地)培地中で培養される、請求項7に記載の抗がん剤の製造方法。
- 培養培地中で細胞を特殊化するステップ中に、好ましくは10 ng/ml bFGF、10 ng/ml EGF、1% B7サプリメント、1% ITS(インスリン、トランスフェリンおよびセレン)、10% グルタミンおよび1% PSAを含むNeurobasal液を調製し、次いで、2日に1回、12〜14日間、6ウェル細胞培養プレートに播種された細胞にこの特殊化溶液を投与することによって、特殊化プロトコルが適用される、請求項7に記載の抗がん剤の製造方法。
- 45.75 mgのCAPEを3.22 mLのDMSO(ジメチルスルホキシド)に溶解することによって、最終濃度が約50,000 μMである原液が調製される、請求項7に記載の抗がん剤の製造方法。
- 特殊化皮膚細胞からの微小胞単離の段階で、培養培地から収集した溶液を、300 gで10分間遠心分離して、不要細胞を除去する、請求項7に記載の抗がん剤の製造方法。
- 遠心後のチューブ上部に残っている上澄みを新しいチューブに移し、可能性のある細胞成分を除くために14000 gで30分間遠心する、請求項11に記載の抗がん剤の製造方法。
- 遠心後のチューブ上部に残っている上澄みを新しいチューブに移し、1/2体積のA液を加え、+4度にて1日間インキュベートする、請求項11に記載の抗がん剤の製造方法。
- 1日後、16000 gで1時間遠心した後、ペレットを蒸留水(dH2O)に溶解する、請求項13に記載の抗がん剤の製造方法。
- CAPEの微小胞構造へのローディングが、室温でのインキュベーションによって行われる、請求項7に記載の抗がん剤の製造方法。
- 微小胞溶液を、最終濃度が100 μg/mlになるように、2 mlのPBSで調製した50 μM CAPE溶液に添加し、混合物を室温(25℃)にて20分間インキュベートする、請求項15に記載の抗がん剤の製造方法。
- 物質ロードされた小胞を得るために、沈殿した物質ロードペレットが、蒸留水(dH2O)に溶解される、請求項16に記載の抗がん剤の製造方法。
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US11274139B2 (en) * | 2013-04-12 | 2022-03-15 | Evox Therapeutics Ltd | Therapeutic delivery vesicles |
US20170209499A1 (en) * | 2014-07-18 | 2017-07-27 | Manuka Health New Zealand Limited | Propolis and Extracts Thereof for the Treatment of Skin Cancers and Improvement of Skin Health |
CN106692984B (zh) * | 2016-12-08 | 2020-02-18 | 武汉大学 | 一种基于细胞源性微囊泡的肿瘤靶向递送载体及制备方法和应用 |
-
2017
- 2017-12-18 TR TR2017/20642A patent/TR201720642A2/tr unknown
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2018
- 2018-12-17 EP EP18894456.5A patent/EP3727590A4/en active Pending
- 2018-12-17 US US16/955,087 patent/US11510891B2/en active Active
- 2018-12-17 CA CA3086056A patent/CA3086056A1/en active Pending
- 2018-12-17 CN CN201880089594.4A patent/CN112020380A/zh active Pending
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- 2018-12-17 JP JP2020533249A patent/JP7509423B2/ja active Active
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2022
- 2022-06-15 US US17/840,700 patent/US20220362194A1/en active Pending
Non-Patent Citations (2)
Title |
---|
ANDALOUSSI, S. EL ET AL: "Extracellular vesicles: biology and emerging therapeutic opportunities", NATURE REVIEWS, vol. 12, JPN6022043145, 2013, pages 347 - 357, XP055096689, ISSN: 0005086865, DOI: 10.1038/nrd3978 * |
TOMIYAMA, R. ET AL: "3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester induce preconditioning ER stress and aut", J CELL PHYSIOL, vol. Vol.233, Issue2, JPN6022043142, 6 July 2017 (2017-07-06), ISSN: 0005086864 * |
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US20210023038A1 (en) | 2021-01-28 |
US11510891B2 (en) | 2022-11-29 |
CA3086056A1 (en) | 2019-07-04 |
WO2019132831A3 (en) | 2019-09-26 |
TR201720642A2 (tr) | 2019-07-22 |
AU2018395740B2 (en) | 2024-02-15 |
AU2018395740A1 (en) | 2020-07-09 |
US20220362194A1 (en) | 2022-11-17 |
JP7509423B2 (ja) | 2024-07-02 |
RU2020123531A (ru) | 2022-01-20 |
EP3727590A2 (en) | 2020-10-28 |
EP3727590A4 (en) | 2021-09-29 |
CN112020380A (zh) | 2020-12-01 |
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