JP5739883B2 - 金属ナノ粒子、その調製および使用 - Google Patents
金属ナノ粒子、その調製および使用 Download PDFInfo
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- JP5739883B2 JP5739883B2 JP2012519006A JP2012519006A JP5739883B2 JP 5739883 B2 JP5739883 B2 JP 5739883B2 JP 2012519006 A JP2012519006 A JP 2012519006A JP 2012519006 A JP2012519006 A JP 2012519006A JP 5739883 B2 JP5739883 B2 JP 5739883B2
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Description
−本明細書に同定された金属元素、好ましくは、25に等しいか、またはそれを超える原子番号(Z)を有する金属元素を提供し、
−還元剤の存在下、媒体中の該金属元素の析出により該金属元素から金属ナノ粒子を調製し、次いで、所望により、
−錯化剤を媒体に添加し(錯化剤は、還元剤の添加前、添加中または添加後に添加する)、還元剤および錯化剤は、所望により同一化合物であり、次いで、所望により、
−前記の表面処理剤を用いてナノ粒子を覆う。
a)先駆物質として、本明細書に同定された金属元素、好ましくは、25に等しいかまたは25を超える原子番号(Z)を有する金属元素を提供し、
b)好ましくは、先駆物質および/または還元化合物の濃度および/または温度を調節することによって、還元化合物の存在下で先に定義された極性媒体中の工程a)の先駆物質を析出させ、
c)所望により、析出工程b)に先立って、その間または後に、極性媒体中の錯化剤を添加し、その錯化剤および還元剤は所望により同一化合物であり、
d)所望により、工程b)またはc)の終わりに得た懸濁液を洗浄して、いずれの不純物、還元剤および/または錯化剤も除去し、
e)所望により、工程d)の終わりに得られた懸濁液を濃縮し、次いで
f)所望により、ナノ粒子を覆う。
a)還元剤(クエン酸塩のごとき)の存在下、水溶液中で塩化金先駆物質(特に、HAuCl4またはKAuCl4のごとき)の溶液を析出させ、ここに、温度は、50℃〜100℃に含まれ、
b)所望により、得られた金属ナノ粒子懸濁液を洗浄して、いずれの不純物も除去し、
c)所望により、このように得られた金属ナノ粒子懸濁液を濃縮し、
d)所望により、先に定義された表面処理剤に接触して該金属ナノ粒子を配置することにより、該金属ナノ粒子を覆う。
さらに、驚くべきことには、本明細書に記載したナノ粒子は、観察された効力の増加で、放射線療法の文脈において単独で用いることができる。
−表面的標的組織に特に効果的な50〜150keVのX線;
−6cmの組織厚みに浸透できる200〜500keVのX線(慣用電圧);
−1000keV〜25,000keVのX線(メガ電圧)。例えば、前立腺癌の処置のためのナノ粒子のイオン化は、15,000keVのエネルギーを持つ5集光X線を介して実行できる。
実施例1:異なるサイズを持つ金ナノ粒子の合成的および物理化学的特徴付け
金ナノ粒子を水溶液中のクエン酸ナトリウムでの塩化金の還元によって得る。プロトコールは、G. Frens Nature Physical Science 241 (1973) 21を適合させた。典型的な実験において、HAuCl4溶液を沸騰まで加熱する。引き続いて、クエン酸ナトリウム溶液を添加する。得られた溶液を、5分間のさらなる期間沸騰下に維持する。ナノ粒子サイズをクエン酸塩−対−金先駆物質比を注意深く変更することにより、15から105nmまでで調節する(表1参照)。次いで、調製した金ナノ粒子懸濁液を30kDaセルロース膜を含む限外濾過装置(Millipore からのAmicon stirred cell model 8400)を用いて濃縮する。得られた懸濁液を薄板フード下の0.22μMカットオッフメンブレンフィルター(Millipore からのPES膜)を介して最終的に濾過し、4℃にて貯蔵する。金含量はICP−MSによって決定し、g/lの[Au]として示す。粒子サイズは、200を超える粒子(図1A)を計数することにより、透過型電子顕微鏡(TEM)を用いて決定し、サイズ測定用の最長のナノ粒子寸法を取る。ヒストグラムを確立し、平均および標準偏差を報告する(図1B)。
表1に記載した金ナノ粒子はすべて、同一合成プロセスにより調製して、同一の表面特徴特性を確実にする。TEM画像は、合成した金ナノ粒子がすべて形状において球状および/または卵形であることを示す。TEM電子回折パターンは、合成した金ナノ粒子がすべてCFC構造を示すことを示す。従って、金ナノ粒子のサイズだけが、先行技術に従うよく特徴付けされた平均粒子サイズおよびサイズ多分散性で変化する。
細胞に内部移行するか、または細胞に結合する金ナノ粒子(GNP)(以下、細胞レベルでの金濃度として示す)の放射線応答の増強を調査するために、本発明者らは、後記した特定のクローン原性生存アッセイを用いた:
HT29細胞を20000細胞/cm2の密度にて蒔いた。GNPをμM範囲での種々の金濃度で媒体に添加した。1時間〜24時間の培養時間後、細胞上清を除去した。次いで、細胞をPBSで簡単に洗浄し、細胞に非結合または非内部移行のGNPのすべてを除去した。次に、本発明者らは細胞トリプシン化を行ない、血球計算器を用いて、細胞数を計数した。各条件については、本発明者らは、100000細胞/mL〜220000細胞/mLの試料を採取し、さらにICP−MSによる金濃度につき分析した。
細胞:Au=1:X(ナノモルで示したX):
以下の計算によれば、
細胞=1
金(Au)濃度(μM)×1(mL)
X(ナノモルで示す)=−−−−−−−−−−−−−−−−−−−−−−
1000(mL)×mL当たりの細胞数
プレーティング効率(PE)は、いずれの照射もなく形成したコロニー数−対−播種した細胞数の比である:
PE=形成したコロニー数×100/播種した細胞数
SF=処理後に形成したコロニー数/(播種した細胞数*PE)
驚くべきことには、DEF値における閾値を粒子サイズ≧80nmを持つ金ナノ粒子につき観察する(図5Aおよび5Bを参照)。
異なる金濃度([Au]g/lで示す)を持つ金ナノ粒子は、200μLチューブにおいて調製し、特注設計のポリスチレンホルダーに入れた。μCTは陽極電圧を持つGeneral Electric Locus μCTシステム、およびそれぞれ50kVおよび450μAの電流を用いて行った。走査は90μmの等方性解像度モードを用いて行った。注目する円柱状小領域は、各チューブの中心にわたり3D画像に注意深く配置して、金ナノ粒子分散液を含む流体充填チューブの減衰値を測定した。
同様のX線減衰値を15nm〜105nmに含まれたサイズにつき、いずれの金ナノ粒子サイズでも観察する(図6Aおよび6Bを参照)。この結果は、ナノ粒子サイズ≧80nmにつき観察した効力に対する閾値効果を確認する。かかるナノ粒子は、所与の吸収されたX線エネルギーにつき細胞レベルにてより多くの損傷を生成できる(図4Aおよび4Bを参照)。
HT29細胞を適切な細胞数で蒔いて、処置により50〜200コロニー間で形成する。細胞が付着する場合、50μM、100μMまたは400μMの金を5分間(培養なし)または12時間未満の培養時間で添加する。60nmの粒子サイズを持つ金ナノ粒子(実施例1からの金−60)を試験した。細胞を照射しない(シャム対照)、または200kVpのX線装置を用いて、2Gyおよび4Gyの線量で照射した。照射後、細胞を37℃で10〜12日間培養した。クローンを固定し、クリスタルバイオレットで染色し、計数して、クローン原性生存率を見積もった。
データは、400μMの金濃度では、細胞の先の照射で、5分間未満培養した金ナノ粒子および12時間培養した金ナノ粒子につき、同様のかなりのDEF値を示す。これらの結果は、金ナノ粒子(GNP)が、GNPが細胞により内部移行されることを必要とすることなく、標的細胞放射線応答を増強することを示す。実際には、当業者により知られるごとく、生物学的媒体中に存在するナノ粒子の約50%の細胞取込みを可能にするのに、2時間が必要である(例えば、Chitraniら, 2006参照)。
- ‘Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice’, Meng-Ya Changら, Cancer Sci., 2008, 99(7) pp 1479-1484
- ‘Elucidating the Mechanism of Cellular Uptake and Removal of Protein-Coated Gold Nanoparticles of Different Sizes and Shapes’, B. Devika Chithraniら, Nano Lett., 2007, 7 (6), pp 1542-1550
- ‘Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells’, B. Devika Chithraniら, Nano Lett., 2006, 6 (4), pp 662-668
- ‘Enhancement of Radiation Cytotoxicity in Breast-Cancer Cells by Localized - Attachment of Gold Nanoparticles’, Tao Kongら, Small, 2008, 4(9), pp 1537-1543
- ‘Understanding biophysicochemical interactions at the nano-bio interface’, Andre E. Nelら, Nature Materials, 2009, 8, pp 543 - 557
- ‘The use of gold nanoparticles to enhance radiotherapy in mice’, James F Hainfeldら, Phys. Med. Biol., 2004, 49, pp N309-N315
- ‘Recent Advances in the Liquid-Phase Syntheses of Inorganic Nanoparticles’, Brian L. Cushingら, Chem. Rev., 2004, 104, pp 3893-3946
- “Folate-targeted, cationic liposome-mediated gene transfer into disseminated peritoneal tumors’ ; J A Reddyら, Gene therapy, 2002, 9, pp 1542-1550
- ‘Folate targeting of drug carriers: A mathematical model’, Ketan B. Ghaghadaら, Journal of Controlled Release, 2005, 104, pp 113-128
- ‘Controlled Nucleation for the Regulation of the Particle Size in Monodisperse Gold Suspensions’, G. Frens, Nature Physical Science, 1973, 241, pp 21-22.
Claims (11)
- ヒト対象における固形腫瘍からの細胞が電離放射線に曝露される場合に、該細胞を破壊する医薬組成物を調製するための金属ナノ粒子の集団の使用であって、
ナノ粒子が、少なくとも25の原子番号(Z)を有する金属より調製され、その集団のナノ粒子の平均最大寸法が80〜105nmであり、金属ナノ粒子が、生物学的適合性コーティングで覆われていることを特徴とする該使用。 - 生物学的適合性コーティングが、シリカ、アルミナ、糖、リン酸塩、シラン、チオール、双性イオン化合物、脂質、飽和炭素ポリマーおよび無機ポリマーよりなる群から選択される生物分解性でないコーティング;または生物学的ポリマー、リン脂質、糖類、オリゴ糖および多糖よりなる群から選択される生物分解性コーティングある請求項1記載の使用。
- 金属が、金(Au)、銀(Ag)、白金(Pt)、パラジウム(Pd)、スズ(Sn)、ジルコニウム(Zr)、鉄(Fe)より選択される請求項1または2記載の使用。
- 組成物が、標的細胞当たり10−6ナノモル〜10−3ナノモルの金属を含む請求項2または3記載の使用。
- 金属ナノ粒子が、生物学的な組織または細胞を特異的に標的とできる表面成分を含む請求項1〜4のいずれか1記載の使用。
- 金属ナノ粒子が、形状において、球状または卵形である請求項1〜5のいずれか1記載の使用。
- 該電離放射線が、X線、γ線、電子ビームおよび放射性同位体の照射よりなる群から選択される請求項1〜6のいずれか1記載の使用。
- 電離放射線が50KeV〜12000KeVである請求項7記載の使用。
- X線放射が50KeV〜6000KeVである請求項7記載の使用。
- 医薬組成物が、さらに、金属ナノ粒子の集団とは異なる、癌を処置するさらなる治療化合物を含む請求項1〜9のいずれか1記載の使用。
- 金属ナノ粒子の集団および医薬上許容される賦形剤を含む、ヒト対象における固形腫瘍からの細胞が電離放射線に曝露される場合に該細胞を破壊するための医薬組成物であって、
ナノ粒子は、少なくとも25の原子番号(Z)を有する金属で調製され、集団のナノ粒子の平均最大寸法は80〜105nmである該医薬組成物。
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CN (1) | CN102470173B (ja) |
AU (1) | AU2010270225B2 (ja) |
BR (2) | BR122019025997B8 (ja) |
CA (1) | CA2765290C (ja) |
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HR (2) | HRP20170175T1 (ja) |
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Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
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MX350309B (es) | 2009-07-08 | 2017-09-01 | Clene Nanomedicine Inc | Nanocristales novedosos basados en oro para tratamientos medicos y procedimientos de fabricacion electroquimica para los mismos. |
EP2275137A1 (en) * | 2009-07-10 | 2011-01-19 | Nanobiotix | Metallic nanoparticles, preparation and uses thereof |
US20120190979A1 (en) | 2011-01-24 | 2012-07-26 | Actium BioSystems, LLC | System for automatically amending energy field characteristics in the application of an energy field to a living organism for treatment of invasive agents |
RU2635653C2 (ru) | 2011-08-26 | 2017-11-14 | Эндомагнетикс Лтд | Устройство для генерирования энергетического поля для лечения рака полостей тела и полостных органов тела |
JP6042450B2 (ja) * | 2011-12-16 | 2016-12-14 | ナノビオティックスNanobiotix | 金属材料および酸化ハフニウム材料を含むナノ粒子、その製造および使用 |
CA2897362C (en) * | 2013-01-25 | 2023-02-14 | Nanobiotix | Inorganic nanoparticles compositions in combination with ionizing radiations for treating cancer |
SG11201509436TA (en) * | 2013-05-30 | 2015-12-30 | Nanobiotix | Pharmaceutical composition, preparation and uses thereof |
JP6560665B2 (ja) * | 2013-06-20 | 2019-08-14 | ナノビオティックスNanobiotix | 医療診断に使用するための組成物および方法 |
TWI689310B (zh) | 2014-07-11 | 2020-04-01 | 巨生生醫股份有限公司 | 治療鐵缺乏症之方法 |
JP6778371B2 (ja) * | 2015-01-23 | 2020-11-04 | ミヨシ油脂株式会社 | 金微粒子マトリックスメタロプロテアーゼ阻害剤 |
CN107708668A (zh) | 2015-05-28 | 2018-02-16 | 纳米生物技术公司 | 用作治疗性疫苗的纳米粒子 |
DE102017101057A1 (de) * | 2017-01-20 | 2018-07-26 | Fraunhofer-Institut für Angewandte Polymerforschung IAP | Zwitterionische Nanopartikel |
JP7376901B2 (ja) * | 2017-11-13 | 2023-11-09 | 国立大学法人北海道大学 | 修飾金属ナノ粒子及び医薬組成物 |
CN110883341B (zh) * | 2018-09-11 | 2021-03-30 | 清华大学 | 金纳米团簇制备方法 |
JPWO2021060498A1 (ja) * | 2019-09-27 | 2021-04-01 | ||
KR20230038659A (ko) * | 2020-05-26 | 2023-03-21 | 나노비오띡스 | 나노 입자, 전리 방사선 및 그의 혁신적인 치료용 조합 |
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WO2000006244A2 (en) * | 1998-07-30 | 2000-02-10 | Hainfeld James F | Loading metal particles into cell membrane vesicles and metal particle use for imaging and therapy |
US20070031337A1 (en) * | 2004-06-22 | 2007-02-08 | Reinhard Schulte | Nanoparticle enhanced proton computed tomography and proton therapy |
DE102007040934A1 (de) | 2007-08-30 | 2009-03-05 | Man Diesel A/S | Verfahren und Vorrichtung zur Reinigung von Abgas |
EP2130553A1 (en) * | 2008-06-05 | 2009-12-09 | Nanobiotix | Inorganic nanoparticles of high density to destroy cells in-vivo |
EP2275137A1 (en) * | 2009-07-10 | 2011-01-19 | Nanobiotix | Metallic nanoparticles, preparation and uses thereof |
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