JP2008514686A - 抗原及びアジュバントを含むナノ粒子、並びに免疫原性構造 - Google Patents
抗原及びアジュバントを含むナノ粒子、並びに免疫原性構造 Download PDFInfo
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- 210000003932 urinary bladder Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 229910052984 zinc sulfide Inorganic materials 0.000 description 1
- DRDVZXDWVBGGMH-UHFFFAOYSA-N zinc;sulfide Chemical compound [S-2].[Zn+2] DRDVZXDWVBGGMH-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
Parish D.C. et al., 1991, Southern Medical Jounal, 84, 426−430 Pietersz G.A. et al., 1998, Cancer Immunol. Immunother., 45, 321−326
概して、本発明は、アジュバントと抗原とを含むナノ粒子、及び糖鎖を有する免疫原性構造に関する。
(ナノ粒子)
ナノ粒子は、固定化リガンドの基質として使用可能な、小さな粒子、例えば、金属又は半導体原子のクラスターである。
抗原は、適応的免疫反応の細胞、すなわち、T細胞若しくはB細胞、又はその両方により特異的に認識される分子である。
アジュバントは、抗原への免疫反応を増強する薬剤である。アジュバントは、適応的免疫反応の細胞を刺激することにより抗体反応を増強してよく、及び/又は先天性免疫反応の活性を非特異的に押し上げることにより作用してよい。一般に、抗体反応を増強する抗原は、それらが、リンパ球に曝露される適切な部位で抗原を濃縮するか、又はサイトカイン産生を刺激することによるかのいずれかにより、それを行う。
本発明のナノ粒子組成物は、経腸又は非経口を含む、かなり多数の異なる経路により患者に投与されてよい。非経口投与には、以下の経路による投与が含まれる:静脈内、皮膚又は皮下、経鼻、筋内、眼内、経上皮、腹腔内、及び局所(皮膚、眼、直腸、鼻、吸入及びエアロゾルを含む)、並びに直腸の全身経路。
免疫原性構造などの本発明の組成物は、ガンなどの病気の予防及び治療のため、とりわけ免疫療法のために用いられてよい。
[実施例1]
糖鎖抗原、Tヘルパーキャリア、及び金表面に結合したグルコースを負荷したナノ粒子の調製及び特徴付けを以下に記載する。
HAuCl4及びNaBH4を、Aldrich Chemical Companyから購入した。全ての実験及び溶液について、ナノピュア(Nanopure)水(18.1 mΩ)を用いた。
a)BC11 I(Glc:STn:BC11=28:1:1)
ペプチドBC11(3.1 mg、1.31μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(8.8 mg、36.7μmol)及びSTn(0.8 mg、1.31μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、及びBC11のシグナル間で28:1:1の比を示した。
ペプチドBC11(4.0 mg、1.7μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(8.1 mg、33.9μmol)及びSTn(9.3 mg、15.2μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、及びBC11のシグナル間で20:9:1の比を示した。
ペプチドBC11(2.8 mg、1.2μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(5.1 mg、21.3μmol)、Ley(0.9 mg、1.2μmol)、及びSTn(7.3 mg、11.8μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、Ley、及びBC11のシグナル間で18:10:1:1の比を示した。
ペプチドBC11(2.7 mg、1.1μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(4.9 mg、20.6μmol)、Ley(8.8 mg、11.4μmol)、及びSTn(0.7 mg、1.1μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、Ley、及びBC11のシグナル間で18:1:10:1の比を示した。
a)BMIX I(Glc:STn:BMIX=28:1:1)
ペプチドBMIX(3.5 mg、1.31μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(8.8 mg、36.6μmol)及びSTn(0.8 mg、1.31μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、及びBMIXのシグナル間で28:1:1の比を示した。
ペプチドBMIX(3.5 mg、1.31μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(6.3 mg、26.2μmol)及びSTn(7.2 mg、11.7μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、及びBMIXのシグナル間で20:9:1の比を示した。
ペプチドBMIX(3.9 mg、1.46μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(6.3 mg、26.2μmol)、Ley(1.1 mg、1.46μmol)、及びSTn(9.0 mg、14.6μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、Ley、及びBMIXのシグナル間で18:10:1:1の比を示した。
ペプチドBMIX(3.7 mg、1.38μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(6.0 mg、24.8μmol)、Ley(10.7 mg、13.8μmol)、及びSTn(0.85 mg、1.38μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、STn、Ley、及びBMIXのシグナル間で18:1:10:1の比を示した。
ペプチドBMIX(3.7 mg、1.4μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(9.4 mg、39.1μmol)及びLey(1.1 mg、1.4μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、Ley、及びBMIXのシグナル間で28:1:1の比を示した。
ペプチドBMIX(3.5 mg、1.31μmol)を、CF3COOD(100μL)に溶解し、オイルの形成が観察されるまで、溶液をアルゴン流下で濃縮した。ついで、Glc(6.3 mg、26.2μmol)及びLey(9.2 mg、11.8μmol)を添加し、混合物をCD3OD(500μL)に溶解した。1H NMRスペクトルは、Glc、Ley、及びBMIXのシグナル間で20:9:1の比を示した。
ナノ粒子BC11 I、II、III、及びIVを用いて、マウスに接種し、結合抗原に対する免疫反応をモニタリングした。200μLのアジュバント(Sigma M−6536−MPL+TDM)中、30μgのナノ粒子を注入した。4回の2×100μLの注入を、0、28、40、及び157日目に与えた。初めの3回は、皮下に与え、最後の注入は腹腔内に与えた。39、48、及び67日目に血液(bleed)を回収し、HSA−Leyに対するIgG力価を測定した(図7及び8)。BC11 I/IIとBC11 III/IVで見られた結果の間には大きな差がある。BC11 I/IIにおけるLeyに対する力価の上昇は、アジュバントの使用に起因する、非特異的な効果である。免疫付与を繰り返した場合には、力価は増加せず、減少し始める。対照的に、BC11 III/IVを用いた場合には、力価は追加免疫付与とともに増加し、実際(real)の免疫効果を実証する。
(免疫原性構造としての金ナノ粒子)
金ナノ粒子の配合を、国際公開第02/32404号に記載のとおりの技術に従って行う。アルファ−シアリル−Tn:ルイス y=30:3及び3:30の比率を有する、金ナノ粒子の異なる構築物を、様々な密度のペプチド配列FKLQTMVKLFNRIKNNVAを用いて調製する。Glc−C2を用いて、残りのスペースをブロックできる。別法として、リンカーもまた、配列FKFQILYNSIMGのものであり得る。
HE2へのシアリルTn糖鎖のカップリング
シアリルTn−O(CH2)3NH(CH2)4COO−pNpをHE2にカップリングした。シアリルTn糖鎖リガンドの数を増加させるために、当分野で周知の分岐したリンカーを用いて、抗体上に糖鎖リガンドをカップリングできる。最終生成物を、SEC、LDS−PAGE、ウエスタンブロット、及び異なるELISA試験により分析した。
(材料及び方法)
・HE2 Panorex、10 mg/mL、ロット番号170901
・シアリルTn−O(CH2)3NH(CH2)4COO−pNp、2×5 mg、Fa. Lectinity
・DMF(N,N−ジメチルホルムアミド(無水、Merck))
・カップリングバッファー:0.1 M Na2HPO4+0.15 M NaCl(pH=8)
・フォーミュレーションバッファー(Formulation buffer):NaCl 0.86%+1 mM Na2HPO4(pH=6.0)
1.最大で〜10 mLの体積で、SEC〜10 mg/mLに応じた濃度で、4℃、20時間、Slide−A−Lyzer透析カセットを用いて、2×700 mLのカップリングバッファーに対して、100 mgのHE2(V=10 mL;Conc:10 mg/mL)を透析した。
2.2×5 mgのシアリルTn−O(CH2)3NH(CH2)4COO−pNpを、2×100μLのDMF(100μL/バイアル)で溶解した。
3.シアリルTn(DMF中)の溶液を、〜10 mL(〜100 mg)の氷冷HE2(カップリングバッファー中)に添加した。
4.両方のシアリルTn−バイアルを、100μLのDMF(バイアル1からバイアル2に移す)ですすぎ、これを、反応混合物にさらに添加した。
5.反応混合物を、4℃で一晩(28時間)回転させた。反応物の反応速度をSECにより観察した(5.3.1及び6.3.1を参照されたい)。
6.4℃、20時間、Slide−A−Lyzer透析カセットを用いて、2×800 mLのフォーミュレーションバッファーに対して、HE2−シアリルTn(10 mL、〜10 mg/mL)の最終溶液を透析した。
サイズ排除クロマトグラフィー
Dionexシステムにおける、ZORBAX GF−250カラム上のサイズ排除クロマトグラフィー(SEC)により、HE2−シアリルTnの濃度を定量化した。ゲルろ過標準(Fa. BioRad)を用いてHPLCシステムを試験した。HE2−シアリルTnを定量するための参照標準としてHE2を用いた。保持時間の減少(分子量の増加と相関する)は、HE2へのシアリルTnのカップリング反応の有効性と相関する。受け取ったデータは、カップリングの有効性が、23〜27時間で飽和状態に達する、反応時間とともに増加することを示す。
ビス−Tris−ゲル(4〜12%)「SilverXpress(商標)−染色」を用いたLDS−PAGE:「NuPAGE Bis−Tris−Gel」取扱説明書の13頁を参照されたい。結果を図7に示す。
ウサギxマウスIgG2aを用いたウエスタンブロット
手順:
1.ビス−Tris−ゲル(4〜12%)を用いたLDS−ゲル
2.ウエスタントランスファー:「NuPAGE Bis−Tris−Gel」取扱説明書の14〜20頁を参照されたい(Immobilon トランスファーメンブレン PVDF 0.45μm、Fa. Millipore)。
3.メンブレン現像
複合体:ウサギxマウスIgG2a−HRP、#61−0220、Fa. Zymed
染色溶液1:5 mLのMetOH中、15 mgのHRP−Color Reagent(Fa. BioRAD)
染色溶液2:25 mLのPBS def. 1×中、15μLの30%H2O2
・PBS中3%スキムミルク粉末を用いて、室温、1時間、メンブレンをブロッキングする。
・PBSを用いてメンブレンを洗浄する。
・複合体(PBSで1:1000に希釈)とともに、室温、1時間、インキュベートする。
・PBSを用いてメンブレンを洗浄する。
・染色溶液1+2を用いて現像し、水を用いて止める。
1.ビス−Tris−ゲル(4〜12%)を用いたLDS−PAGEゲル
2.ウエスタントランスファー:「NuPAGE Bis−Tris−Gel」取扱説明書の14〜20頁を参照されたい(Immobilon トランスファーメンブレン PVDF 0.45μm、Fa. Millipore)。
3.メンブレン現像
二次抗体(Secondary Ab):抗−シアリルTn CD175s(IgGタイプ)、90μg/mL、Fa. DAKO、コード番号M0899、ロット089(601)
複合体:ウサギxマウスIgG1−HRP、Fa. Becton Dickinson、Mat.No. 559626、バッチ:37205
PBS def. 1×中、3%のスキムミルク粉末
染色溶液1:5 mLのMetOH中、15 mgのHRP−Color Reagent(Fa. BioRAD)
染色溶液2:25 mLのPBS中、15μLの30%H2O2
・PBS中3%スキムミルク粉末を用いて、室温、1時間、メンブレンをブロッキングする。
・PBSを用いてメンブレンを洗浄する。
・二次抗体(濃度10μg/mL)V=5 mLとともに、室温、1時間、インキュベートする。
・PBSを用いてメンブレンを洗浄する。
・複合体(PBSで1:1000に希釈)とともに、室温、1時間、インキュベートする。
・PBSを用いてメンブレンを洗浄する。
・染色溶液1+2を用いて現像し、水を用いて止める。
固定化IGN111は、抗マウスIgG2a−HRPにより検出される抗イディオタイプHE2を捕捉する。HE2は、HE2−シアリルTnよりも、約2〜3倍反応することが示された。これは、非常に緩やかな(very moderate)結合の消失のみが、カップリング後に生じることを示す。
シアリルTnは、首尾よく、HE2抗体とカップリングしている。カップリング反応は、およそ24時間後に飽和状態に達する、かなり長期間の反応速度(kinetic)を有する。視アリルTnは、主に、HE2抗体の重鎖とカップリングしており、一方、軽鎖はシアリルTnと部分的にのみカップリングしている。HE2−シアリルTnカップリング生成物は、HE2の大部分のイディオタイプ特異性を保持しており、この新規糖タンパク質のシアリルTn部分は、シアリルTn特異抗原により認識される。内毒素レベルは、検出限界未満である。
本明細書に記載の参考文献は、その全体が参照として、すべて明確に援用される。
Claims (69)
- 金属及び/又は半導体原子を含む核を含むナノ粒子であって、ここで、前記核が複数のリガンドと共有結合しており、かつ前記リガンドが少なくとも1つの抗原と少なくとも1つのアジュバントとを含む、ナノ粒子。
- 前記少なくとも1つのアジュバントが、先天性免疫反応を刺激する、請求項1記載のナノ粒子。
- 前記少なくとも1つのアジュバントが、T細胞反応を刺激する、請求項1又は2記載のナノ粒子。
- 前記T細胞反応が、Tヘルパー細胞反応を含む、請求項3記載のナノ粒子。
- 糖鎖部分であるアジュバントを含む、請求項1又は2記載のナノ粒子。
- 前記糖鎖部分が、グルコース、マンノース、フコース、及び/又はN−アセチルグルコサミンを含む、請求項5記載のナノ粒子。
- ペプチド部分であるアジュバントを含む、請求項1乃至6のいずれか一項記載のナノ粒子。
- 前記ペプチド部分が、Tヘルパー細胞を活性化するペプチドである、請求項3又は4記載のナノ粒子。
- 前記ペプチド部分が、プロテアーゼ切断部位を含む、請求項7又は8記載のナノ粒子。
- 前記ペプチドが、アミノ酸配列FKLQTMVKLFNRIKNNVAを含む、請求項9記載のナノ粒子。
- 前記抗原が、腫瘍特異抗原である、請求項1乃至10のいずれか一項記載のナノ粒子。
- 前記抗原が、糖鎖抗原である、請求項11記載のナノ粒子。
- 前記抗原が、シアル化されている、請求項12記載のナノ粒子。
- 前記抗原が、シアル化されている、請求項12記載のナノ粒子。
- 前記抗原が、シアリルTn、シアリルルイスa、シアリルルイスx、又はシアリルルイスyである、請求項14記載のナノ粒子。
- 前記抗原が、病原体特異抗原である、請求項1乃至15のいずれか一項記載のナノ粒子。
- 前記病原体が、細菌、ウイルス、又は寄生虫である、請求項16記載のナノ粒子。
- 前記リガンドの少なくとも1つが、リンカー基を介して前記ナノ粒子と結合している、請求項1乃至17のいずれか一項記載のナノ粒子。
- 前記リンカー基が、チオール基、アルキル基、グリコール基、又はペプチド基を含む、請求項18記載のナノ粒子。
- 前記リンカー基が、C2〜C15アルキル及び/又はC2〜C15グリコールを含む、請求項19記載のナノ粒子。
- 前記リンカー基が、C2〜C15アルキル又はヘキサエチレングリコール−C11アルキルである、請求項20記載のナノ粒子。
- 前記ナノ粒子が、標識を含む、請求項1乃至21のいずれか一項記載のナノ粒子。
- 前記標識が、蛍光基、放射性核種、磁気標識、色素、NMR活性原子、又は表面プラズモン共鳴を用いて検出可能な原子である、請求項22記載のナノ粒子。
- 前記磁気標識が、Mn+2、Gd+3、Eu+2、Cu+2、V+2、Co+2、Ni+2、Fe+2、Fe+3、又はランタニド+3を含む常磁性基である、請求項23記載のナノ粒子。
- 前記NMR活性原子が、Mn+2、Gd+3、Eu+2、Cu+2、V+2、Co+2、Ni+2、Fe+2、Fe+3、又はランタニド+3である、請求項23記載のナノ粒子。
- 前記ナノ粒子が水溶性である、請求項1乃至25のいずれか一項記載のナノ粒子。
- 前記ナノ粒子の核が、0.5〜10 nmの平均径を有する、請求項1乃至26のいずれか一項記載のナノ粒子。
- 前記ナノ粒子の核が、1〜2.5 nmの平均径を有する、請求項1乃至27のいずれか一項記載のナノ粒子。
- そのリガンドを含む前記ナノ粒子が、10〜30 nmの平均径を有する、請求項1乃至28のいずれか一項記載のナノ粒子。
- 前記核が金属核である、請求項1乃至29のいずれか一項記載のナノ粒子。
- 前記金属核が、Au、Ag、又はCuを含む、請求項30記載のナノ粒子。
- 前記金属核が、Au/Ag、Au/Cu、Au/Ag/Cu、Au/Pt、Au/Pd、Au/Ag/Cu/Pd、Au/Fe、Au/Cu、Au/Gd、Au/Fe/Cu、Au/Fe/Gd、又はAu/Fe/Cu/Gdから選択される合金である、請求項30又は31記載のナノ粒子。
- 前記ナノ粒子の核が磁性である、請求項30乃至32のいずれか一項記載のナノ粒子。
- 前記ナノ粒子が、前記核中に、約5:0.1〜約2:5の比率の不動態化金属原子及び磁性金属原子を含む、請求項33記載のナノ粒子。
- 前記不動態化金属が、金、白金、銀、又は銅であり、かつ前記磁性金属が、鉄又はコバルトである、請求項34記載のナノ粒子。
- 前記核が、半導体原子を含む、請求項1乃至29のいずれか一項記載のナノ粒子。
- 前記半導体原子が、量子ドットとして作用できる、請求項36記載のナノ粒子。
- 前記リガンドが、ペプチド、タンパク質ドメイン、核酸セグメント、糖脂質、又は糖タンパク質をさらに含む、請求項1乃至37のいずれか一項記載のナノ粒子。
- 前記リガンドが、DNA又はRNAを含む、請求項1乃至38のいずれか一項記載のナノ粒子。
- 請求項1乃至39のいずれか一項記載のナノ粒子の1つ以上の集団を含む、組成物。
- 医薬として許容可能なキャリアをさらに含む、請求項40記載の組成物。
- 糖鎖リガンド及び少なくとも1つのT細胞ヘルパーペプチドリガンドと共有結合した核分子からなる、免疫原性構造。
- 複数の糖鎖リガンドと共有結合した核分子からなり、ここで、前記糖鎖リガンドが、少なくとも1つのネオエピトープ構造を含む、免疫原性構造。
- 前記核分子が、金属若しくは半導体原子と、抗体又はそれらの誘導体若しくは断片との核からなるナノ粒子から選択される、請求項42又は43記載の免疫原性構造。
- 前記金属核が、Au、Ag、Cu、Pd、又はAlを含む、請求項42乃至44のいずれか一項記載のキャリア分子。
- ネオエピトープ構造を含む、請求項42記載の免疫原性構造。
- 前記糖鎖リガンドが、ルイス抗原又はシアリルTnである、請求項42乃至46のいずれか一項記載の免疫原性構造。
- 前記ルイス抗原が、シアル化されている、請求項47記載の免疫原性構造。
- 前記ルイス抗原が、シアル化されている、請求項47記載の免疫原性構造。
- 前記T細胞ヘルパーペプチドリガンドが、破傷風トキソイド、ジフテリアトキソイド、又はキーホールリンペットヘモシアニンからなる群から選択されるトキソイドに由来する、請求項42乃至49のいずれか一項記載の免疫原性構造。
- 前記T細胞ヘルパーペプチドリガンドが、アミノ酸配列FKLQTMVKLFNRIKNNVAのものである、請求項42乃至50のいずれか一項記載の免疫原性構造。
- 請求項42乃至51のいずれか一項記載の免疫原性構造の1つ以上を含む、医薬組成物。
- 少なくとも1つのワクチンアジュバントを含有する、請求項52記載の医薬組成物。
- 免疫療法の治療用薬剤を調製するための、請求項52又は53記載の組成物の使用。
- 前記薬剤が、ガンの予防又は治療用である、請求項54記載の使用。
- 腫瘍細胞の検出及び単離に適した抗体を単離するための、請求項42乃至51のいずれか一項記載の免疫原性構造の使用。
- 以下の工程:
・リンカーを用いて抗原を誘導体化する工程;
・リンカーを用いてアジュバントを誘導体化する工程;及び
・前記リンカー誘導体化抗原とアジュバントとを、ナノ粒子の核を製造するための反応物質と反応させて、前記ナノ粒子の自己集合の間に、前記ナノ粒子核が、前記リンカーを介して前記抗原及びアジュバントと結合する工程、
を含む、少なくとも1つの抗原と少なくとも1つのアジュバントとを、ナノ粒子の核に結合させることによる、請求項1乃至39のいずれか一項記載のナノ粒子の製造方法。 - 前記リンカー基が、チオール基、アルキル基、グリコール基、又はペプチド基を含む、請求項57記載の方法。
- 前記リンカー基が、C2〜C15アルキル及び/又はC2〜C15グリコールを含む、請求項57記載の方法。
- 前記リンカー基が、C2〜C15アルキル又はヘキサエチレングリコール−C11アルキルである、請求項57記載の方法。
- 前記反応混合物が、前記誘導体化抗原、前記誘導体化アジュバント、金属及び/又は半導体原子の塩、及び前記ナノ粒子を製造するための還元剤を含む、請求項57乃至60のいずれか一項記載の方法。
- 請求項57乃至61のいずれか一項記載の方法により得られる、ナノ粒子。
- 予防療法又は一時療法における使用のための、請求項1乃至39のいずれか一項記載のナノ粒子、又は請求項40若しくは41記載の組成物。
- ワクチンとして使用するための、請求項1乃至39のいずれか一項記載のナノ粒子、又は請求項40若しくは41記載の組成物。
- ガンの治療用薬剤を調製するための、請求項11乃至15のいずれか一項記載のナノ粒子の使用。
- 前記ガンが、結腸、膵臓、腸、肺、肝臓、卵巣、又は膀胱のガンである、請求項65記載の使用。
- 感染症の治療用薬剤を調製するための、請求項16又は17記載のナノ粒子の使用。
- 前記病気が、マラリア又は結核症である、請求項67記載の使用。
- 前記ナノ粒子が膜輸送シグナルを含み、細胞膜を通過できる、請求項65乃至68のいずれか一項記載の使用。
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Also Published As
Publication number | Publication date |
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WO2006037979A3 (en) | 2007-04-05 |
CA2582668A1 (en) | 2006-04-13 |
EP1793863B1 (en) | 2017-04-12 |
JP5117191B2 (ja) | 2013-01-09 |
EP1793863A2 (en) | 2007-06-13 |
CA2582668C (en) | 2013-10-01 |
WO2006037979A2 (en) | 2006-04-13 |
ES2625905T3 (es) | 2017-07-20 |
AU2005291058B2 (en) | 2011-09-29 |
US9079765B2 (en) | 2015-07-14 |
AU2005291058A1 (en) | 2006-04-13 |
US20090104268A1 (en) | 2009-04-23 |
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