JP2018506515A - 両親媒性ポリマー系 - Google Patents
両親媒性ポリマー系 Download PDFInfo
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- JP2018506515A JP2018506515A JP2017534723A JP2017534723A JP2018506515A JP 2018506515 A JP2018506515 A JP 2018506515A JP 2017534723 A JP2017534723 A JP 2017534723A JP 2017534723 A JP2017534723 A JP 2017534723A JP 2018506515 A JP2018506515 A JP 2018506515A
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- Prior art keywords
- formula
- oxazoline
- amphiphilic polymer
- segment
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- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
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- 150000002632 lipids Chemical class 0.000 description 1
- 238000010552 living cationic polymerization reaction Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- WCSNOLUUFIWIHY-UHFFFAOYSA-N methyl pent-4-ynoate Chemical compound COC(=O)CCC#C WCSNOLUUFIWIHY-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
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- 239000013612 plasmid Substances 0.000 description 1
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- 229920001559 poly(2-methyloxazoline)-block-poly(dimethylsiloxane) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 125000005630 sialyl group Chemical group 0.000 description 1
- 229910052710 silicon Chemical group 0.000 description 1
- 239000010703 silicon Chemical group 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
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- 150000007970 thio esters Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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- 229960001134 von willebrand factor Drugs 0.000 description 1
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Abstract
Description
第1の態様において、本発明は、一般式(I):
B−(L0−A−Z)n
(式中、nは1または2であり;
Bは疎水性ポリシロキサンセグメントであり;
L0は二価のリンカーセグメントであり;
Aは親水性ポリ−2−オキサゾリンコポリマーセグメントであり;
Zは末端基であるか、またはリガンドにコンジュゲートさせたリンカーである)
の両親媒性ポリマーを含む自己集合型粒子に関する。
B−(L0−C−Z)n
(式中、nは1または2であり;
Bは疎水性ポリシロキサンセグメントであり;
L0は二価のリンカーセグメントであり;
Cは親水性ポリ−2−オキサゾリンホモポリマーセグメントであり;
Zは末端基であるか、またはリガンドにコンジュゲートさせたリンカーである)
の両親媒性ポリマーとの組合せで含む自己集合型粒子に関する。また、一態様において、本発明の自己集合型粒子は、Zが末端基である式(II)の少なくとも1種類の両親媒性ポリマーと、Zがリンカーにコンジュゲートさせたリガンドである式(II)の少なくとも1種類の両親媒性ポリマーとを含み得る。
またさらなる一態様において、本発明は、一般式(I)の両親媒性ポリマーおよびその調製方法に関する。
第1の態様において、本発明は、一般式(I):
B−(L0−A−Z)n
(式中、nは1または2であり;
Bは疎水性ポリシロキサンセグメントであり;
L0は二価のリンカーセグメントであり;
Aは親水性ポリ−2−オキサゾリンコポリマーセグメントであり;
Zは末端基であるか、またはリガンドにコンジュゲートさせたリンカーである)
の両親媒性ポリマーを含む自己集合型粒子に関する。
から選択され、ここで、R9は水素またはC1〜C4アルキルであり、uは0、1または2である。
−N3、
および
R11は、小分子、抗体、抗原結合断片(fab)、シングルドメイン抗体、オリゴヌクレオチド、ポリペプチドおよび炭水化物から、特に、フォレート、ビオチンおよびペプチドから選択されるリガンドである。
B−(L0−C−Z)n
(式中、nは1または2であり;
Bは疎水性ポリシロキサンセグメントであり;
L0は二価のリンカーセグメントであり;
Cは親水性ポリ−2−オキサゾリンホモポリマーセグメントであり;
Zは、末端基またはリガンドにコンジュゲートさせたリンカーから選択される)
の両親媒性ポリマーを含む。
のセグメントCを含み得る。
B−(L0−A−Z)n
の両親媒性ポリマーであって、式中、nが1または2であり、Bが疎水性ポリシロキサンセグメントであり;L0、ZおよびAが以下のとおりであるものに関する:
Q0は存在しないか、またはH、非置換もしくは置換されたアルキル、アルケニル、アラルキル、アルキニル、ヘテロシクリルもしくはアリール、−C(O)−(CH2)q−COOH、−C(O)O−R10、−(CH2)q−C(O)O−R10、−C(O)R10、−NHC(O)−(CH2)q−N3、−(CH2)q−N3もしくは−SR10から選択され、ここで、R10は、非置換または置換されたアルキル、アルケニル、アラルキル基から選択され、qは整数1〜10である。
R2は独立して、C1〜C20アルキルまたはアラルキル基から選択され;
e、fは、0〜500から独立して選択される整数である、ただし、eおよびfが同時に0として選択されることはないものとし;
pは2〜500から選択される整数であり;
aは、整数e、fおよびpによって規定される単位がランダムに存在するランダムコポリマーを示すranから、または整数e、fおよびpによって規定される単位が連続するセグメントであるブロックコポリマーを示すブロックから選択される。
式中、
L5、L6およびL7は独立して、C1〜C20アルキレン、C4〜C12アリーレンおよびヘテロ原子O、N、Sのうちの1個以上が介在しているC1〜C20アルキレンまたはC4〜C12アリーレンから選択され;
R12は、−H(H)、−(H)R13、−(R13)2または−(R13)2R14Xから選択され、ここで、R13、R14は独立して、置換または非置換のC1〜C20アルキルおよび置換または非置換のアラルキルから選択され、Xは負の対イオンである。
式中、
R18およびR19は独立して、各モノマー単位について、診断用薬剤、治療用薬剤、リガンド、ならびに好ましくは水素、C1〜C20アルキレンおよびC1〜C20アリーレンから選択される置換基から選択される;ただし、少なくとも1つのモノマー単位ではR18および/またはR19が診断用薬剤、治療用薬剤またはリガンドであるものとし;
L6およびL7は独立して、C1〜C20アルキレン、C4〜C12アリーレンおよびヘテロ原子O、N、Sのうちの1個以上が介在しているC1〜C20アルキレンまたはC4〜C12アリーレンから選択され;
L8は式−R20(Y)sの二価のリンカーであり、ここで、R20はC1〜C20アルキレンもしくはアリーレンまたはヘテロ原子O、N、Sのうちの1個以上が介在しているC1〜C20アルキレンもしくはアリーレン基であり;Yは−S−S−、−NHC(O)−、−C(O)NH−、−OC(O)NH−、−NHC(O)O−、−OC(O)−、−OC(O)O−、−C(O)O−、−NHC(O)NH−、−SC(O)−、−C(O)S−、−NHC(S)NH−、−NH−および−C(O)−NH−N=であり、sは0、1または2であり;
tは、0または1の整数から選択され;
Zは、−OH、−NH2、
式中、
L6およびL7は独立して、C1〜C20アルキレン、C4〜C12アリーレンおよびヘテロ原子O、N、Sが介在しているC1〜C20アルキレンまたはC4〜C12アリーレンから選択され;
R21は、H(H)、H(R22)、(R22)2および(R22)2R23Xから選択され、ここで、R22およびR23は独立して、置換または非置換のC1〜C20アルキルおよび置換または非置換のアラルキルから選択され、Xは負の対イオンである。
実施例1
2−(4−アジドブチル)−オキサゾリン(1)の調製
ビス(ヒドロキシアルキル)末端型ポリ(ジメチルシロキサン)(5.6g,1mmol)のトルエン(25mL)溶液に2,6−ルチジン(0.35mL,3mmol)を添加した後、トリフルオロメタンスルホン酸無水物(0.4mL,2.4mmol)のヘキサン(2.5mL)溶液を氷浴中でアルゴン下にて滴下した。反応混合物を同温度で3時間撹拌した。次いで、溶媒を真空除去し、活性中間体を黄色油状物として得た。この油状物をクロロホルム(15mL)とアセトニトリル(20mL)の混合溶媒に溶解させた。第1のモノマーの2−(4−アジドブチル)−オキサゾール(1.03g,6.1mmol)を室温で添加した。反応混合物を加熱し、60℃で43時間撹拌し、次いで、これを室温まで冷却し、第2のモノマーの2−メチル−オキサゾリン(1.7mL,20mmol)を添加した。反応混合物を再度60℃まで加熱し、同じ温度で48時間撹拌し、次いで、トリエチルアミンの水溶液により室温でクエンチした。溶媒をエバポレーションによって除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回。最初は、5mlの飽和NaHCO3溶液を添加した)を溶離剤として用いて精製し、6.5gの化合物(2)をわずかに黄色の固形物として得た。収率:78%,1H NMR(400MHz,CDCl3)δ 3.30-3.75(m,128H),2.30-2.50(m,12H),2.05-2.21(m,60H),1.50-1.75(m,28H),0.50(m,4H),0.02-0.09(m,444H)ppm.
化合物(3)を、化合物(2)の合成と同様にして調製した。収率75%.1H NMR(400MHz,CD3OD)δ 3.40-3.75(m,212H),3.37(m,24H),2.30-2.57(m,20H),2.05-2.19(m,120H),1.58-1.75(m,44H),0.56(m,4H),0.03-0.17(m,444H)ppm.
化合物(2)(840mg,0.1mmol)のメタノール(5mL)溶液にトリエチルアミン(0.56mg,4.0mmol)を室温で添加した後、1,3−プロパンジチオール(0.40mL,4.0mmol)を添加した。反応混合物を室温で12時間撹拌した。溶媒を真空除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回)を溶離剤として用いて精製し、560mgの化合物(2)をわずかに黄色の固形物として得た。収率:67%.1H NMR(400MHz,CD3OD)δ 3.38-3.79(m,116H),2.68(m,12H),2.30-2.53(m,12H),2.05-2.15(m,60H),1.45-1.70(m,28H),0.57(m,4H),0.03-0.17(m,444H)ppm.
化合物(5)を化合物(3)から、化合物(4)の調製と同様にして調製した。収率:70%.1H NMR(400MHz,CD3OD)δ 3.38-3.75(m,212H),2.68(m,20H),2.30-2.53(m,20H),2.05-2.15(m,120H),1.45-1.70(m,44H),0.57(m,4H),0.03-0.17(m,444H)ppm.
化合物(2)(840mg,0.1mmol)のTHF(6mL,使用前にアルゴンで脱気)溶液に3−ジメチルアミノ−1−プロピン(83mg,1.0mL)を室温で添加した。混合物を同じ温度で5分間撹拌した。ナトリウム−L−アスコルベート(15mg,0.08mmol)水溶液(0.5mL)を添加した後、CuSO4.5H2O(7.5mg,0.03mmol)水溶液(0.5mL)を添加した。反応混合物を室温で24時間撹拌した。溶媒をエバポレーションによって除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回)を溶離剤として用いて精製し、780mgの化合物(2)をわずかに黄色の固形物として得た。収率:88%.1H NMR(400MHz,CD3OD)δ 7.93(m,6H),4.45(m,12H),3.38-3.75(m,128H),2.30-2.53(m,12H),2.27(s、36H),2.05-2.15(m,60H),1.95(m,12H),1.59(m,16H),0.59(m,4H),0.05-0.11(m,444H)ppm.
化合物(6)(100mg,0.011mmol)のTHF(2mL)溶液にヨウ化メチル(14.2mg,0.10mmol)をアルゴン下で室温にて添加した。混合物を室温で12時間撹拌した。溶媒をエバポレーションによって除去し、残渣を得た。この残渣をヘキサンで2回洗浄した。次いで、これを高真空下で乾燥させ、110mgの化合物(7)を黄色固形物として得た。収率100%.1H NMR(400MHz,CD3OD)δ 8.30-8.50(m,6H),4.50-4.80(m,24H),3.38-3.75(m,116H),2.94-3.20(m,54H),2.40-2.60(s、12H),2.05-2.18(m,60H),2.00(m,12H),1.60(m,16H),0.56(m,4H),0.05-0.11(m,444H)ppm.
ポリマー(3)(550mg,0.05mmol)のTHF(4mL)(これは、事前にアルゴン下で20分間脱気した)溶液に3−ジメチルアミノ−1−プロピン(11.4mg,0.13mmol)のt−BuOH(0.3mL)溶液を室温で添加した後、L−アスコルビン酸ナトリウム(5.4mg,0.027mmol)水溶液(0.25mL)とCuSO4.5H2O(3.4mg,0.014mmol)水溶液(0.25mL)を連続的に添加した。得られた混合物を室温で24時間撹拌した。次いで、溶媒をエバポレーションによって除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回)を溶離剤として用いて精製し、500mgの中間体をわずかに黄色の固形物として得た。収率:88%.
ポリマー(3)(550mg,0.05mmol)のTHF(脱気,4mL)溶液にペント−4−イン酸メチル(84mg,0.75mg)のt−BuOH(0.5mL)溶液を添加した。反応混合物を室温で5分間撹拌した。L−アスコルビン酸ナトリウム(7.5mg,0.04mmol)水溶液(0.25mL)と水性CuSO4.5H2O(3.75mg,0.015mmol)を連続的に添加した。得られた混合物を室温で12時間撹拌した。溶媒をエバポレーションによって除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回)を溶離剤として用いて精製し、430mgの中間体をわずかに黄色の固形物として得た。収率:71%.1H NMR(400MHz,CD3OD)δ 7.78(m,10H),4.38(m,20H),3.64(s、30H),3.40-3.70(m,212H),2.97(m,20H),2.70(m,20H),2.30-2.55(m,20H),2.05-2.18(m,120H),1.91(m,20H),1.57(m,24H),0.54(m,4H),0.05-0.15(m,444H)ppm.
ポリマー(4)(82.0mg,0.01mmol)のアセトニトリル(2mL)溶液にDIPEA(0.04mL,0.3mmol)を添加した後、化合物(10A)(60mg,0.09mmol)
ビス(ヒドロキシアルキル)末端型のポリ(ジメチルシロキサン)(5.6g,1mmol)のトルエン(25mL)溶液に2,6−ルチジン(0.35mL,3mmol)を添加した後、トリフルオロメタンスルホン酸無水物(0.4mL,2.4mmol)のヘキサン(2.5mL)溶液を氷浴中でアルゴン下にて滴下した。反応混合物を同温度で3時間撹拌した。次いで、溶媒を真空除去し、活性中間体を黄色油状物として得た。この油状物をクロロホルム(15mL)とアセトニトリル(20mL)の混合溶媒に溶解させた。モノマーの2−メチル−オキサゾリン(3.4mL,40mmol)を室温で添加した。反応混合物を再度60℃まで加熱し、同(some)温度で48時間撹拌した。次いで、これをアジ化ナトリウム(2.6g,40mmol)により室温でクエンチした。溶媒をエバポレーションによって除去し、残渣を得た。この残渣を再生セルロース膜(カットオフは5000ダルトン)での限外濾過により、エタノール/水(80:20,v/v,少なくとも4回。最初は、5mlの飽和NaHCO3溶液を添加した)を溶離剤として用いて精製し、6.5gの化合物(11)をわずかに黄色の固形物として得た。収率:72%,1H NMR(400MHz,CDCl3)δ 3.25-3.70(m,160H),2.05-2.21(m,120H),1.56(m,4H),0.50(m,4H),-0.02-0.20(m,444H)ppm.
ポリマー(11)(440mg,0.05mmol)のDMF(5mL)溶液にN,N,N’,N”,N”−ペンタメチルジエチレントリアミン(PMDETA,17.3mg,0.1mmol)を添加した後、フォレート誘導体(12a)(59mg,0.12mmol)
一般的な調製方法
本発明の両親媒性ポリマー、すなわち、式(I)〜(II)は、自己集合型粒子、特に、ミセルおよび小胞の調製のための成分として使用される。一部の実施形態では、自己集合型粒子が独立した治療用もしくは診断用薬剤またはオリゴヌクレオチドを含む。自己集合型粒子は以下の方法によって得られ得る:
1種類以上の両親媒性ポリマー成分を撹拌下で有機溶媒(例えば、エタノール)に溶解させる。次いで、水溶液(例えば、PBS)をこの溶液に滴下する。2時間〜24時間の連続撹拌後、この溶液を規定の孔径のフィルター(例えば、Millex−GV,0.22μm;Millipore)に通して濾過し、均一な自己集合型粒子集団を得る。この方法はミセルの調製に特に好ましい。有機溶媒をエバポレーションによって除去する。さらなる精製をサイズ排除カラム(例えば、セファロース2B)で行なう。
1種類以上の両親媒性ポリマーを有機溶媒に溶解させる。この溶媒を高真空下で蒸発させ、得られたポリマー膜を水溶液中で再水和させ、次いで、ポリカーボネートフィルター(例えば、0.2mmの孔径)から押出し、次いで、サイズ排除カラム(例えば、セファロース2B)で精製する。この方法は小胞の調製に特に好ましい。
バルク粉末の形態の1種類以上の両親媒性ポリマーを直接、水溶液に添加する。混合物を、ポリマーの完全な水和が観察されるまで連続撹拌する。次いで、得られた混合物をポリカーボネートフィルター(例えば、0.2mmの孔径フィルター)から押出し、次いで、サイズ排除カラム(例えば、セファロース2B)で精製する。
このミセルを調製するため、5mgの両親媒性ポリマー(6)を撹拌下で50μLのエタノールに溶解させる。この溶液に0.95mLのリン酸緩衝生理食塩水(PBS)を滴下する。2時間の連続撹拌後、この溶液を規定の孔径のフィルター(Millex−GV,0.22μm;Millipore)に通して濾過し、均一なミセル集団を得る。
この小胞を調製するため、10mgのポリマー(6)と10mgのポリマー(13)を10mLのクロロホルムに溶解させる。溶媒を高真空下で蒸発させて乾燥ポリマー膜を得、得られたポリマー膜を、20mLの1×PBSバッファー(PH=7.4)中で12時間、撹拌しながら再水和させ、次いで、ポリカーボネートフィルター(0.2mmの孔径)から押出し、小胞を得る。
このミセルを調製するため、5mgの両親媒性ポリマー(13)と0.5mgの両親媒性ポリマー(12)を撹拌下で50μLのエタノールに溶解させる。この溶液に0.95mLのリン酸緩衝生理食塩水(PBS)を滴下する。6時間の連続撹拌後、この溶液を規定の孔径のフィルター(Millex−GV,0.22μm;Millipore)に通して濾過し、均一なミセル集団を得る。
このミセルを調製するため、5mgの両親媒性ポリマー(13)、0.5mgの両親媒性ポリマー(12)および1.5mgのパクリタキセルを撹拌下で50μLのエタノールに溶解させる。0.95mLのリン酸緩衝生理食塩水(PBS)をこの溶液に滴下する。6時間の連続撹拌後、この溶液を規定の孔径のフィルター(Millex−GV,0.22μm;Millipore)に通して濾過し、均一なミセル集団を得る。このミセルをサイズ排除カラムでさらに精製し、未封入パクリタキセルを除去する(PBSバッファーを溶離剤として使用)。得られた溶液を凍結乾燥させ、固形ナノ粒子を得る。
このミセルを調製するため、5mgのポリマー(9)(ドキソルビシンがコンジュゲートされている)、0.5mgのポリマー(12)を撹拌下で50μLのエタノールに溶解させる。0.95mLのリン酸緩衝生理食塩水(PBS)をこの溶液に滴下する。5時間の連続撹拌後、この溶液を規定の孔径のフィルター(Millex−GV,0.22μm;Millipore)に通して濾過し、均一なミセル集団を得る。
このミセルを調製するため、5mgのポリマー(13)、0.5mgのポリマー(12)および0.1mgのローダミンB誘導体を撹拌下で50μLのエタノールに溶解させる。0.95mLのリン酸緩衝生理食塩水(PBS)をこの溶液に滴下する。6時間の連続撹拌後、この溶液を規定の孔径のフィルター(Millex−GV,0.22μm;Millipore)に通して濾過し、均一なミセル集団を得る。
両親媒性ポリマー(4)と(12)ベースのsiRNA負荷ミセルは水性自己集合によって調製される。ポリマーを各々、撹拌下で200μlのエタノールに溶解させ、2.5%(w/v)溶液を得る。次いで、この2つのポリマー溶液を、所望のN/P比(オリゴヌクレオチドのリン酸基のモルに対するポリマー(4)のアミン基のモルの比)が得られるとともに、両親媒性ポリマー混合物が0.5mol%含有量のポリマー(12)を有するように合わせる。続いて、所望の量のこの混合物を、40pmolのsiRNAを含む100μlの10mM PBSバッファーに添加する。得られた混合物を2分間ボルテックスした後、室温で1時間、穏やかに撹拌する。
両親媒性コポリマー(5)と(12)ベースのsiRNA負荷ミセルを、実施例21に記載の方法と同様にして調製した。この2種類のポリマーをエタノールに溶解させ、40pmolのsiRNAを含む100μlの10mM PBS(pH7.4)と穏やかに混合し、所望のN/P比5を得る。得られた混合物を室温で1時間、さらにインキュベートした。
70wt%の式(15)の両親媒性ポリマーと、腫瘍受容体特異的標的化リガンド、すなわちフォレートを末端の位置に含む20wt%の式(16)の両親媒性ポリマーと、ローダミンB色素を末端の位置に含む10wt%の式(17)の両親媒性ポリマーとを含む標的化ミセルをナノ沈殿法により、記載の一般的な方法および先の実施例、例えば実施例20と同様にして調製した。対照として、90wt%の(15)と10wt%の(17)を含む非標的化ミセルも、かかる方法を用いて調製した。得られたミセルのサイズは、DLSによる測定時、直径がおよそ20〜120nmである。
Claims (22)
- 一般式(I):
B−(L0−A−Z)n
(式中
nは1または2であり;
Bは疎水性ポリシロキサンセグメントであり;
L0は二価のリンカーセグメントであり;
Aは親水性ポリ−2−オキサゾリンコポリマーセグメントであり;
Zは末端基であるか、またはリガンドにコンジュゲートさせたリンカーである)
で表される両親媒性ポリマーを含む自己集合型粒子。 - さらに、式(II):
B−(L0−C−Z)n
(式中、B、L0、Zおよびnは請求項1に規定のとおりであり、
Cは親水性ポリ−2−オキサゾリンホモポリマーセグメントである)
で表される少なくとも1種類の両親媒性ポリマーを含む、請求項1に記載の自己集合型粒子。 - Zが末端基である式(II)の少なくとも1種類の両親媒性ポリマーを含む自己集合型粒子であって、
ミセルであり;任意で
Zがリガンドにコンジュゲートさせたリンカーである式(II)の少なくとも1種類の両親媒性ポリマーを含む、
自己集合型粒子。 - Zが末端基である式(II)の少なくとも1種類の両親媒性ポリマーを含む自己集合型粒子であって、Zが、抗体、抗原結合断片(fab)、シングルドメイン抗体、オリゴヌクレオチド、ポリペプチドおよび炭水化物から選択されるリガンドにコンジュゲートさせたリンカーであるかまたはリンカーが受容体特異的リガンドに、好ましくはフォレートまたはその誘導体にコンジュゲートされている式(II)の少なくとも1種類の両親媒性ポリマーを含む、自己集合型粒子。
- 親水性ポリ−2−オキサゾリンコポリマーセグメントAに診断用薬剤、治療用薬剤または抗体、抗原結合断片(fab)、シングルドメイン抗体、オリゴヌクレオチド、ポリペプチドもしくは炭水化物などのリガンドがコンジュゲートされている、請求項1または2に記載の自己集合型粒子。
- 親水性ポリ−2−オキサゾリンコポリマーセグメントAが少なくとも2種類の2−置換−2−オキサゾリンモノマーの共重合により得られ得るものであり、該モノマーの少なくとも1種類が2−アルキル−2−オキサゾリンまたは2−アリール−2−オキサゾリンである、請求項1、2または5に記載の自己集合型粒子。
- 一般式(I)の両親媒性ポリマーの疎水性ポリシロキサンセグメントBがポリジメチルシロキサンセグメントであり;
ポリ−2−オキサゾリンコポリマーセグメントAが少なくとも1つのポリ−2−メチル−オキサゾリンブロックを含み、 Zが末端基である、
請求項1、2、5または6のいずれかに記載の自己集合型粒子。 - 式(II)の両親媒性ポリマーの疎水性ポリシロキサンセグメントBがポリジメチルシロキサンであり、
Cがポリ−2−メチル−オキサゾリンである、
請求項2、3、4または7に記載の自己集合型粒子。 - ミセルもしくは小胞であるか、またはミセルである、請求項1〜8のいずれかに記載の自己集合型粒子。
- 独立して、治療用薬剤、診断用薬剤もしくはオリゴヌクレオチドまたはその組合せを含む、請求項1〜9のいずれかに記載の自己集合型粒子。
- 一般式(I)
B−(L0−A−Z)n
の両親媒性ポリマーであって、
式中、B、L0、A、Zおよびnは請求項1に規定のとおりであり、ここで、
(a)L0は式R8(Q)uであり、ここで、
R8は、1〜20個の炭素原子を含むアルキレンまたはアリーレン基およびヘテロ原子O、N、Sのうちの1個以上が介在している1〜20個の炭素原子を含むアルキレンまたはアリーレン基から選択され;
Qは、−O−、−S−、−S−S−、−NR9−、−NHC(O)−、−C(O)NH−、−OC(O)NH−、−NHC(O)O−、−OC(O)、C(O)O−、−NHC(O)NH−、−SC(O)−、−C(O)S−、−NHC(S)NH−、
から選択され;
(b)Zは、式−X1−Q0の末端基であるか、または式−L3−R11のリガンドにコンジュゲートさせたリンカーであり、ここで、
X1は、−O−、−S−、−NH−、−NR10−、
Q0は存在しないか、またはH、非置換もしくは置換されたアルキル、アルケニル、アラルキル、アルキニル、ヘテロシクリル、アリール、−C(O)−(CH2)q−COOH、−C(O)O−R10、−(CH2)q−C(O)O−R10、−C(O)R10、−NHC(O)−(CH2)q−N3、−(CH2)q−N3もしくは−SR10から選択され、ここで、R10は非置換または置換されたアルキル、アルケニルまたはアラルキル基であり、qは整数1〜10であり;
L3は−S−、−O−、−OC(O)−、−OC(O)NH−、−NHC(O)−、−NHC(O)NH、−NHC(S)NH−、−NHC(O)O−、
または
R11は、小分子、抗体、抗原結合断片(fab)、シングルドメイン抗体、オリゴヌクレオチド、炭水化物から選択されるリガンド、特に、フォレート、ビオチンまたはペプチドから選択されるリガンドであり;
(c)Aは、式(I−a):
R1およびR3は独立して、治療用薬剤、診断用薬剤、リガンドにコンジュゲートさせたリンカーならびにアミン、アジド、アルキン、アルデヒド、アセタール、アルコール、カルボン酸、活性化カルボン酸、オキシアミン、ケトン、ケタール、エステル、マレイミド、ビニルスルホン、オルトピリジルジスルフィドおよびクロロホルメートから選択される官能基を含むリンカーから選択され;
R2はC1〜C20アルキルまたはアラルキル基であり;
eおよびfは0〜500から独立して選択される整数である、ただし、eおよびfが同時に0として選択されることはないものとし;
pは2〜500から選択される整数であり;
aは、ranおよびブロックから選択され、ここで、ranは、整数e、fおよびpによって規定される単位がランダムに存在するランダムコポリマーを示し、ブロックは、整数e、fおよびpによって規定される単位が連続するセグメントであるブロックコポリマーを示す)
の親水性ポリ−2−オキサゾリンコポリマーセグメントである
両親媒性ポリマー。 - Aが、式(I−b):
Zは、−OH、−NH2、
の親水性ポリ−2−オキサゾリンコポリマーセグメントである、請求項11に記載の両親媒性ポリマー。 - fが0であり、Aが、式(I−c):
- Aが、式(I−d):
の親水性ポリ−2−オキサゾリンコポリマーセグメントである、請求項11に記載の両親媒性ポリマー。 - fが0であり、Aが、式(I−e):
ただし、少なくとも1つのモノマー単位ではR18が治療用薬剤または診断用薬剤であるものとする)
の親水性ポリ−2−オキサゾリンコポリマーセグメントである、請求項14に記載の組成物。 - eが0であり、Aが、式(I−f):
ただし、少なくとも1つのモノマー単位ではR19が治療用薬剤または診断用薬剤であるものとする)
の親水性ポリ−2−オキサゾリンコポリマーセグメントである、請求項14に記載の両親媒性ポリマー。 - ポリシロキサン開始剤と、少なくとも1種類の2−(アジドアルキル)−2−オキサゾリンモノマーおよび少なくとも1種類の2−アルキル−2−オキサゾリンまたは2−アラルキル−2−オキサゾリンモノマーとのカチオン開環重合の工程を含む、請求項11に記載の両親媒性ポリマーの調製方法。
- さらに、アジド還元工程および/またはアルキニル成分との1,3双極子付加環化工程を含む、請求項17に記載の方法。
- Aが、式(I−g):
の親水性ポリ−2−オキサゾリンコポリマーセグメントである、請求項11に記載の両親媒性ポリマー。 - fが0であり;
Aが、式(I−h):
請求項19に記載の両親媒性ポリマー。 - eが0であり、 R21がH(H)であり、 Aが、式(I−i)
Zが、−OH、−N3、−NH2、
請求項19に記載の両親媒性ポリマー。 - Zが、請求項11において規定した末端基であるか、または小分子、抗体、抗原結合断片(fab)、シングルドメイン抗体、オリゴヌクレオチド、ポリペプチドおよび炭水化物から選択されるリガンドにコンジュゲートさせたリンカーである、請求項1〜10のいずれかに記載の自己集合型粒子。
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