JP4927726B2 - ゲムシタビン誘導体ナノ粒子 - Google Patents
ゲムシタビン誘導体ナノ粒子 Download PDFInfo
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- JP4927726B2 JP4927726B2 JP2007518660A JP2007518660A JP4927726B2 JP 4927726 B2 JP4927726 B2 JP 4927726B2 JP 2007518660 A JP2007518660 A JP 2007518660A JP 2007518660 A JP2007518660 A JP 2007518660A JP 4927726 B2 JP4927726 B2 JP 4927726B2
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- derivative
- nanoparticles
- gemcitabine
- polyethylene glycol
- squalenoyl
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Images
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Description
R1、R2、およびR3は、同一でも異なっていてもよく、互いに独立に、水素原子、または極性溶媒媒質中において一般式(I)を有する前記化合物に、特にナノ微粒子型のコンパクト化された形態を付与することが可能である立体配座を有する少なくともC18の炭化水素アシル基、を表し;
R1、R2、およびR3基の少なくとも1つが、水素原子以外のものである。
・ 本発明によるゲムシタビン誘導体を少なくとも1種の有機溶媒中に溶解させるステップであって、得られる混合物を撹拌しながら水性相に添加した場合に、前記水性相中に懸濁した前記誘導体のナノ粒子の瞬間的形成が得られるのに十分な濃度で溶解させるステップと、所望により、
・ 前記ナノ粒子を単離するステップと
を含む方法に関する。
・ 静脈内注射液または灌流液;
・ 食塩水または精製水;
・ 吸入用組成物;
・ 眼投与用組成物;
・ カプセル剤、糖衣剤、および貼剤であり、特にビヒクルとして、水、リン酸カルシウム、糖(例えば、ラクトース、デキストロースまたはマンニトール)、タルク、ステアリン酸、デンプン、重炭酸ナトリウム、および/またはゼラチンを組み込んでいるもの
である。
〔実施例1:4-(N)-スクアレノイルゲムシタビン(SQgem)の調製〕
a)スクアレン酸(SQCOOH)の合成
11mlの蒸留水に1.16mlの硫酸を添加し;次に0.615g(2.06ミリモル)のNa2Cr2O7.2H2Oを注意深く添加して、クロム酸が得られた。0.794g(2.06ミリモル)のスクアレンアルデヒド(SQCHO)(Ceruti M. et al, J. Chem. Soc, Perkin Trans, 1; 2002,1477〜1486)を、磁気撹拌機を使用して撹拌しながら16mlのジエチルエーテルに溶解し、次いでフラスコを0℃に冷却した。次に、このSQCHO溶液にクロム酸を1滴ずつ添加した。この反応液を、0℃で2時間磁気攪拌機により撹拌した。粗生成物を、有機相を水で洗浄することにより、次いでシリカゲルフラッシュクロマトグラフィーにより、石油エーテル/エーテル95:5で溶離して精製した。収率:35%(0.286g、0.714ミリモル)。
1H NMR (CD3COCH3 99.5% 300MHz) δ:5.11 (5H, m, CH ビニル)、2.38 (2H, t, CH2CH2COOH)、2.26 (2H, t, CH2CH2COOH)、2.13〜1.86 (16H, m, CH2 アリル)、1.65〜1.59 (15H, m, CH3 アリル)、1.26 (3H, s, CH3 アリル)。
CIMS (イソブタン) m/z 401 (100)。
EIMS m/z 400 (5)、357 (3)、331 (5)、289 (3)、208 (6)、136 (3)、81 (100)。
1mlの無水テトラヒドロフラン(THF)に溶解した、a)で得られた0.209g(0.522ミリモル)のSQCOOHを、流量計を備えた三ツ口フラスコに入れ、次いで、磁気攪拌機で撹拌しかつアルゴンを流しながら、0.5mlの無水THFに溶解した0.053g(0.522ミリモル)のトリエチルアミン(TEA)を添加した。次いでフラスコを-15℃まで冷却した。この反応混合物に、2.15mlの無水THFに溶解した0.057g(0.522ミリモル)のエチルクロロホルメートを1滴ずつ添加した。-15℃において20分後、2.72mlのジメチルホルムアミド(DMF)に溶解した0.137g(0.522ミリモル)のゲムシタビンを添加し、+5℃まで温度を上昇させ、さらに最後に室温まで温度を上昇させた。反応を薄層クロマトグラフィー(ジクロロメタン/アセトン、50:50)によりモニターして、アミドが生成するまで磁気撹拌を数日継続した。粗生成物を、シリカゲルフラッシュクロマトグラフィーにより、ジクロロメタン/アセトン95:5混合物で溶離して精製した。収率:55%(0.185g、0.287ミリモル)。
1H NMR (ピリジン-d5 99.5% 300MHz) δ:12.05 (1H,s,NHCO)、8.77 (1H,d,CH-6)、7.74 (1H,d,CH-5)、6.99 (1H,t,CH-1')、5.30〜5.02 (1H,m,CH-3'および5H,m,CH ビニル)、4.47〜4.31 (3H,m,CH-4'およびCH2-5')、2.81 (2H,t,NHCOCH2)、2.53 (2H,t,NHCOCH2CH2)、2.18〜2.00 (16H,m,CH2 アリル)、1.68〜1.55 (18H,m,CH3 アリル)。
CIMS (イソブタン) m/z 646 (100)。
EIMS m/z 645 (10)、577 (8)、523 (7)、509 (18)、494 (10)、454 (15)、429 (24)、372 (100)。
Fessi H. et al., Int. J. Pharm., 55; 1989, R1〜R4に記載されたナノ析出技術を使用して、SQgemにより構成される粒子が得られた。エタノール中のSQgem10mg/ml溶液の試料を取り出し、所望の濃度までアセトンに添加して、合計2mlの有機相が得られた。次いで、エタノール/アセトン混合物中のこのSQgem溶液を、磁気撹拌しながら4mlのMilliQ(登録商標)水に添加した。瞬間的に粒子が生成した。真空下で有機溶媒を蒸発除去した後、SQgemの安定粒子の懸濁液が得られた。この懸濁液は、+4℃で保存しなければならなかった。
a)ナノ粒子の粒径の測定
実施例1において得られたコロイド粒子の粒径を、ナノサイザー(Coulter(登録商標)N4MD、Coulter Electronics社、Hialeah、米国)を使用して準弾性光散乱によりモニタした。
Wilhemyブレード型張力計を使用して、種々の濃度で一定表面積におけるSQgem水溶液の表面張力を測定し、ゲムシタビン(Gem)、および4-(N)-ステアロイルゲムシタビン(C18gem)(Myhren F et al, Gemcitabine derivatives, 米国特許第2002/0042391号)の溶液の表面張力と比較した。
2つのヒト腫瘍細胞株(KB3-1、鼻咽頭の癌、およびMCF-7、乳癌)についてのSQgemの細胞毒性活性を、SQgemに72時間曝露することにより評価し、ゲムシタビンの活性と比較した。
4-(N)-スクアレノイルゲムシタビン2mgと、ポリエチレングリコールにカップリングしたコレステロール(Chol-PEG PEGYLATED CHOLESTEROL、SUNBRIGHT CS-20) 1.4mgとを、1mlのアセトン中に溶解した。磁気撹拌しながら、この有機相を2mlのMillQ(登録商標)水に添加した。真空下でアセトンを蒸発除去した後、ナノ粒子の安定懸濁液が得られた。ナノ粒子の粒径は、実施例2に記載したプロトコルを使用して測定して、約75nmであり、ゼータ電位は-32.7mVであった。
4-(N)-スクアレノイルゲムシタビンについて実施例1に記載した手順を使用して、シタラビンとの反応によりスクアレン酸から4-(N)-スクアレノイルシタラビンを合成した。SQgem粒子について記述したように、ナノ析出技術によって、SQara-Cにより構成される粒子が得られ、最終懸濁液中のSQara-Cの濃度1mg/mlについてその平均流体力学的直径は、110.4±34.1nmであった(多分散性指数:0.168)。
28mgのN-ヒドロキシベンゾトリアゾール(0.18ミリモル)、36mgのジダノシン(ddI、0.15ミリモル)、70mgのO-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロボレート(0.18ミリモル)、および最後に62mgのジイソプロピルエチルアミン(0.5ミリモル)を、無水ジメチルホルムアミド(1.2ml)中の31mgの(4,8,13,17,21-ペンタメチル-ドコサ-4,8,12,16,20-ペンタエン酸(SqCOOH、0.15ミリモル)の溶液に添加した。この混合物を、窒素雰囲気中において20℃で84時間撹拌し、次いで減圧(0.05torr)下で濃縮した。その残渣を、5mlの重炭酸ナトリウムの飽和水溶液中に溶解し、酢酸エチルで抽出した(3×10ml)。有機相をNaCl水溶液で洗浄し、MgSO4上で乾燥し、かつ真空下で濃縮した。残渣をシリカゲル上のクロマトグラフィーにかけて(CH2Cl2/MeOH:92/8)、無色の非晶質固体の形態で37mgの5'-スクアレノイルジダノシンを得た(収率58%)。
IR (cm-1) 3550〜2700、2921、2856、1734、1691、1590、1548、1449、1380、1261。
1H NMR (200MHz, CDCl3) δ:13.0 (s broad, 1H)、8.18 (s, IH)、8.08 (s, IH)、6.38 (t, J = 4.2Hz, 1H)、5.17〜5.00 (m, 5H)、4.40〜4.20 (m, 3H)、2.60〜1.90 (m, 24H)、1.67 (s, 3H)、1.60 (s broad, 15H)。
13C NMR (50MHz, CDCl3) δ:173.27 (CO2)、159.20 (CO)、148.34 (C)、144.3 (CH) 138.60 (CH)、135.23 (C)、135.03 (C)、135.00 (C)、133.09 (C)、131.31 (C)、125.56 (CH)、125.38 (C)、125.54 (CH)、124.53 (CH)、124.40 (2 CH)、85.94 (CH)、79.60 (CH)、65.07 (CH2)、39.86 (CH2)、39.83 (CH2)、39.68 (CH2)、34.67 (CH2)、33.12 (CH2)、33.01 (CH2)、28.39 (CH2)、28.38 (CH2)、29.9 (CH2)、26.83 (CH2)、26.79 (CH2)、26.28 (CH2)、25.77 (CH3)、17.77 (CH3)、16.51 (2 CH3)、16.10 (CH3)、16.00 (CH3)。
45mgのN-ヒドロキシベンゾトリアゾール(0.29ミリモル)、79mgのジドブジン(AZT、0.24ミリモル)、113mgのO-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロボレート(0.29ミリモル)、および最後に102mgのジイソプロピルエチルアミン(0.5ミリモル)を、無水ジメチルホルムアミド(2ml)中の50mgの4,8,13,17,21-ペンタメチル-ドコサ-4,8,12,16,20-ペンタエン酸(SqCOOH、0.15ミリモル)の溶液に添加した。この混合物を、窒素雰囲気中において20℃で90時間撹拌し、次に減圧下(0.05Torr)で濃縮した。残渣を、10mlの重炭酸ナトリウムの飽和水溶液中に溶解し、酢酸エチルで抽出した(3×15ml)。有機相をNaCl水溶液で洗浄し、MgSO4上で乾燥し、真空下で濃縮した。残渣をシリカゲル上でのクロマトグラフィーにかけ(CH2Cl2/MeOH:97/3)、無色の非晶質固体の形態で52mgの5'-スクアレノイルジドブジンを得た(収率43%)。
IR (cm-1) 3158、2920、2854、2105、1741、1690、1449、1381、1270。
1H NMR (200MHz, CDCl3) δ:8.2 (s broad, 1H)、7.22 (s, 1H)、6.12 (t, J = 6.4Hz, 1H)、5.17〜5.00 (m, 5H)、4.40 (dd, J = 12.2Hz, 4.6Hz, 1H)、4.30 (dd, 12.2Hz, 3.8Hz, 1H)、4.10〜4.05 (m, 1H)、2.55〜2.20 (m, 5H)、2.10〜1.90 (m, 18H)、1.94 (s, 3H)、1.69 (s, 3H)、1.60 (s broad,15H)。
13C NMR (50MHz, CDCl3) δ:172.87 (CO2)、163.57 (CO)、150.12 (CO)、135.31 (C)、135.27 (CH)、135.04 (C)、134.91 (C)、132.86 (C)、131.35 (C)、125.79 (CH)、124.67 (CH)、124.56 (CH)、124.40 (CH)、124.37 (CH)、111.43 (C)、85.64 (CH)、82.00 (CH)、63.36 (CH2)、60.81 (CH)、39.88 (CH2)、39.85 (CH2)、39.68 (CH2)、37.75 (CH2)、34.62 (CH2)、33.18 (CH2)、29.81 (CH2)、28.41 (CH2)、28.39 (CH2)、26.91 (CH2)、26.82 (CH2)、26.81 (CH2)、25.80 (CH3)、17.79 (CH3)、16.17 (2 CH3)、16.16 (CH3)、16.12 (CH3)、16.05 (CH3)、12.73 (CH3)。
4-(N)-スクアレノイルアシクロビルを、アシクロビルとの反応によりスクアレン酸から合成した。使用した上記手順で、スクアレン鎖とアシクロビルの間にエステル結合またはアミド結合のいずれかを得ることが可能であった。SQACVにより構成される粒子は、SQgemの粒子について記述したナノ析出技術を使用して得られ、最終懸濁液中のSQACVの濃度1mg/mlについてその平均流体力学的直径は、217.5 + 37.9nmであった(多分散性指数:0.038)。
Claims (19)
- R1基として、スクアレノイル基またはその誘導基を含むことを特徴とする、請求項1に記載の2',2'-ジフルオロ-2'-デオキシシチジン誘導体。
- R2およびR3がそれぞれ水素原子を表すことを特徴とする、請求項3に記載の誘導体。
- 請求項1から4のいずれか一項に記載の誘導体のナノ粒子。
- 4-(N)-スクアレノイルゲムシタビンのナノ粒子。
- 平均径が30nmから500nmであることを特徴とする、請求項5または6に記載のナノ粒子。
- ポリエチレングリコールの親油性誘導体の少なくとも1種と結合していることを特徴とする、請求項5から7のいずれか一項に記載のナノ粒子。
- 前記のポリエチレングリコールの親油性誘導体が、ポリエチレングリコールコレステロールであることを特徴とする、請求項8に記載のナノ粒子。
- 請求項5から9のいずれか一項に記載のナノ粒子を製造する方法であって、少なくとも、
・ 請求項1から4のいずれか一項に記載の少なくとも1種の誘導体を、少なくとも1種の有機溶媒中に溶解させるステップであって、得られる混合物を撹拌しながら水性相に添加した場合に、前記水性相中に懸濁したナノ粒子の瞬間的形成が得られるのに十分である濃度で溶解させるステップと、所望により、
・ 前記ナノ粒子を単離するステップと
を含むことを特徴とするナノ粒子の製造方法。 - 界面活性剤の不在下で行うことを特徴とする、請求項10に記載の製造方法。
- ポリエチレングリコールの親油性誘導体の存在下で行うことを特徴とする、請求項10に記載の製造方法。
- 前記のポリエチレングリコールの親油性誘導体が、ポリエチレングリコールコレステロールであることを特徴とする、請求項12に記載の製造方法。
- 活性物質として、請求項1から4のいずれか一項に記載の少なくとも1種の誘導体、または請求項5から9のいずれか一項に記載のナノ粒子を、少なくとも1種の医薬として許容可能なビヒクルと組み合せて含む医薬組成物。
- 活性物質として、請求項1から4のいずれか一項に記載の少なくとも1種の誘導体、または請求項5から9のいずれか一項に記載のナノ粒子を、少なくとも1種の医薬として許容可能なビヒクルと組み合せて含む、抗ガン用医薬組成物。
- 活性物質として、請求項1から4のいずれか一項に記載の少なくとも1種の誘導体、または請求項5から9のいずれか一項に記載のナノ粒子を、少なくとも1種の医薬として許容可能なビヒクルと組み合せて含む、抗ウイルス用医薬組成物。
- 抗ガン剤としての、請求項5から9のいずれか一項に記載のナノ粒子。
- 抗ウイルス剤としての、請求項5から9のいずれか一項に記載のナノ粒子。
- 抗ガン活性もしくは抗ウイルス活性を備えた医薬組成物を製造するための、請求項1から4のいずれかに記載の誘導体または請求項5から9のいずれか一項に記載のナノ粒子の使用。
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ES2776100T3 (es) * | 2006-03-31 | 2020-07-29 | Massachusetts Inst Technology | Sistema para el suministro dirigido de agentes terapéuticos |
FR2924024B1 (fr) * | 2007-11-27 | 2012-08-17 | Centre Nat Rech Scient | Nanoparticules d'actifs therapeutiques de faible solubilite aqueuse |
FR2931152B1 (fr) * | 2008-05-16 | 2010-07-30 | Centre Nat Rech Scient | Nouveau systeme de transfert d'acide nucleique |
WO2010039039A1 (en) * | 2008-10-03 | 2010-04-08 | Clavis Pharma Asa | Oral formulations of gemcitabine derivatives |
FR2937537A1 (fr) * | 2008-10-29 | 2010-04-30 | Centre Nat Rech Scient | Nanoparticules de statine |
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WO2010050624A1 (en) * | 2008-10-31 | 2010-05-06 | Hitachi Koki Co., Ltd. | Centrifuge |
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FR2968662B1 (fr) | 2010-12-10 | 2013-11-22 | Roussy Inst Gustave | Nouveaux derives d'oxazaphosphorines pre-activees, utilisation et methode de preparation |
EP2729180B1 (en) | 2011-07-08 | 2019-01-23 | The University of North Carolina At Chapel Hill | Metal bisphosphonate nanoparticles for anti-cancer therapy and imaging and for treating bone disorders |
FR2988092B1 (fr) | 2012-03-16 | 2014-04-25 | Centre Nat Rech Scient | Complexes de vitamine c, nanoparticules desdits complexes, procedes pour leur preparation, leurs compositions, leurs utilisations cosmetiques et procede de traitement cosmetique |
KR20150082606A (ko) | 2012-11-13 | 2015-07-15 | 보옌 테라퓨틱스, 인크. | 겜시타빈 전구약물 및 그의 용도 |
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EP3045169B1 (en) * | 2013-09-13 | 2018-05-02 | Akiko Itai | Aqueous solution formulation, and manufacturing method for same |
CN105873569B (zh) | 2013-11-06 | 2020-07-28 | 芝加哥大学 | 用于化疗剂、核酸和光敏剂的递送或共递送的纳米级载体 |
CN103599073A (zh) * | 2013-11-15 | 2014-02-26 | 无锡中科光远生物材料有限公司 | 一种负载有靶向抗癌药物的plga微米颗粒的制备方法 |
WO2015081867A1 (zh) * | 2013-12-04 | 2015-06-11 | 杭州民生药物研究院有限公司 | 吉西他滨衍生物、含该衍生物的组合物及所述衍生物的制药用途 |
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EP3439666A4 (en) | 2016-05-20 | 2019-12-11 | The University of Chicago | NANOPARTICLES FOR CHEMOTHERAPY, TARGETED THERAPY, PHOTODYNAMIC THERAPY, IMMUNOTHERAPY AND ANY COMBINATION THEREOF |
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AU2018312224A1 (en) | 2017-07-31 | 2020-02-27 | January Therapeutics, Inc. | Organophosphate derivatives |
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