JP5918274B2 - 薬物送達のためのセルロース系ナノ粒子 - Google Patents
薬物送達のためのセルロース系ナノ粒子 Download PDFInfo
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- JP5918274B2 JP5918274B2 JP2013552078A JP2013552078A JP5918274B2 JP 5918274 B2 JP5918274 B2 JP 5918274B2 JP 2013552078 A JP2013552078 A JP 2013552078A JP 2013552078 A JP2013552078 A JP 2013552078A JP 5918274 B2 JP5918274 B2 JP 5918274B2
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Description
下記のステップ:すなわち
a)少なくとも1つのPEGおよび少なくとも1つの疎水性薬物をCMC-Acと共有結合させるステップと;
b)ステップ(a)の生成物を単離するステップと;
c)ステップ(b)の単離生成物を適切な有機溶媒、好ましくはDMFまたはDMSO、更に好ましくはTHFまたはアセトニトリルに溶解して、溶液を形成するステップと;
d)自己集合性ナノ粒子組成物の形成のために適切な条件下でステップ(c)の溶液を水溶液に滴下するステップ
とを含む、自己集合性ナノ粒子組成物を調製する方法が提供される。
nは、94より大きい整数である。
nは、94より大きい整数である。
下記の説明では、本発明を十分に理解するために、多くの具体的詳細が記載される。しかし、本発明は、これらの具体的詳細以外で実施されうることが理解される。
下記のステップ:すなわち
a)少なくとも1つのPEGおよび少なくとも1つの疎水性薬物をCMC-Acと共有結合させるステップと;
b)ステップ(a)の生成物を単離するステップと;
c)ステップ(b)の単離生成物を適切な有機溶媒、好ましくはDMFまたはDMSO、更に好ましくはTHFまたはアセトニトリルに溶解して、溶液を形成するステップと;
d)自己集合性ナノ粒子組成物の形成のために適切な条件下でステップ(c)の溶液を水溶液に滴下するステップ
とを含む、自己集合性ナノ粒子組成物を調製する方法が提供される。
nは、94より大きい整数である。
カルボキシメチルセルロースナトリウム(CEKOL 30K (DS)=0.82)は、CPKelco(Atlanta, Georgia, USA)から入手され、FDAおよびEUの食品等級材料である。氷酢酸、無水酢酸、硫酸、アセトン、アセトニトリル、ポリ(エチレングリコール)メチルエーテル(mPEG-OH、MN=2000)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド HCl(EDC HCL)、N-ヒドロキシスクシンイミド(NHS)、4-ジメチルアミノピリジン(DMAP)、およびジエチルエーテルは、Sigma Aldrich(Oakville, ON)から購入された。ドセタキセル(DTX)は、LC Laboratories(Woburn, MA, USA)から購入された。Slide-a-Lyzer 10および20 kDa MWCO透析カートリッジは、Pierce Biotechnology(Rockford, IL)から購入された。Vivaspin 10 kDa MWCO超遠心濃縮フィルターは、Fisher(Ottawa, ON, Canada)から購入された。
サンプルを、重水素化クロロホルム(CDCl3)、酸化重水素(D20)、またはN,N-ジメチルスルホキシド(DMSO)に溶解し、Bruker 500装置で解析した。スペクトルは、TOPSpinソフトウェアを用いて処理された。
Waters e2696 Separation Module、2414 RIおよび2998 PDA検出器から構成され、Empower Pro 2によって操作されるHPLCシステムで、DTX分析を行った。サンプルを、Agilent XDB-C18カラム(1.8μm、4.6×50 mm)に、0.35 mL/分の95/5アセトニトリル/水 無勾配プログラムを用いて注入した。タキサン類の分析および検出方法は、いくつかの報文69-71に基づき、研究室の機器に合わせて変更した。通常の分析では、既知のタキサンの同一性(ドセタキセル、パクリタキセル、および7-エピドセタキセル)は、PDA検出器によって、274 nmの選択波長を用いて同定された。方法開発の際には、サンプルは、PDAおよびSQ MS検出器を備えたWaters Acquity UPLC/MSシステムによって分析された。これらの分析では、サンプルを、Acquity UPLC BEH C18カラム(1.7μm、2.1×50 mm)に、0.4 mL/分の流速で、5分間にわたる95〜10%の水/アセトニトリルの勾配プログラムによって注入した。DTX(および他の生成物)の検出は、ES+モードであった。ポリマーは、Waters e2696 Separation Module、2414 RIおよび2998 PDA検出器から構成され、Empower Pro 2によって操作されるGPCシステムによって分析された。THF可溶性サンプルは、Waters Styragel HR5EおよびHR 3カラムに(連続して)、0.35 mL/分のTHF 流速で注入された。水溶性サンプルは、Waters Ultrahydrogel 1000カラムを用いて、水の1 mL/分の流速で分析された。遊離DTXおよびPEGの検出は、それぞれPDA(724 nm)およびRIによって行われた。
CMC-Naポリマーはカルボキシメチル基によって修飾されており、0.82の分析DS値を有するものが製造業者により供給された。すなわち、各ガラクトースモノマー単位は、0.82モルのカルボン酸基および2.18モルのヒドロキシル基を含む。従って、各モノマーの分子量は、162 g/mol(ガラクトース)+(59.01 g/mol(酸性基)×0.82)=210 g/molのように概算される。これらの化学組成値は、CMCポリマーに対して行われる反応のストイキオメトリーを計算するために用いられた。
CMCをアセチル化する方法は、Namikoshi72によって報告された方法から改変された。カルボキシメチルセルロースナトリウム(CMC-Na CEKOL 30K, 10 g)を丸底フラスコに秤量し、室温で2時間激しく撹拌しながら20%硫酸(200 mL)に懸濁した。CMC-COOH粉末のスラリーを、水の検査結果が中性になるまで水で洗浄し、その後、CMC-COOHの完全な脱水を確実にするために、30 mLの量の氷酢酸で3回洗浄した。CMC-COOHを氷浴中に置いた丸底フラスコに移し、氷酢酸(glacial acid)(50 mL)に懸濁した。無水酢酸(30 mL)および硫酸(1.2 mL)を冷却したスラリーに加え、その後、温度を50℃まで上昇させ、溶液を3時間または清澄化するまで激しく撹拌した。反応溶液を回転蒸発(58℃、58 mbar)によって濃縮し、脱イオン水中で沈澱させた。水の検査結果が中性pHになるまで、繰り返しろ過することによって、水を交換した。高真空下で一晩、アセチル化CMC(CMC-Ac)粉末を乾燥させ、最小限のアセトンに溶解し、水によって沈澱させた。ポリマーを溶液から遠心分離し、凍結乾燥によって乾燥させ、DMSO溶媒中でのH NMRによって分析した。
本明細書全体にわたって記載されるCellaxの調製をここに記載し(50 mol%DTX供給、30 mol%PEG供給、または50/30)、その後、許容できる粒子を形成しない組成物を詳述する関連反応を記載した。50/30合成:アセチル化カルボキシメチルセルロース(CMC-Ac、300 mg、1.5 mmol酸)を25 mLのガラスバイアルに秤量し、MeCN(2 mL)に溶解した。EDC HCl (441 mg、2.3 mmol)をMeCN(12 mL)および水(0.5 mL)に溶解した。NHS(265 mg、2.3 mmol)およびDMAP(28 mg、0.23 mmol)をMeCN(1 mL)に溶解した。mPEG-OH(690 mg、0.35 mmol)を穏やかに加熱しながらMeCN(2 mL)に溶解した。DTX(465 mg、0.58 mmol)をMeCN(12 mL)およびDMF(1 mL)に溶解した。EDC HCL、NHS、およびDMAP試薬をCMC-Ac溶液に加え、その後、mPEG-OHおよびDTXを添加した。溶液を、一晩室温で、遮光しながら撹拌した。溶媒を回転蒸発(55℃、5 mbar)によって除去し、生成物(Cellax)をMeCN(3 mL)に溶解し、40 mLジエチルエーテルによって沈澱させた。Cellaxを乾燥させ、MeCNに再度溶解し、沈澱を2回繰り返した。溶媒を高真空によって除去し、微粉末を水(25 mL)で洗浄し、遠心分離によって回収した。Cellax生成物を、未反応のPEGおよびDTXについてゲル浸透クロマトグラフィーによって分析し、残存試薬が検出された場合には、洗浄を繰り返した。1H NMR解析(CDCl3)を行って、DTXおよびPEGの存在を確認し、分子組成を推定した。PEGを一定に保ちながらDTXの供給率を変化させて、様々なDTX含量のCellaxモデルを作り出した。CMC-Ac(50 mg、0.19 mmol酸)を、DMAP(5 mg、0.04 mmol)の存在下でEDC HCl(75 mg、0.39 mmol)およびNHS(45 mg、0.39 mmol)で活性化し、その後、様々なDTX(16、31、47、63、142 mg、0.02、0.04、0.06、0.08、0.18 mmol)およびmPEG-OH(117 mg、0.06 mmol)を加えた。DTXを一定に保ちながらPEGの供給率を変化させて、様々なPEG含量のCellaxモデルを作り出した。CMC-Ac(100 mg、0. 39 mmol酸)を、DMAP(48 mg、0.39 mmol)の存在下でEDC HCl(224 mg、1.17 mmol)およびNHS(135 mg、1.17 mmol)で活性化し、その後、様々なPEG(78、156、390、546、780、1169 mg、0.04、0.08、0.19、0.27、0.39、0.58 mmol)およびDTX(157 mg、0.19 mmol)を加えた。すべての類似体を、上述の好ましい組成物と同様の方法で精製した。1H NMR解析のために、化合物をCDCl3に溶解し、選択されたピークの積分によって組成を推定した。
Cellaxのために記載されたものと同じ条件を用いて、CMC-Ac-PEG対照分子を合成した。CMC-Ac(100 mg、0.38 mmol酸)を、アセトニトリル溶媒(6 mL)中EDC HCl(147 mg、0.77 mmol)、NHS(88 mg、0.77 mmol)、およびDMAP(9 mg、0.08 mmol)の存在下でmPEG2000(230 mg、0.12 mmol)と反応させた。一晩の反応後、溶媒を回転蒸発(55℃、5 mbar)によって除去し、水(5mL)に溶解し、20kDa MWCO Slide-a-lyzer透析カートリッジを用いて、複数回の水の交換に対して透析した。精製された生成物を凍結乾燥によって回収し、水性GPCによって分析して、未反応のPEGが完全に抽出されたことを検証した。化学組成の分析は、D20中での1H NMRによって行われた。
PEGビスアミン(169 mg、0.084 mmol)を、DMAP(1 mg、0.008 mmol)およびCy5.5 NHSエステル(050 mg、0.084 mmol、0.5 mLアセトニトリル)が添加されたアセトニトリル(2 mL)に溶解した。溶液を室温で4時間、遮光して撹拌した。アセチル化カルボキシメチルセルロース(CMC-Ac、100 mg、0.39 mmol酸)を25 mLガラスバイアルにに秤量し、MeCN(2 mL)に溶解した。EDC HCl (149 mg、0.78 mmol)をMeCN(4 mL)および水(0.15 mL)に溶解した。NHS(90 mg、0.78 mmol)およびDMAP(10 mg、0.08 mmol)をMeCN(0.5 mL)に溶解した。mPEG2000-OH(156 mg、0.08 mmol)を穏やかに加熱しながらMeCN(1 mL)に溶解した。DTX(157 mg、0.19 mmol)をMeCN(4mL)およびDMF(0.25 mL)に溶解した。EDC HCL、NHS、およびDMAP試薬をCMC-Ac溶液に加え、その後、Cy5.5-PEG反応溶液ならびにmPEG-OHおよびDTXを添加した(スキーム1B)。溶液を、一晩室温で、遮光しながら撹拌した。生成物(Cy5.5 Cellax)を、Cellaxの精製のために用いたのと同様の方法によって精製した。1H NMR解析(CDCl3)を行って、DTXおよびPEGの存在を確認し、分子組成を推定した。
Sun73によって発表された方法に従って、超常磁性酸化鉄ナノ粒子(SPION)を調製した。鉄(III)アセチルアセトナート(353 mg、1 mmol)を、37℃の水浴中で、1,2-ヘキサデカンジオール(1292 mg、5 mmol)、オレイン酸(1224 mg、4.3 mmol)、オレイルアミン(oleic amine)(1214 mg、4.5 mmol)、およびジフェニルエーテル(10 mL)と混合し、窒素下で撹拌した。バイアルを、時々混合しながら加熱ブロック上で200℃に加熱した。反応混合物を室温に冷却し、窒素雰囲気を流し、溶液を265℃に加熱して、窒素保護下で30分間還流した。溶液を室温に冷却した。イソプロパノール(20 mL)を反応系に加え、遠心分離(2500 rpm、5分間)によって粒子を回収した。ヘキサン(1 mL)を加えて化合物を溶解し、溶液を2500 rpmで5分間遠心分離した。上清を回収し(沈殿物は捨てた)、溶媒を蒸発させた。この方法を(ヘキサン再懸濁液へのIPA添加から)3回繰り返した。SPIONを乾燥させ、秤量し、ヘキサンを加えて濃度を10 mg/mLにした。
加水分解したポリマーサンプルのHPLC 解析によって、Cellax中のDTX含量を推定した。すなわち、Cellax(2 mg)をアセトニトリル(1 mL)に溶解し、8.5%オルトリン酸(0.3 mL)を用いて30秒間ボルテックス装置で処理した。サンプルを直ちに酢酸エチル(3 mL)で抽出した。15 mLコニカルチューブ中で各サンプル(3 mL)に水を加え、チューブを3000 rpmで5分間遠心分離して、有機層と水層を分離した。酢酸エチル画分を分離し、回転蒸発によって乾燥させ、アセトニトリル(0.5 mL)を加えて、HPLC解析のためのサンプルを溶解させた。
Cellax(250 mg)を加熱せずにアセトニトリル(25 mL)に溶解した。何回かに分けて粒子を調製した。すなわち、0.2 mL Cellax溶液を、15 mLコニカルチューブ中で1.9 mLの0.9% NaCl溶液のボルテックスしている溶液に滴下した。溶液添加後1分間、ボルテックスを継続した。その結果得られた粒子溶液を合わせて、Slide-a-lyzer 10 000 MWCOカートリッジに移し、透析液を2回交換しながら、0.9%NaClに対して3時間透析した。粒子を0.22μm 25 mm Millipore PVDFフィルターを通してろ過し、Vivaspin遠心ろ過フィルターユニット(25 mL、10 000 MWCO)に移し、3000 rpmで1時間回転させて、粒子を1 mLの容量に濃縮した。粒子分析器(Zetasizer Nano-ZS, Malvern Instruments Ltd, Malvern, UK)を用いた動的光散乱によって粒子のサイズを決定した。サンプルを90/10 生理食塩水/DMSO中で20×に希釈し、274 nmでのUV吸光度を測定し(Nanodrop, ThermoScientific)、DTX検量線を用いてDTX濃度を計算することによって、コンジュゲートのDTX含量を測定した。
臨界ミセル濃度を決定する方法は、Zhangから改変され、蛍光ベースの解析で構成される67,74。1,6-ジフェニル-l,3,5-ヘキサトリエン(DPH、1.175 mg)をアセトニトリル(10 mL)に溶解し、原液を調製した。Cellax(10 mg)を1 mLのDPH原液に溶解して10 mg/mL溶液を調製し、DPH溶液で段階希釈して、一定濃度のDPH中に一連の10濃度のCellaxを調製した。100μL容量の各サンプルを1分間ボルテックス装置で900μLの0.9%NaCl中に滴下して析出させた。50μLの各粒子溶液を黒色96ウェルマイクロプレートに移し、Chameleonプレートリーダーにおいて蛍光を測定した(Ex 360、Em 460)。対数濃度に対する蛍光のプロットにおいて、2つの異なる線形曲線が合流し、臨界ミセル濃度は、曲線の交点に対する線形代数の解を用いることによって計算された。
Cellax粒子のDTX含量を分析し、溶液を500μg DTX / mLに調整し、Millipore PVDF 0.22μmフィルターを通してろ過滅菌した。パクリタキセル内部標準を粒子溶液に添加した(5μg PTX / mL)。等量の粒子溶液とウシ胎仔血清(FBS)を無菌条件下で混合し、37℃でインキュベートした。選択された時点(1、2、3、4、7および14日)で、1 mL容量を取り、3 mLの酢酸エチルと合わせて、サンプルを30分間よく混合し、その後、4000 rpmで5分間遠心分離して層を分離させた。2.5 mLの酢酸エチル層を取り出し、溶媒を回転蒸発させ、0.5 mLのアセトニトリルに再懸濁して、HPLCによって分析した。DTXおよびPTXのピークは、それぞれ7.8分および8.1分に出現した。生理食塩水/FBS溶液にDTXおよびPTX内部標準を加えてDTXの校正曲線を作成し、その後、同一の抽出手順を行い、この校正曲線を用いて、インキュベートしたサンプル中のDTX含量を計算した。インキュベートしたサンプルの分析において8.4分に新たなピークが出現し、LC/MS分析によってDTXの異性体(ES+ 878質量)であることが決定された。DTXと同様の方法で、異性体を定量化した。
EMT-6マウス乳がん細胞およびLL/2マウスLewis肺細胞がん細胞を、10%FBS(Invitrogen)、ペニシリン(100 U/ml)およびストレプトマイシン(100μg/ml)(Invitrogen)を添加した高グルコースを含むDMEM培地(Invitrogen)中で培養した。マウス乳がん細胞株EMT-6は、CHEO Research Institute のDavid Stojdl博士およびUniversity of Ottawa のDouglas Mahoney博士からの寛大な寄贈であった。播種のために、トリプシン(Invitrogen)を用いて細胞を培養フラスコから剥がし、1×1O5細胞/mLの濃度に再懸濁し、100μLの細胞懸濁液を96ウェルポリスチレンプレートのウェルに加えた。粒子の添加前に、細胞を24時間培養下(37℃、5%CO2、加湿)で維持した。DMSO中でDTX溶液を調製し、培地で希釈して、0.1%DMSO含量を有する100 nM原液を調製した。これらのDTXサンプルを、0.1%DMSO培地で2×段階希釈した。Cellax粒子のDTX含量を分析し、培地で10×段階希釈した。培養を3日間維持し、その時点で細胞の生存をXTTアッセイによって分析した。簡潔には、XTT試薬(Sigma)の1 mg/mL水溶液を調製し、フェナジン(Sigma)を分析の直前に添加した(x mg/mL)。培養プレートを37℃で2時間インキュベートし、その後、各ウェルの480 nmでの吸光度を読み取った。培地(すなわち0.1%DMSO培地)で処理されたウェルは、100%生存培養物を表し、細胞を含まないウェルはバックグラウンドシグナルを表す。並列実験では、4段階で、12時間毎に2日間、1/4用量を加えることによって、DTXまたはCellax含有培地をEMT-6およびLL/2培養物に添加した。GraphPad Prismでデータを解析し、それぞれの系のIC50を計算した。
メスのBALB/cおよびC57/BL6マウス(6週齢、18〜20 g)をThe Jackson Laboratory(Bar Harbor, ME)から購入した。この研究のすべての実験プロトコールは、Canadian Council of Animal Careによって作成された実験動物の管理と使用に関する指針に制定された方針に従って、Animal Care Committee of the University Health Network(Toronto, Ontario, Canada)の承認を受けた。それぞれの実験において、DTXは、Tween80/エタノール/生理食塩水(20:13:67)溶液中で調製され(4 mg DTX/mL)、ろ過滅菌された。Cellax粒子は、生理食塩水中4、7.5または15 mg DTX/mLに調整され、ろ過滅菌された。
マウスからの組織(臓器、骨、および腫瘍)を生理食塩水で洗い、10%ホルマリンで2日間固定し、その後70%エタノール中に保存した。組織のスライド作製は、Toronto General Hospital Pathology Research Program lab(Toronto, ON)で行われた。Ki67(SP6)抗体(ThermoFisher)は、クエン酸塩中1/1000希釈で1時間使用された。CD31(PECAM)抗体(Santa Cruz)は、Tris-EDTAバッファー、pH 9中1/2000希釈で1時間使用された。TUNEL染色は、Wijsmanの方法に従って行われた75。プレパラートは、Princess Margaret Hospital(Toronto, ON)のAdvanced Optical Microscopy Facility(AOMF)でAperio Scannerにおいて分析された。画像解析は、Aperio scannerに付属しているImageScopeソフトウェアによって行われた。H&Eサンプルについては、ImageScope Color Deconvolution V9アルゴリズムを用いて、ヘマトキシリンおよびエオジン陽性ピクセルを同定した。TUNEL、Ki67、およびCD31染色サンプルについては、ImageScope Positive Pixel Countアルゴリズムを用いて、茶色のピクセルを数えた。解析されるそれぞれの腫瘍または臓器について、3つの組織切片をそれぞれ3つの同等の領域に分割し、n=9のデータ点を作り出した。画像解析出力は、解析された面積で割った陽性ピクセル数であった。
健康なBALB/cマウスを、200μLのi.v.尾静脈注射によって、20および40 mg/kg用量の遊離DTXで処理した。同様に、健康なBALB/cマウスを、20、40、85、および170 mg/kg DTX等価用量のCellaxで処理した。対照マウスは、Tween80/エタノール/生理食塩水または生理食塩水の注射を受けた。体重を7日間測定し、屠殺の際、臓器を組織学的解析および免疫組織化学的解析のために採取した。血液を採取し、血清および全血の血清学的および血液学的パラメーターを分析し、対照血液サンプルに対して参照した。
EMT-6細胞は上述のように培養された。接種前に、TrypLE Expressを用いて細胞を培養プレートから剥がし、添加物を含まない(FBSなし、抗生物質なし)DMEM培地に再懸濁した。EMT-6細胞(2×105細胞/50μl培地)を、BALB/cマウスの毛を剃った右側脇腹部にs.c.接種した。7日後、腫瘍が触知可能になった時、MTD試験に記載されるように、マウスに40 mg/kg用量のDTXおよびCellaxを投与した。対照動物には、生理食塩水を注射した。各郡(DTX、Cellax、および対照)は6匹のマウスで構成された。腫瘍サイズを測径器(caliper)で測定し、体重を測定した。14日後、マウスを頸椎脱臼によって屠殺し、組織切片ならびにH&E、TUNEL、Ki67、およびCD31による染色のために、心臓、肺、肝臓、腎臓、および腫瘍を採取した。C57/BL6マウスにs.c.接種したLL/2細胞による二次試験(EMT-6試験と同様)が行われた。LL/2細胞は、添加物を含まないDMEM培地に懸濁された。
健康なBALB/cマウスは、尾静脈注射(50μL、2.5×105細胞/mL)によるEMT-6細胞(添加物を含まないDMEM培地中)のi.v.投与を受け、1日後にCellax(40 mg DTX /kg)、40 mg/kg DTX、または生理食塩水(n=10/群)の投与を受けた。細胞注入後7日目に、2回目の投与(20 mg/kg DTX)を行った。>20%体重減少を記録した時、または行動もしくは運動機能障害の最初の兆候時に、マウスを屠殺した。組織学的分析のために、肺、心臓、肝臓、腎臓、脾臓、大腿骨、および脳を摘出した。生存データから、生存率のカプランマイヤープロットを作成した。
10%FBS(Invitrogen)、ペニシリン(100 U/ml)およびストレプトマイシン(100μg/ml)(Invitrogen)、およびピルビン酸塩(1 mM)を添加したRPMI 1640中で、PAN02細胞(マウス膵臓がん)を培養した。接種前に、TrypLE Express(Invitrogen)を用いて細胞を培養プレートから剥がし、添加物を含まない(FBSなし、抗生物質なし)RPMI培地に再懸濁した。PAN02細胞(5×106細胞/mL、0.5 mL)をC57/BL6マウスの腹腔内に注射した。細胞の投与1日後に、マウス(群あたりn=3)を、DTX(40 mg/kg)、Cellax(40 mg DTX eqv/kg)、または生理食塩水で処理した。>20%体重減少を記録した時、または行動もしくは運動機能障害の最初の兆候時に、マウスを屠殺した。
STTARR facility(Radiation Medicine Program, University of Toronto, Ontario, Canada)にある7T micro-MRI(BioSpec 70/30 USR, Bruker Biospin, Ettlingen, Germany)を用いて、腫瘍内のCellax-SPION分布のMRI観察を行った。データ収集は、呼吸に対してゲートされ、腫瘍造影期間あたり8〜12スライスが収集された。TE=10 msに対応する画像を、MIPAVソフトウェアで処理した。簡潔には、腫瘍体積を通る8〜12スライス全体にわたり、腫瘍体積を多角形によって線引きして、三次元関心領域(volume of interest)(VOI)を定義した。同様に、隣接する筋肉組織の断面を、VOIによって線引きした。低信号の腫瘍ボクセルは、平均筋肉ボクセル信号強度の5×標準偏差を引いた腫瘍ボクセル信号強度として定義された。各腫瘍VOIに対して5×SD限度を超えるボクセルを除外する閾値演算を行うことによって、低信号の体積を計算した。低信号ボクセルを含む各腫瘍の体積率を、非閾値体積/閾値体積として計算した。
アセチル化カルボキシメチルセルロース(CMC-Ac、75 mg、0.29 mmol酸)を25 mLのガラスフラスコに秤量し、窒素保護下で無水DMF(1 mL)に溶解した。カンプトテシン(CMT、50.0 mg、0.15 mmol)を25 mLのガラスバイアルに秤量し、穏やかに加熱しながら無水DMF(15 mL)に溶解した。CMT溶液を反応器に加え、溶液を0℃に冷却した。PyBOP(137 mg、0.26 mmol)、DMAP(64 mg、0.53 mmol)、およびmPEG-OH(175 mg、0.09 mmol)をガラスバイアルに秤量し、無水DMF(それぞれ1 mL)に溶解し、反応器に加えた。DIPEA(38μL、0.22 mmol)を注射器によって反応器に添加した。反応物を1時間後室温に上昇させ、窒素保護下で一晩撹拌しておいた。反応溶液を回転蒸発によって濃縮し、氷浴で冷却し、10%NaCl(25 mL)を加えた。その後、0.1N HClの添加によって溶液をpH 2.5に酸性化した。懸濁液を室温で1時間撹拌し、固形物を遠心分離によって回収し、4回水で洗浄し、一晩乾燥させた。固形物をDMF(2 mL)に溶解し、メタノールに対して3時間透析して、未反応のCMTを抽出した。粒子懸濁液を蒸発乾固し、DMF中の1 mg/mL溶液として再懸濁した。1H NMR(CDCl3)δ: 7.29-8.51(5H, CMT)、7.28(1H, CMT)、5.76(2H, CMT)、5.32(2H, CMT)、3.0-5.5(m, CMCポリマー)、3.658(PEG)、1.027(3H, CMT)。10×容量の0.9%生理食塩水中への析出(precipitation)によって、粒子を調製した。
アセチル化カルボキシメチルセルロース(CMC-Ac、50 mg、0.19 mmol酸)を25 mLガラスバイアルに秤量し、MeCN(0.5 mL)に溶解した。EDC HCl(112 mg, 0.58 mmol)をMeCN(3 mL)および水(0.1 mL)に溶解した。NHS(67 mg、0.58 mmol)およびDMAP(24 mg、0.19 mmol)をMeCN(1 mL)に溶解した。mPEG-OH(117 mg、0.06 mmol)を穏やかに加熱しながらMeCN(1 mL)に溶解した。PTX(67 mg、0.08 mmol)をMeCN(2 mL)およびDMF(0.2 mL)に溶解した。EDC HCL、NHS、およびDMAP試薬をCMC-Ac溶液に加え、その後、mPEG-OHおよびPTXを添加した。反応物精製は、DTXコンジュゲートの精製と同様であった。組成をH NMRによって確認した(41重量% PTX、5.7 wt% PEG)。粒子は、115 nmのサイズおよび0.1のPDIで単離された。
アセチル化カルボキシメチルセルロース(CMC-Ac、100 mg、0.38 mmol酸)を25 mLガラスバイアルに秤量し、DMF(4 mL)に溶解した。DCC(158 mg、0.76 mmol)およびDMAP(9 mg、0.08 mmol)をDMF(0.5 mL)に溶解した。mPEG-OH(574 mg、0.11 mmol)をDMF(1 mL)に溶解した。DOX(83 mg, 0.15 mmol)をDMF(0.25 mL)に溶解した。DCCおよびDMAP試薬をCMC-Ac溶液に添加し、その後、mPEG-OHおよびDOXを加えた。一晩反応させた後、反応溶液を4 mLの水と混合し、水に対して透析して未反応のDOXを抽出した。溶液を乾燥させ、DMFに再懸濁し、エーテルによって沈澱させ、エーテル溶液中のポリマーを回転蒸発によって回収した。NMRでは、ほとんどのDOXシグナルはポリマーと重複したが、生成物は暗赤色である。1H NMR(DMSO)δ:7.1-7.8(m, Ar H, DOX)、5.1(dd, 1H, DOX)、3.63(s, 4H, PEG)、3.32(s, 3H, PEG)、3.0-5.5(m, CMCポリマー)、1.96(m, 3H, アセチル)、1.25(d, DOX)。CMC-PEG-DOX生成物はDMSOに溶解され、生理食塩水中に沈澱した。すなわち、個別の粒子集団を形成せず、自己集合はDOXのような比較的親水性の薬物によって妨げられることを示唆する。
アセチル化カルボキシメチルセルロース(CMC-Ac、100 mg、0.38 mmol酸)を25 mLガラスバイアルに秤量し、MeCN(1 mL)に溶解した。EDC HCl(147 mg、0.76 mmol)をMeCN(4 mL)および水(0.2 mL)に溶解した。NHS(88 mg、0.76 mmol)をMeCN(1 mL)に溶解した。mPEG-OH 5000(574 mg、0.11 mmol)を穏やかに加熱しながらMeCN(2 mL)に溶解した。DTX(216 mg、0.27 mmol)をMeCN(4 mL)に溶解した。EDCおよびNHS試薬をCMC-Ac溶液に加え、その後、mPEG-OHおよびDTXを添加した。生成物の精製は、mPEG-OH 2000を用いて合成したCellaxの精製と同様であった。1H NMR(CDCl3)δ:8.03(d, 2H, C25およびC29)、7.62(t, 1H, C27)、7.49(t, 2H, C26およびC28)、7.41(m, 4H, C31, C32, C34, C35)、7.38(m, 1H, C33)、6.23(m, 1H, C13)、5.70(m, 1H, C2)、5.25(m, 1H, C4')、5.08(br, 1H, C10)、4.79(d, 1H, C5)、4.37(m, 1H, C20-A)、3.62(s, 4H, PEG)、3.0-5.5(m, CMCポリマー)、1.99(m, 3H, アセチル)、1.29(s, 3H, C16)。前述のように、MeCN溶液の析出によって粒子を調製した(119nm、PDI=0.3)。
カルボキシメチルセルロースナトリウム(CEKOL 4K, lOg)を、Cekol 30K材料に適用したものと同じ方法に従ってアセチル化した。アセチル化カルボキシメチルセルロース(CMC-Ac、100 mg、0.39 mmol酸)を25 mLガラスバイアルに秤量し、MeCN(1 mL)に溶解した。EDC HCl(149 mg、0.78 mmol)をMeCN(4 mL)および水(0.2 mL)に溶解した。NHS(90 mg、0.78 mmol)およびDMAP(10 mg, 0.08 mmol)をMeCN(0.25 mL)に溶解した。mPEG-OH(234 mg、0.12 mmol)を穏やかに加熱しながらMeCN(1 mL)に溶解した。DTX(157 mg、0.19 mmol)をMeCN(4 mL)およびDMF(0.3 mL)に溶解した。EDC HCL、NHS、およびDMAP試薬をCMC-Ac溶液に加え、その後、mPEG-OHおよびDTXを添加した。生成物の精製は、CEKOL 30K CMC-Ac類似体のために記載された方法に記載される精製と同様である。粒子は、この調製物から140 nmのサイズで分離された。
Cellax粒子を脱イオン水に100×希釈し、溶液の2μL分割量を、フォルムバー被覆銅TEMグリッド(TedPella, Redding, CA)の表面上にピペットで取り、風乾させた。Centre for Nanostructure Imaging(Department of Chemistry, University of Toronto)のHitachi HD-2000 STEMにおいて、高角度環状暗視野検出器を用いて、200 kVの活性化電圧および10 mAの電流によって、分析を行った。粒子のTEM分析は、Zetasizer測定(104 +/- 15 nm)を裏付け、実施例6に見られるように、粒子は球状である。
Cellax(3 mg)をTHF(0.27 mL)に溶解し、DMSO中1.0 mg/mLのカンプトテシン(CMT)溶液30μLを加えた。その後、CMT/Cellax溶液を、激しく撹拌されている0.9%生理食塩水(2.7 mL)に滴下し、この溶液を0.22μM PVDFフィルターを通してろ過し、凝集体を除去した。Zetasizerによって粒径を測定した(120 nm、PDI=0.3)。粒子をDMSOに希釈し(10×)、蛍光(Ex 325nm、Em 460 nm)を測定して、100%カプセル化効率が計算された。
Cellaxの合成
カルボキシメチルセルロースのアセチル化
CMCポリマーのアセチル化は、手順の各段階においてCMCポリマーを綿密に洗浄すれば、円滑に進行した。例えば、残存する硫酸は、材料の変色を引き起こし、残存する水は、無水物の反応を妨げた。アセチル化に成功しなかった物質は、結局は酢酸溶媒に溶解しなかった。しかし、洗浄手順を適切に徹底した場合、反応は、H NMR解析によって評価されたように、定量的であった。1H NMR(CDCl3)δ:3.0-5.5(m, CMC H)、2.02(m, アセチルCH3)。
CMC-AcはDMFに可溶であるが、DMF中で行われたDTXおよびPEGのカップリング反応は、高い収率を示さず、これらの物質から形成された粒子は、不安定で不均一であった。溶媒の予備選択において、MeCNはより高い変換を促進し、以後、すべてのコンジュゲート形成反応は、この溶媒中で行われた。加えて、試薬の希釈を最小限にするために、MeCN溶媒中、1.5容量%の水がEDCを溶解するために必要とされ、3.0容量%のDMFがDTXを溶解するために必要とされた。最初は透析によるポリマーの精製が試みられたが、PEG、DTX、およびCMC試薬は異なる溶解度プロフィールを有するため、沈澱および低い精製効率による問題が生じた。粉末状のCellax生成物の水による洗浄は、未反応のPEGの抽出に有効であり、エーテルによる沈澱は、未反応のDTXの抽出に有効であることを示した。未反応のPEGおよびDTXの効果的な抽出は、生成物のGPC分析によって確認された。しかし、CMCポリマーはポリスチレンカラムに吸収されたため、GPC分析は不純物の同定に限定された。1H NMR(CDCl3)δ:8.12(d, 2H, C25およびC29)、7.61(t, 1H, C27)、7.51(t, 2H, C26およびC28)、7.41(m, 4H, C31, C32, C34, C35)、7.34(m, 1H, C33)、6.23(m, 1H, C13)、5.71(m, 1H, C2)、5.25(m, 1H, C4')、5.10(br, 1H, C10)、4.98(d, 1H, C5)、4.32(m, 1H, C20-A)、4.25(m, 1H, C7)、4.19(br, 1H, C20-B)、3.64(s, 4H, PEG)、3.38(s, 3H, PEG)、3.0-5.5(m, CMCポリマー)、2.57(m, 1H, C6-A)、2.38(3H, C22)、2.02(m, 3H, アセチル)、1.86(m, 4H, C6およびC18)、1.75(br, 3H, C19)、1.34(s, 9H, C7', C8', C9')、1.29(s, 3H, C16)、1.14(s, 3H, C17)。記載されたスペクトルについては図2A、DTXの炭素番号をつけた図については図2Bを参照せよ。コンジュゲート中の各単位(CMC、PEG、およびDTX)の相対モル%は、スペクトルの積分によって推定され、各成分の分子量を用いた逆算によって、重量パーセントが計算された(表1)。Cellax 中のDTX含量は、更に、オルトリン酸による処理を用いてコンジュゲートから加水分解されたDTXのHPLC分析によって推定され、この分析は、30 wt%のDTX組成を確認した。
Cellax粒子形成、in vitroでのDTX放出、および動物実験
水溶液に対する透析による溶媒交換、薄膜水和、および沈澱を含む、異なる粒子調製方法を用いて、一連の試験を行った。水性析出(aqueous precipitation)を用いて良好な結果が得られたが、他の一般的な粒子形成技術は、特定の粒子を生じなかった。表2に記載されるように、粒子を調製するために使用される水溶液系は、粒子の大きさおよび安定性に影響を与えた。例えば、リン酸緩衝生理食塩水(25 mM PBS)中で調製された粒子は、最初は134 nmのサイズであったが、数時間の間に、これらの粒子は明らかに凝集した。反対に、10%ショ糖または0.9%生理食塩水中で調製された粒子は、120〜130 nmの範囲にわたり、4℃保存で少なくとも1か月間(これまでの試験の上限)安定なままであった。しかも、生理食塩水中で調製され、FBS とともにインキュベートされたCellax粒子は、サイズが変化しなかった。DPHアッセイによって決定された臨界ミセル濃度は、0.1 mg/mLであった。
カンプトテシン粒子、ドキソルビシン(DOX)粒子、およびパクリタキセル粒子
カンプトテシン-PEG-CMCの合成は、非常に疎水性の高い薬物がCMC-Acとうまくコンジュゲートを形成することができ、そうしなければ不溶性の薬物の送達を可能にすることを明らかにする。DTXに対するよりも、この化合物の特定の化学的性質および溶解性に合わせた、異なる合成および精製計画が使用された。
CellaxのPEG5000類似体
粉砕による過剰なPEGの抽出が容易であるため、MW=2000のPEGを使用することが好ましい。しかし、より高い分子量のPEGコンジュゲートは特定のナノ粒子のPKを向上させるかもしれず、従ってPEG5000類似体が合成された。その材料は望ましい自己集合特性を示す。
低分子量のCMC類似体
CMCは様々な分子量の物が入手可能であるが、当業者には明らかであるように、分子量の分析が困難であるため、主に粘性および置換度によって特徴付けられる。CMC(MW 20000)を用いて生成された変形例は、140 nmの粒子を生じた。
Cellax粒子のTEM分析
CellaxのTEM分析が行われた。Zetasizerからの粒度測定データとTEM測定結果は同様である(100〜120 nm)。
Cellax粒子へのCMTの取り込み
CMT(およびSPION)のような疎水性物質の取り込みが実証されている。すなわち、粒径は安定してCellaxと同様であり、高い取り込み効率が観察される。薬物または造影剤の非共有結合的な取り込みは、2つ以上の薬物または造影機能を含有する多機能性粒子を提供する。
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Claims (60)
- 少なくとも1つのポリ(エチレングリコール)(PEG)および少なくとも1つの疎水性薬物と共有結合しているアセチル化カルボキシメチルセルロース(CMC-Ac)を含む化合物。
- 前記共有結合がエステル結合である、請求項1に記載の化合物。
- 少なくとも1つの疎水性薬物が抗がん薬である、請求項1または2に記載の化合物。
- 少なくとも1つの疎水性薬物が、ドセタキセル、カンプトテシン、およびパクリタキセルのうちの1つである、請求項3に記載の化合物。
- 少なくとも1つのPEGが、550〜10,000の平均Mnを有するポリ(エチレングリコール)メチルエーテル(mPEG)である、請求項4に記載の化合物。
- 少なくとも1つのPEGが、2000の平均M n を有するポリ(エチレングリコール)メチルエーテル(mPEG)である、請求項5に記載の化合物。
- 前記CMCが、95〜3600モノマー単位からなる、請求項5または6に記載の化合物。
- 前記CMCが、3500モノマー単位からなる、請求項7に記載の化合物。
- (CMC-Acアセチル基):(CMC-Acカルボン酸基/ PEG /疎水性薬物)のモル比が、2.5:0.5〜1.8:1.2である、請求項7または8に記載の化合物。
- (CMC-Acアセチル基):(CMC-Acカルボン酸基/ PEG /疎水性薬物)のモル比が、2.18:0.82である、請求項9に記載の化合物。
- mPEGが、3.5〜22.7重量%の量で存在し、ドセタキセルが、22.5〜43.3重量%の量で存在する、請求項9または10に記載の化合物。
- mPEGが、4.7〜5.3重量%の量で存在し、ドセタキセルが、30.1〜39.5重量%の量で存在する、請求項11に記載の化合物。
- mPEGが、4.7重量%の量で存在し、ドセタキセルが、36.9重量%の量で存在する、請求項12に記載の化合物。
- mPEG:ドセタキセル:(CMC-Acカルボン酸基)のモル比が、1H NMR解析によって推定された際に、0.9 : 13.4 : 85.7〜5.4 : 26.4 : 68.2である、請求項13に記載の化合物。
- mPEG:ドセタキセル:(CMC-Acカルボン酸基)のモル比が、 1 H NMR解析によって推定された際に1 : 15.1 : 83.6〜1.1 : 23.7 : 75.3である、請求項14に記載の化合物。
- mPEG:ドセタキセル:(CMC-Acカルボン酸基)のモル比が、 1 H NMR解析によって推定された際に1 : 20.5 : 78.5である、請求項15に記載の化合物。
- 前記CMC-Acが更に、少なくとも1つの造影剤と共有結合している、請求項1〜16のいずれか1項に記載の化合物。
- 前記少なくとも1つの造影剤がCy5.5である、請求項17に記載の化合物。
- 請求項1〜18のいずれか1項に記載の化合物を含む、自己集合性ナノ粒子組成物。
- 前記組成物が、0.1 mg/mLの臨界ミセル濃度(cmc)を有する、請求項19に記載の自己集合性ナノ粒子組成物。
- ナノ粒子の平均直径が49〜278 nmであり、および/または、前記自己集合性ナノ粒子組成物中のすべてのナノ粒子の直径が16〜396 nmの範囲にある、請求項19または20に記載の自己集合性ナノ粒子組成物。
- 前記自己集合性ナノ粒子組成物中にカプセル化された少なくとも1つの疎水性物質を更に含み、前記疎水性物質が造影剤または他の治療薬のいずれかより選択される、請求項19〜21のいずれか1項に記載の自己集合性ナノ粒子組成物。
- 少なくとも1つの造影剤が、超常磁性酸化鉄ナノ粒子(SPION)である、請求項22に記載の自己集合性ナノ粒子組成物。
- 少なくとも1つの造影剤が、7〜30重量%のSPIONである、請求項23に記載の自己集合性ナノ粒子組成物。
- 少なくとも1つの造影剤が、30重量%のSPIONである、請求項24に記載の自己集合性ナノ粒子組成物。
- 請求項19〜25のいずれか1項に記載の自己集合性ナノ粒子組成物ならびに製薬上許容されうる担体および/または希釈剤を含む、医薬組成物。
- それを必要とする患者に疎水性薬物の持続放出送達を提供するのに用いるための、請求項19〜25のいずれか1項に記載の自己集合性ナノ粒子組成物。
- それを必要とする患者において癌を治療するのに用いるための、請求項3〜18のいずれか1項に記載の化合物を含む自己集合性ナノ粒子組成物。
- 癌が、乳がん、肺がん、転移がん、および膵臓がんより選択される、請求項28に記載の自己集合性ナノ粒子組成物。
- 自己集合性ナノ粒子組成物を調製する方法であって、
a)少なくとも1つのPEGおよび少なくとも1つの疎水性薬物をCMC-Acと共有結合させるステップと;
b)ステップ(a)の生成物を単離するステップと;
c)ステップ(b)の単離生成物を適切な有機溶媒に溶解して、溶液を形成するステップと;
d)自己集合性ナノ粒子組成物の形成のために適切な条件下でステップ(c)の溶液を水溶液に滴下するステップ
とを含む方法。 - 前記共有結合がエステル結合である、請求項30に記載の方法。
- 前記ステップ(d)における適切な条件が、ステップ(c)の溶液の滴下の間、前記水溶液を激しく混合することを含む、請求項30または31に記載の方法。
- ステップ(c)の溶液が、10〜25 mg/mLの濃度を有する、請求項30〜32のいずれか1項に記載の方法。
- ステップ(c)の溶液が、10 mg/mLの濃度を有する、請求項33に記載の方法。
- ステップ(d)が、水溶液への添加が完了した時点で、ステップ(c)の溶液の10倍希釈であることを含む、請求項30〜34のいずれか1項に記載の方法。
- ステップ(d)の水溶液が、0.9% NaCl、10%ショ糖、または水より選択される、請求項30〜35のいずれか1項に記載の方法。
- ステップ(c)における有機溶媒が、アセトニトリル(CH3CN)またはテトラヒドロフラン(THF)より選択される、請求項30〜36のいずれか1項に記載の方法。
- ステップ(c)における有機溶媒がCH 3 CNである、請求項37に記載の方法。
- ステップ(b)が、エーテルを用いたステップ(a)の生成物の沈澱、および水による沈殿物の洗浄を含む、請求項30〜38のいずれか1項に記載の方法。
- 透析および/またはろ過によって、ステップ(d)で形成された自己集合性ナノ粒子組成物を単離することを更に含む、請求項30〜39のいずれか1項に記載の方法。
- 少なくとも1つの疎水性薬物が、ドセタキセル、カンプトテシン、およびパクリタキセルのうちの1つである、請求項30〜40のいずれか1項に記載の方法。
- 前記CMC-Acが、0.75〜0.85の置換度(DS)を有するカルボキシメチルセルロースのアセチル化によって調製される、請求項41に記載の方法。
- 前記CMC-Acが、0.82の置換度(DS)を有するカルボキシメチルセルロースのアセチル化によって調製される、請求項42に記載の方法。
- 少なくとも1つのPEGが、550〜10,000の平均Mnを有するポリ(エチレングリコール)メチルエーテル(mPEG)である、請求項42または43に記載の方法。
- 少なくとも1つのPEGが、2000の平均M n を有するポリ(エチレングリコール)メチルエーテル(mPEG)である、請求項44に記載の方法。
- ステップ(a)が、前記CMC-Acのカルボン酸基に対して、30 mol%の量のmPEGを供給すること、および40〜50 mol%の量のドセタキセルを供給することを含む、請求項44または45に記載の方法。
- ステップ(a)が、前記CMC-Acのカルボン酸基に対して、30 mol%の量のmPEGを供給すること、および40 mol%または50 mol%の量のドセタキセルを供給することを含む、請求項46に記載の方法。
- ステップ(c)の溶液が、前記自己集合性ナノ粒子組成物中にカプセル化される少なくとも1つの疎水性物質を更に含み、前記疎水性物質が造影剤または他の治療薬のいずれかより選択される、請求項30〜47のいずれか1項に記載の方法。
- 少なくとも1つの造影剤が、超常磁性酸化鉄ナノ粒子(SPION)である、請求項48に記載の方法。
- ステップ(c)の有機溶媒がTHFである、請求項49に記載の方法。
- 少なくとも1つの造影剤が、少なくとも1つの造影剤およびステップ(b)の単離生成物を合わせた重量に基づき、9〜50重量%の量でステップ(c)の溶液中に存在する、請求項50に記載の方法。
- (a):(b+c+d)の比率が2.18 : 0.82である、請求項52に記載の化合物。
- nが95〜3600モノマー単位である、請求項53に記載の化合物。
- nが3500モノマー単位である、請求項54に記載の化合物。
- 疎水性薬物が、ドセタキセル、カンプトテシン、およびパクリタキセルのうちの1つである、請求項54または55に記載の化合物。
- PEGがm(PEG)である、請求項56に記載の化合物。
- それを必要とする患者に疎水性薬物の持続放出送達を提供するための医薬品の製造における、請求項19〜25のいずれか1項に記載の自己集合性ナノ粒子組成物の使用。
- それを必要とする患者において癌を治療するための医薬品の製造における、請求項3〜18のいずれか1項に記載の化合物を含む自己集合性ナノ粒子組成物の使用。
- 癌が、乳がん、肺がん、転移がん、および膵臓がんより選択される、請求項59に記載の使用。
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US8993614B2 (en) | 2012-03-15 | 2015-03-31 | F. Hoffmann-La Roche Ag | Substituted pyrrolidine-2-carboxamides |
WO2014015422A1 (en) * | 2012-07-27 | 2014-01-30 | Ontario Institute For Cancer Research | Cellulose-based nanoparticles for drug delivery |
JP6172507B2 (ja) * | 2013-05-15 | 2017-08-02 | 川研ファインケミカル株式会社 | アシルカルボキシメチルセルロース、及びアシルカルボキシメチルセルロースを含有する化粧料 |
EP3024495A4 (en) * | 2013-07-26 | 2017-03-22 | The University Of British Columbia | Method and device for manufacturing polymer particles containing a therapeutic material |
WO2016037274A1 (en) * | 2014-09-09 | 2016-03-17 | Ontario Institute For Cancer Research (Oicr) | Cellulose-based nanoparticles for drug delivery |
GB2538717B (en) * | 2015-05-26 | 2018-01-31 | Siemens Medical Solutions Usa Inc | Method for reducing variability of representations of regions of interest on reconstructions of medical imaging data |
CN110800755B (zh) * | 2019-11-21 | 2020-12-29 | 中国农业科学院农业环境与可持续发展研究所 | 阿维菌素纳米农药制剂及其制备方法 |
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US4520192A (en) | 1984-07-03 | 1985-05-28 | Daicel Chemical Industries Ltd. | Carboxyalkyl acetyl celluloses, their salts and a process for the preparation of them |
US6063396A (en) * | 1994-10-26 | 2000-05-16 | Houston Biotechnology Incorporated | Methods and compositions for the modulation of cell proliferation and wound healing |
US5792856A (en) | 1996-01-29 | 1998-08-11 | Allen; John Michael | Process for preparing carboxyalkyl cellulose esters |
US20060235211A1 (en) * | 2000-01-28 | 2006-10-19 | Heindel Ned D | Lactones of carboxylic acid polysaccharides and methods for forming conjugates thereof |
CA2351253A1 (en) * | 2000-11-10 | 2002-05-10 | Groupe Lysac Inc./Lysac Group Inc. | Crosslinked polysaccharide, obtained by crosslinking with substituted polyethylene glycol, as superabsorbent |
ITMI20041373A1 (it) | 2004-07-09 | 2004-10-09 | Lima Lto S P A | N-metil-ammidi di carbossimetilcellulosa acido alginico o carbossimetalamido |
CN100423719C (zh) * | 2004-12-30 | 2008-10-08 | 中国科学院上海药物研究所 | 一种多烯紫杉醇纳米粒及其制备方法 |
JP5069920B2 (ja) * | 2007-02-08 | 2012-11-07 | 公益財団法人東京都医学総合研究所 | マンノース6−リン酸−ポリエチレングリコール結合体 |
EP1967854B8 (en) | 2007-03-06 | 2010-12-29 | Cell Therapeutics, Inc. | Method for determining the amount of conjugated taxane in polyglutamic acid-taxane conjugates |
CN101785757B (zh) * | 2009-01-22 | 2012-02-22 | 美迪思生物科技(北京)有限公司 | 一种紫杉醇自乳化制剂及其制备方法和用途 |
JP5818055B2 (ja) * | 2010-03-17 | 2015-11-18 | 静岡県公立大学法人 | トリアセチルセルロースブロック共重合体、その中間体、充填剤、および、界面活性剤 |
CN101829061A (zh) * | 2010-05-14 | 2010-09-15 | 无锡纳生生物科技有限公司 | 一种紫杉醇纳米颗粒组合物及其制备方法 |
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WO2012103634A1 (en) | 2012-08-09 |
CN103476801B (zh) | 2016-06-29 |
ES2547326T3 (es) | 2015-10-05 |
EP2670780A4 (en) | 2014-08-06 |
CA2825926A1 (en) | 2012-08-09 |
US8591877B2 (en) | 2013-11-26 |
US20140079644A1 (en) | 2014-03-20 |
JP2014504614A (ja) | 2014-02-24 |
EP2670780A1 (en) | 2013-12-11 |
CN103476801A (zh) | 2013-12-25 |
EP2670780B1 (en) | 2015-08-19 |
US20120219508A1 (en) | 2012-08-30 |
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