JP2018536012A - 生体直交型組成物 - Google Patents
生体直交型組成物 Download PDFInfo
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- JP2018536012A JP2018536012A JP2018532532A JP2018532532A JP2018536012A JP 2018536012 A JP2018536012 A JP 2018536012A JP 2018532532 A JP2018532532 A JP 2018532532A JP 2018532532 A JP2018532532 A JP 2018532532A JP 2018536012 A JP2018536012 A JP 2018536012A
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Abstract
Description
本出願は、2015年9月10日に出願された米国仮特許出願第62/216,858号明細書、2015年10月16日に出願された米国仮特許出願第62/242,896号明細書、2015年12月24日に出願された米国仮特許出願第62/387,480号明細書、2016年4月24日に出願された米国仮特許出願第62/327,924号明細書、2016年6月1日に出願された米国仮特許出願第62/344,341号明細書、2016年7月1日に出願された米国仮特許出願第62/357,647号明細書および2016年8月30日に出願された米国仮特許出願第62/381,442号明細書に対する優先権を主張し、これらのそれぞれは、その全体が参照により本明細書に組み込まれる。
本発明は、アメリカ国立科学財団(National Science Foundation)から授与された、契約番号1549133の政府支援により行なわれた。政府は、本発明において一定の権利を有する。
別途定義しない限り、本明細書で使用される全ての技術用語および科学用語は、当業者が一般に理解するのと同じ意味を有する。矛盾する場合には、定義を含む本文書が支配する。好ましい方法および材料が下記で説明されているが、本明細書で説明されているものと類似のまたは等価の方法および材料を本発明の実施または試験で使用することができる。本明細書で言及される全ての刊行物、特許出願、特許および他の参考文献は、その全体が参照により組み込まれる。本明細書で開示されている材料、方法および例は一例にすぎず、限定することを意図するものではない。
本開示は、対象中で薬剤を送達するための組成物を提供する。この組成物は、官能化ペイロード組成物と担体組成物とを含むことができる。特定の実施形態では、この組成物を使用して1種または複数種の薬剤を対象中の特定の位置に選択的に送達し、例えば対象中の標的とされる器官または組織(またはそれらの一部)に選択的に送達する。薬剤の標的型送達により、この薬剤の有効量が標的とされる器官また組織に送達されて、この標的とされる器官または組織(またはそれらの標的とされる部分)への所望の効果が生じ得る。従って、本発明の組成物は、対象中の標的とされる器官または組織(またはそれらの一部)の選択的な標的化および処置を容易にする。
上記で説明されているように、本開示の官能化ペイロードは、ペイロードと、相補的結合剤と、このペイロードをこの相補的結合剤に付着させる任意選択のリンカーとを含むことができる。ペイロードとは、対象中で所望の効果を生じることが可能な薬剤のことである。例えば、本開示のペイロードとして、治療薬、診断薬、標的化剤および同類のものが挙げられる。
Dは本明細書で定義されているペイロードであり、
Lは本明細書で定義されているリンカーであり、
BAは本明細書で定義されている相補的結合剤である。
Dは本明細書で定義されているペイロードであり、
Lは本明細書で定義されているリンカーであり、
R1は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR1a、−NR1bR1c、−SR1d、−SO2R1e、−S(O)R1fおよび−P(O)OR1gR1h、
R1a、R1b、R1c、R1d、R1e、R1f、R1gおよびR1hは、以下からなる群からそれぞれ独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
nは0、1、2、3、4、5、6、7、8、9、10、11、12または13であり、
前記アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニルは各存在で、0個、1個、2個、3個、4個、5個、6個、7個、8個、9個または10個の置換基で独立して置換されており、この置換基は、以下からなる群からそれぞれ独立して選択される:ハロゲン、=O、=S、シアノ、ニトロ、フルオロアルキル、アルコキシフルオロアルキル、フルオロアルコキシ、アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルコキシ、ヘテロアルキル、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、複素環、シクロアルキルアルキル、ヘテロアリールアルキル、アリールアルキル、ヒドロキシ、ヒドロキシアルキル、アルコキシ、アルコキシアルキル、アルキレン、アリールオキシ、フェノキシ、ベンジルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アミノアルキル、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、スルホニル、アルキルスルホニル、アリールスルホニル、アミノスルホニル、スルフィニル、−COOH、ケトン、アミド、カルバメート、シリル、置換シリル、t−ブチルジメチルシリル、アルキルスルファニル、スルファニルおよびアシル。
R1は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR1a、−NR1bR1c、−SR1d、−SO2R1e、−S(O)R1fおよび−P(O)OR1gR1h、
R2は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR2a、−NR2bR1c、−SR2d、−SO2R2e、−S(O)R2fおよび−P(O)OR2gR2h、
R3は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR3a、−NR3bR3c、−SR3d、−SO2R3e、−S(O)R3fおよび−P(O)OR3gR3h、
R4は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR4a、−NR4bR4c、−SR4d、−SO2R4e、−S(O)R4fおよび−P(O)OR4gR4h、
R5は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR5a、−NR5bR5c、−SR5d、−SO2R5e、−S(O)R5fおよび−P(O)OR5gR5h、
R6は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR6a、−NR6bR6c、−SR6d、−SO2R6e、−S(O)R6fおよび−P(O)OR6gR6h、
R7は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR7a、−NR7bR7c、−SR7d、−SO2R7e、−S(O)R7fおよび−P(O)OR7gR7h、
R8は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR8a、−NR8bR8c、−SR8d、−SO2R8e、−S(O)R8fおよび−P(O)OR8gR8h、
R10は各存在で、以下からなる群から独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
R11は各存在で、以下からなる群から独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
R12は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR12a、−NR12bR12c、−SR12d、−SO2R12e、−S(O)R12fおよび−P(O)OR12gR12h、
R1a、R1b、R1c、R1d、R1e、R1f、R1g、R1h、R2a、R2b、R2c、R2d、R2e、R2f、R2g、R2h、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R4a、R4b、R4c、R4d、R4e、R4f、R4g、R4h、R5a、R5b、R5c、R5d、R5e、R5f、R5g、R5h、R6a、R6b、R6c、R6d、R6e、R6f、R6g、R6h、R7a、R7b、R7c、R7d、R7e、R7f、R7g、R7h、R8a、R8b、R8c、R8d、R8e、R8f、R8g、R8h、R12a、R12b、R12c、R12d、R12e、R12f、R12g、R12hは、以下からなる群からそれぞれ独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
Zは、O、N(Ra)、N(Rb)またはSからなる群から選択され、
Ra、Rb、Rc、RdおよびReは、水素、C1〜C6アルキルおよびC1〜C6ハロアルキルからなる群からそれぞれ独立して選択され、
L1はアルキレンであり、
nは0、1、2、3、4、5、6、7、8、9、10、11、12または13であり、
pは0、1、2、3または4であり、
qは0、1、2、3、4または5であり、
前記アルキル、アルキレン、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニルは各存在で、0個、1個、2個、3個、4個、5個、6個、7個、8個、9個または10個の置換基で独立して置換されており、この置換基は、以下からなる群からそれぞれ独立して選択される:ハロゲン、=O、=S、シアノ、ニトロ、フルオロアルキル、アルコキシフルオロアルキル、フルオロアルコキシ、アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルコキシ、ヘテロアルキル、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、複素環、シクロアルキルアルキル、ヘテロアリールアルキル、アリールアルキル、ヒドロキシ、ヒドロキシアルキル、アルコキシ、アルコキシアルキル、アルキレン、アリールオキシ、フェノキシ、ベンジルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アミノアルキル、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、スルホニル、アルキルスルホニル、アリールスルホニル、アミノスルホニル、スルフィニル、−COOH、ケトン、アミド、カルバメート、シリル、置換シリル、t−ブチルジメチルシリル、アルキルスルファニル、スルファニルおよびアシル。
特定の実施形態では、本組成物は担体組成物である。この担体組成物は生体適合性の担体組成物であることができる。生体適合性の担体組成物は対象の身体に適合する。一部の場合では、生体適合性の担体組成物は対象に対して非毒性であり、対象中の組織または生体化合物と実質的に反応しない。任意の適切な生体適合性の担体を使用することができる。例えば、生体適合性の担体は、数ある中でもヒドロゲル、架橋ポリマーマトリックス、金属、セラミック、プラスチック、骨移植材料であることができる。
R20は以下からなる群から選択され:水素、ハロゲン、シアノ、ニトル、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、CF3、CF2−R’、NO2、OR’、SR’、C(=O)R’、C(=S)R’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、S(=O)R’、S(=O)2R’’’、S(=O)2NR’R”、C(=O)O−R’、C(=O)S−R’、C(=S)O−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R”、NR’R”、NR’C(=O)R”、NR’C(=S)R”、NR’C(=O)OR”、NR’C(=S)OR”、NR’C(=O)SR”、NR’C(=S)SR”、OC(=O)NR’R”、SC(=O)NR’R”、OC(=S)R’R’’’、SC(=S)R’R”、NR’C(=O)NR”R”およびNR’C(=S)NR”R”、R’およびR”は各存在で、水素、アリールおよびアルキルから独立して選択され、R’’’は各存在で、アリールおよびアルキルから独立して選択され、R30は、水素、シアノ、ニトロ、ヒドロキシ、アルキル、ハロアルキル;アルケニル、アルキニル、アルコキシ;ハルアルコキシ(halalkoxy);ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルまたはシクロアルケニルであり、Ra、R31aおよびR31bはそれぞれ独立して、水素、C1〜C6アルキルまたはC1〜C6ハロアルキルであり、tは0、1、2、3または4である。
R20は以下からなる群から選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、CF3、CF2−R’、NO2、OR’、SR’、C(=O)R’、C(=S)R’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、S(=O)R’、S(=O)2R’’’、S(=O)2NR’R”、C(=O)O−R’、C(=O)S−R’、C(=S)O−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R”、NR’R”、NR’C(=O)R”、NR’C(=S)R”、NR’C(=O)OR”、NR’C(=S)OR”、NR’C(=O)SR”、NR’C(=S)SR”、OC(=O)NR’R”、SC(=O)NR’R”、OC(=S)R’R’’’、SC(=S)R’R”、NR’C(=O)NR”R”およびNR’C(=S)NR”R”、R’およびR”は各存在で、水素、アリールおよびアルキルから独立して選択され、R’’’は各存在で、アリールおよびアルキルから独立して選択され、R22は、連結原子が1〜100個のリンカーであり且つエチレンオキシ基、アミン、エステル、アミド、カルバメート、カーボネートおよびケトン官能基を含むことができる。例えば、リンカーは1〜50個の連結原子または5〜50個の連結原子または10〜50個の連結原子を有することができる。
R20は以下からなる群から選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、CF3、CF2−R’、NO2、OR’、SR’、C(=O)R’、C(=S)R’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、S(=O)R’、S(=O)2R’’’、S(=O)2NR’R”、C(=O)O−R’、C(=O)S−R’、C(=S)O−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R”、NR’R”、NR’C(=O)R”、NR’C(=S)R”、NR’C(=O)OR”、NR’C(=S)OR”、NR’C(=O)SR”、NR’C(=S)SR”、OC(=O)NR’R”、SC(=O)NR’R”、OC(=S)R’R’’’、SC(=S)R’R”、NR’C(=O)NR”R”およびNR’C(=S)NR”R”、R’およびR”は各存在で、水素、アリールおよびアルキルから独立して選択され、R’’’は各存在で、アリールおよびアルキルから独立して選択され、R30は、ハロゲン、シアノ、ニトロ、ヒドロキシ、アルキル、ハロアルキル;アルケニル、アルキニル、アルコキシ;ハルアルコキシ;ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルまたはシクロアルケニルであり、Ra、R31aおよびR31bはそれぞれ独立して、水素、C1〜C6アルキルまたはC1〜C6ハロアルキルであり、tは0、1、2、3または4である。
本開示の化合物が調製され得る手段を説明する以下の合成スキームおよび合成方法に関連して、この化合物をより理解することができる。
本開示の複数の態様は、ペイロードを対象中に標的位置に送達する方法を含む。特定の実施形態では、この方法は、ペイロードを対象中の標的位置に選択的に送達することを含む。ペイロードの選択的送達は、対象中においてこのペイロードの投与を必要としない他の位置(例えば他の器官もしくは組織またはその一部)を標的とすることなく、このペイロードを標的位置(例えば器官もしくは組織またはその一部)に送達することを含む。本明細書で説明されている担体組成物および官能化ペイロードの使用により、ペイロードの選択的送達を達成することができる。
本開示の組成物を様々な異なる方法で製剤化することができる。一般に、1つまたは複数の結合剤または相補的結合剤を含む組成物を、この結合剤および相補的結合剤、処置する状態ならびに使用する投与経路に適合する方法で製剤化する。加えて、この組成物がペイロードを含む場合、この組成物を、このペイロード、処置する状態ならびに使用する投与経路に適合する方法で製剤化する。
本開示の組成物は、ペイロード(例えば親薬物(即ち、この組成物への共役前の薬物))の投与による処置または診断に適している対象中の状態または疾患の処置および/または診断での用途を見出す。「処置」は、対象を苦しめている状態と関連する症状の少なくとも寛解が達成されることを意味しており、寛解は、処置する状態と関連するパラメータ(例えば症状)の大きさの減少を少なくとも指すために広い意味で使用される。従って、処置には、対象が病理学的状態またはこの状態を特徴付ける少なくとも複数の症状にもはや罹患しないように、この状態またはそれに関連する少なくとも複数の症状が完全に抑制されている、例えば発生が予防されているまたは停止されている(例えば終了している)状況も含まれる。従って、処置には以下が含まれる:(i)予防、即ち臨床症状の発症のリスクを低減させること、例えば臨床症状が発症しないようにすること、例えば有害な状態への疾患の進行を予防すること;(ii)抑制、即ち臨床症状の発症または更なる発症を抑止すること、例えば活動性疾患を緩和するもしくは完全に抑制すること;および/または(iii)軽減、即ち臨床症状の退行を引き起こすこと。例えば、癌との関連において、用語「処置する」には以下のいずれかまたは全てが含まれる:固形腫瘍の増殖の減少、癌細胞の複製の阻害、全体的な腫瘍量の減少、生存の延長、および癌に関連する1つまたは複数の症状の寛解。
本開示の複数の態様は、本明細書で説明されている組成物を有するキットを含む。例えば、キットは、本明細書で説明されている担体組成物を含むことができる。このキットの実施形態はまた、本明細書で説明されている官能化ペイロードも含むことができる。特定の実施形態では、このキットは、組成物(例えば担体組成物および/または官能化ペイロード)と、この組成物(例えば担体組成物および/または官能化ペイロード)を含むように構成されたパッケージとを含むことができる。担体組成物および官能化ペイロードをパッケージ中の別々の容器に入れることができる。1種または複数種の担体組成物をキットで提供することができる。同様に、1種または複数種の官能化ペイロードをキットで提供することができる。パッケージは、滅菌密封パッケージ等の密封パッケージであることができる。「滅菌」は、微生物(例えば真菌、細菌、ウイルス、胞子形態等)が実質的に存在しないことを意味する。一部の場合では、パッケージは任意選択で気密および/または真空シール下で密封されるように構成され得、例えば水蒸気耐性パッケージであり得る。
本開示は以下の非限定的な実施例により説明される複数の態様を有する。以下の実施例は、本発明を製造する方法および使用する方法の完全な開示および説明を当業者に提供するために提示されており、本発明者が発見と見なすものの範囲を限定することが意図されておらず、以下の実験が実施される全てのまたは唯一の実験であることを示すことも意図されていない。使用する数字(例えば量、温度等)に関して正確さを確保するために努力しているが、ある程度の実験誤差および偏差を考慮すべきである。別途示さない限り、部は重量部であり、分子量は重量平均分子量であり、温度は摂氏であり、圧力は大気圧または大気圧付近である。「平均」は算術平均を意味する。標準的な略語を使用する場合があり、例えばbp、塩基対;kb、キロベース;pl、ピコリットル;sまたはsec、秒;min、分;hまたはhr、時間;aa、アミノ酸;kb、キロベース;bp、塩基対;nt、ヌクレオチド;i.m.、筋肉内(ly);i.p.、腹腔内(ly);s.c.、皮下(ly);および同類のものを使用する場合がある。
MCF7皮下乳癌異種移植片を担持する胸腺欠損マウスでの有効性
畜産
動物を12時間の明/暗サイクルの温度制御室に収容し、ろ過水および照射食品に自由にアクセスさせた。
MCF7細胞を培養液中で増殖させ、等量のマトリゲルで約20匹の雌の胸腺欠損NCR:nu/nuマウスの脇腹に移植した。カリパス測定により腫瘍が100mm3+/−20mm3の平均腫瘍容積に達すると、15匹の動物を選択し、それぞれ5匹の動物からなる3つの群に無作為化した。無作為化後、以下の表で説明されている試験デザインに従って適切な処置レジメンを動物に施した。腫瘍増殖を1週間に2回記録し、投与完了後に1〜2週間延長した。動物を人道的に安楽死させ、試験完了後(投与が完了してから2週間後)に血液および腫瘍を採取した。
雌の胸腺欠損NCR:nu/nuマウス約5〜7週齢を得て、3〜5日にわたり動物施設に順化させた。試験の開始前に、マウスの耳にタグを付け、各マウスの体重を記録した。MCF7移植の3日前に、各マウスの肩領域にエストラジオールペレットを移植した。標準的な組織培養技術を使用して、Pen−Strepを補充した組織培養培地+10%FBS中でMCF7細胞系統を増殖させ、次いで5%CO2での37℃インキュベーター中でインキュベートした。注射の日に、MCF7細胞をトリプシン処理し、HBSS+1%FBSで洗浄し、続いて血清を含まないHBSSで2回洗浄した。この細胞を計数し、HBSSで懸濁させた。0.050ml体積中の約5×106個のMCF7細胞を等量のMatrigel(BD Biosciences)と混合し、各マウスの脇腹領域に皮下注射した。MCF細胞の移植後、腫瘍が触診可能になった時点で腫瘍増殖を1週間に2回モニタリングした。デジタルカリパスを使用して腫瘍増殖を測定し、以下の式:
触診可能な腫瘍の質量(mm3)=d2xD/2
(ここで、dおよびDはそれぞれ腫瘍の最短および最長の直径(mm)である)
を使用して触診可能な腫瘍の質量を算出した。
群1:生理食塩水(Q3日、3回の用量、静脈内経路)
群2:TCO−ドキソルビシン(5mg/kg×Q3日×3回の用量、静脈内経路)
群3:ドキソルビシン(5mg/kg×Q3日×3回の用量、静脈内経路)
注記:全身治療の開始前に腫瘍部位にヒドロゲルを接種した。
このヒドロゲルを、テトラジン生体直交型官能基を含むように修飾した。
1.ヒドロゲルを充填したシリンジを三方活栓から取り外した。
2.気泡を最小限に抑えるために、シリンジ縁の空間にヒドロゲルを押し込んだ。
3.このシリンジを三方活栓に再び接続し、ダイヤルを回して2つのシリンジポートを開いた。
4.三方活栓を介してヒドロゲルを他のシリンジに30回往復させて、2つの物質を混合した。
5.ヒドロゲルを、以前は白色水性材料を含むシリンジに押し込んだ。
6.ヒドロゲルを形式的に含むシリンジを三方活栓から取り外し、全ての物質を他のシリンジに吸引した。
7.ヒドロゲルの体積を23ゲージ針に充填し、再びキャップした。
TCO−ドキソルビシンは、trans−シクロオクテン生体直交型官能基で修飾されたドキソルビシンであった。
軟部組織肉腫(STS)の処置
軟部組織肉腫(STS)の処置における多くの細胞毒性剤の効力は、それらの乏しい送達および全身性の副作用により制限される。軟部組織肉腫は顕著な不均一性を有し、そのため身体または腫瘍に対して外因性の因子に焦点を当てたアプローチは局所制御にとって理想的であるだろう。局所的に配置された生体材料の空間的制御と全身性プロドラッグの適応性とを組み合わせるシステムを評価した。in vivo化学を使用して、ドキソルビシンプロドラッグ用量を濃縮することおよび活性化することが可能な注射可能ヒドロゲル(HMT)を開発した。このアプローチを、マウス異種移植モデルでの軟部組織肉腫の処置に関して試験した。腫瘍部位の近くでHTMを移植した後、マウスを、臨床ケアの標準であるドキソルビシンの最大耐量と比較して骨髄抑制または悪液質を伴うことなく有意に大きい腫瘍増殖阻害をもたらすドキソルビシンプロドラッグの1日用量で10日にわたり処置した。この戦略は、手術前の腫瘍量を最小限に抑えて切除後に清潔な外科的マージンを最大限に利用するためのネオアジュバントアプローチとみなすべきである。観察した低い全身毒性はまた、第一選択処置に失敗し、切除不能な腫瘍を有するまたは軟部組織肉腫に伴う対処療法的ニーズを有する虚弱な患者にとって、このアプローチをアジュバント療法として魅力的にもする。
化学および材料合成。化学前駆体およびHMT合成に関する詳細なプロトコルについては、SI材料および方法を参照されたい。
局所的な濃縮および活性化のアプローチ。アルギン酸ヒドロゲルをテトラジン部分で修飾した(HMT、図17A)。1H NMR分析(図25)に基づいて、HMTは、物質1ミリグラム当たりテトラジン約120nモルを含む。trans−シクロオクテン部分による共有結合的な修飾によって、ドキソルビシンをプロドラッグへと共有結合的に修飾した。この修飾により、通常のドキソルビシンと比べてHT1080に対して57倍低い活性である薬剤が得られた(図19Aおよび図19B)。
ここで、本発明者らは、局所HMTにより、全身毒性を制限するTCO部分で修飾されたプロドラッグの有効性が増加することを示す。細胞毒性剤の局所的な濃縮および活性化により、骨髄抑制の欠如および体重増加により測定した場合に、既存のケアの臨床基準と比較して良好な腫瘍反応および忍容性が得られた。
治療薬の局所的な濃縮および活性化による全身療法の増強
本明細書で開示されているのは、マウスにおける軟部組織肉腫モデルでのTCO−ドキソルビシンの非確率的効果である。図6〜9から認識することができるように、TCO−ドキソルビシンはドキソルビシンの最大耐量と比べて有効であり、体重減少なしにより、評価される場合に副作用はより少ない。更に、開示されている研究は、Tz−ゲルの非存在下でのTCO−ドキソルビシンは腫瘍増殖に対する長期効果を有しないことを示唆し、このことは、TCO−ドキソルビシン構築物は、この構築物の完全性を身体内で維持し、通常のドキソルビシンを放出しないことを示唆する。局所的なTCO−ドキソルビシンの濃縮および活性化の非効率的効果により、腫瘍の阻害および潜在的な退縮がもたらされると仮定すると、これは、既存の免疫療法アプローチと組み合わせるのに理想的な療法である。
放射性核種の送達
開示されているのは、移植後に全身性分子ペイロードを生体材料に濃縮するために生体直交化学を使用する生分解性で細胞適合性の移植可能な生体材料である。この技術は、分子的に標的とすることが伝統的に困難である腫瘍の予備標的化に放射性核種を送達するのに理想的であるだろう。
抗生物質の送達
感染は初期の感染部位または侵入点を有する場合があり、多くの場合、細菌がこの侵入点から潜在的に敗血症へと至る他の領域へと広がり、この敗血症は広範な感染である。全身性粒子は循環系を介して送達され、初期の感染部位を超えた領域に達する。標的化剤(例えば、モノクローナル抗体、または病原体の表面上の特定の標的への親和性結合)を使用して、本明細書で説明されている担体組成物を細菌の表面へと選択的に送達する。細菌に局在化されるとすぐに、この担体組成物を使用し、治療薬および/または診断薬を、生体直交型TCO−Tz結合を使用して何日にもわたり送達する。10日を超えて治療が必要とされる場合には、Tz官能化ペイロードは、例えばアジド−アルキン化学を使用して生体直交型結合剤を介して再チャージされる。アジド−アルキン生体直交型結合剤を使用して、複数の反応性Tz結合剤を含む粒子を数ヶ月にわたり送達する。
原発腫瘍部位への化学療法剤の送達
腫瘍増殖は概して、対象の身体中の特定位置で始まる。例えば生検中に、in situで残るまたは担体組成部を腫瘍細胞に付着させる標的化剤を有する担体組成物(例えば粒子)を主な腫瘍部位に直接注射する。この担体組成物はまた、診断を容易にするために、放射性部分または光学造影部分等の診断薬も含むことができる。担体組成物に付着したTz官能化ペイロードを使用して、TCOで修飾された治療薬を腫瘍部位に送達する。TCO剤およびTz剤が互いに反応して、腫瘍の標的領域に治療薬が送達される。10日を超えて治療が必要である場合には、Tz活性剤は、例えばアジド−アルキン化学を使用して生体直交型結合剤を介して再チャージされる。アジド−アルキン生体直交型結合剤を使用して、複数のTz結合剤を含む粒子を数ヶ月にわたり送達する。
転移部位への化学療法剤の送達
一部の対象では、腫瘍増殖は局所で始まり、次いで身体の他の器官または領域へと広がる(転移)。癌細胞の表面上のマーカー(例えばタンパク質、ペプチド)を標的とする担体組成物(例えば粒子)を対象に全身投与する。この粒子は、この粒子を癌細胞に付着させる標的化剤を有し、そのため、この粒子は転移部位に局在化され、この粒子は対象の循環系から除去される。この粒子はまた、診断を容易にするために放射性部分または光学造影部分等の診断薬も含むことができる。この粒子に付着したTz官能化ペイロードを使用して、TCOに付着した治療薬を癌細胞に送達する。TCOおよびTzが互いに反応して転移領域に治療薬が送達される。10日を超えて治療が必要である場合には、Tz活性剤は、例えばアジド−アルキン化学を使用して生体直交型結合剤を介して再チャージされる。アジド−アルキン生体直交型結合剤を使用して、複数のTz結合剤を含む粒子を数ヶ月にわたり送達する。
担体組成物
担体組成物
担体組成物
担体組成物
担体組成物
Claims (55)
- 担体組成物であって、
担体であり、ヒドロゲル担体または担体粒子を含む担体と、
前記担体に付着し且つ第1の相補的結合対のメンバーである第1の生体直交型官能基を含む第1の結合剤と、
前記担体に付着し且つ前記第1の相補的結合対とは異なる第2の相補的結合対のメンバーである第2の生体直交型官能基を含む第2の結合剤と
を含み、
前記担体が前記担体粒子を含む場合には、前記担体組成物が前記担体粒子に付着した標的化剤を更に含む、
担体組成物。 - 前記担体がヒドロゲル担体を含む、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記担体が担体粒子であり、前記担体組成物が、前記担体粒子に付着した標的化剤を含む、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の結合剤を前記担体に共有結合的に連結する第1のリンカーを更に含む請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第2の結合剤を前記担体に共有結合的に連結する第2のリンカーを更に含む請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の生体直交型官能基および前記第2の生体直交型官能基がtrans−シクロオクテンおよびアジドである、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の生体直交型官能基および前記第2の生体直交型官能基がtrans−シクロオクテンおよびアルキンである、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の生体直交型官能基および前記第2の生体直交型官能基がテトラジンおよびアジドである、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の生体直交型官能基および前記第2の生体直交型官能基がテトラジンおよびアルキンである、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の結合剤が第1の官能化ペイロードに共有結合している、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1の官能化ペイロードが、前記第1の結合剤に選択的に結合する第1の相補的結合剤と、第1のペイロードと、前記第1の相補的結合剤を前記第1のペイロードに共有結合的に連結するリンカーとを含む、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第1のペイロードが治療薬、診断薬または標的化剤を含む、請求項11に記載の担体組成物。
- 前記リンカーが放出可能なリンカーを含む、請求項11に記載の担体組成物。
- 前記第2の結合剤が第2の官能化ペイロードに共有結合している、請求項1〜3のいずれか一項に記載の担体組成物。
- 前記第2の官能化ペイロードが、前記第2の結合剤に選択的に結合する第2の相補的結合剤と、第2のペイロードと、前記第2の相補的結合剤を前記第2のペイロードに共有結合的に連結するリンカーとを含む、請求項14に記載の担体組成物。
- 前記第2のペイロードが治療薬、診断薬または標的化剤を含む、請求項15に記載の担体組成物。
- 前記リンカーが放出可能なリンカーを含む、請求項15に記載の担体組成物。
- 前記担体粒子がナノ粒子またはマイクロ粒子である、請求項1〜3のいずれか一項に記載の担体組成物。
- 有効な量のペイロードを対象中の標的位置に送達する方法であって、
前記対象に担体組成物を投与することであり、前記担体組成物が、
担体であり、ヒドロゲル担体または担体粒子を含む担体と、
前記担体に付着し且つ第1の相補的結合対のメンバーである第1の生体直交型官能基を含む第1の結合剤と、
前記担体に付着し且つ前記第1の相補的結合対とは異なる第2の相補的結合対のメンバーである第2の生体直交型官能基を含む第2の結合剤と
を含み、
前記担体が前記担体粒子を含む場合には、前記担体組成物が前記担体粒子に付着した標的化剤を更に含む、投与すること、および
前記対象に第1の官能化ペイロードを投与することであり、前記第1の官能化ペイロードが、前記第1の結合剤に選択的に結合する第1の相補的結合剤と、第1のペイロードと、前記第1の相補的結合剤を前記第1のペイロードに共有結合的に連結するリンカーとを含み、その結果、前記第1の官能化ペイロードが前記担体組成物に結合する、投与すること
を含む方法。 - 前記リンカーが放出可能なリンカーを含み、前記方法が、前記第1のペイロードを放出させ、それにより前記第1のペイロードが前記対象中の前記標的位置に送達されることを更に含む、請求項19に記載の方法。
- 前記対象に第2の官能化ペイロードを投与することであって、前記第2の官能化ペイロードが、前記第2の結合剤に選択的に結合する第2の相補的結合剤と、第2のペイロードと、前記第2の相補的結合剤を前記第2のペイロードに共有結合的に連結するリンカーとを含み、その結果、前記第2の官能化ペイロードが前記担体組成物に結合する、投与すること更に含む請求項19に記載の方法。
- 前記リンカーが放出可能なリンカーを含み、前記方法が、前記第2のペイロードを放出させ、それにより前記第2のペイロードが前記対象中の前記標的位置に送達されることを更に含む、請求項21に記載の方法。
- 前記対象に第2の担体組成物を投与することであって、前記第2の担体組成物が、
第2の担体と、
前記第2の結合剤に選択的に結合する、前記第2の担体に付着した第2の相補的結合剤と、
前記第2の担体に付着し且つ第3の生体直交型官能基を含む第3の結合剤と
を含み、
その結果、前記第2の担体組成物が前記担体組成物に結合する、投与することを更に含む請求項19に記載の方法。 - 前記第1の結合剤が前記第2の結合剤と比べて短いin vivo半減期を有する、請求項19に記載の方法。
- 前記第1の結合剤が前記第2の結合剤と比べて長いin vivo半減期を有する、請求項19に記載の方法。
- 担体組成物と、
前記担体組成物が入っているパッケージと
を含むキットであって、
前記担体組成物が、
担体であり、ヒドロゲル担体または担体粒子を含む担体、
前記担体に付着し且つ第1の相補的結合対のメンバーである第1の生体直交型官能基を含む第1の結合剤、および
前記担体に付着し且つ前記第1の相補的結合対とは異なる第2の相補的結合対のメンバーである第2の生体直交型官能基を含む第2の結合剤
を含み、
前記担体が前記担体粒子を含む場合には、前記担体組成物が前記担体粒子に付着した標的化剤を更に含む、
キット。 - 第1の官能化ペイロードを更に含む請求項26に記載のキット。
- 前記第1の官能化ペイロードが、前記第1の結合剤に選択的に結合する第1の相補的結合剤と、第1のペイロードと、前記第1の相補的結合剤を前記第1のペイロードに共有結合的に連結するリンカーとを含む、請求項27に記載のキット。
- 第2の官能化ペイロードを更に含む請求項26に記載のキット。
- 前記第2の官能化ペイロードが、前記第2の結合剤に選択的に結合する第2の相補的結合剤と、第2のペイロードと、前記第2の相補的結合剤を前記第2のペイロードに共有結合的に連結するリンカーとを含む、請求項29に記載のキット。
- 以下の式(I)
式(I)中、
Dはペイロードであり、
Lはリンカーであり、
R1は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR1a、−NR1bR1c、−SR1d、−SO2R1e、−S(O)R1fおよび−P(O)OR1gR1h、
R1a、R1b、R1c、R1d、R1e、R1f、R1gおよびR1hは、以下からなる群からそれぞれ独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
nは0、1、2、3、4、5、6、7、8、9、10、11、12または13であり、
前記アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニルは各存在で、0個、1個、2個、3個、4個、5個、6個、7個、8個、9個または10個の置換基で独立して置換されており、前記置換基は、以下からなる群からそれぞれ独立して選択される:ハロゲン、=O、=S、シアノ、ニトロ、フルオロアルキル、アルコキシフルオロアルキル、フルオロアルコキシ、アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルコキシ、ヘテロアルキル、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、複素環、シクロアルキルアルキル、ヘテロアリールアルキル、アリールアルキル、ヒドロキシ、ヒドロキシアルキル、アルコキシ、アルコキシアルキル、アルキレン、アリールオキシ、フェノキシ、ベンジルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アミノアルキル、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、スルホニル、アルキルスルホニル、アリールスルホニル、アミノスルホニル、スルフィニル、−COOH、ケトン、アミド、カルバメート、シリル、置換シリル、t−ブチルジメチルシリル、アルキルスルファニル、スルファニルおよびアシル、
官能化ペイロード。 - Dが、抗生剤、抗真菌剤、抗ウイルス剤、抗癌剤、心血管治療薬、CNS剤、抗炎症/抗関節炎剤、抗TB/抗ハンセン病剤、抗ヒスタミン/呼吸障害剤、副腎皮質ステロイド薬、免疫抑制剤または抗潰瘍剤である、請求項31に記載の官能化ペイロード。
- Dが、以下のうちの少なくとも1つから選択される:パクリタキセル、ドキソルビシン、ダウノルビシン、エトポシド、イリノテカン、SN−38、ドセタキセル、ゲムシタビン、ポドフィロトキシン、カルムスチン、イキサベピロン、パツピロン、シクロスポリンA、ラパマイシン、アンホテリシン、バンコマイシン、ダプトマイシン、ドキシサイクリン、セフトリアキソン、トリメトプリム、スルファメトキサゾール、アシクロビル、ナイスタチン、アンホテリシンB、フルシトシン、エムトリシタビン、ゲンタマイシン、コリスチン、L−ドーパ、オセルタミビル、セファレキシン、5−アミノレブリン酸、システイン、セレコキシブおよびニモジピン、請求項31または32に記載の官能化ペイロード。
- Dが放射性核種を含む、請求項31〜33のいずれか一項に記載の官能化ペイロード。
- Lが犠牲型リンカーである、請求項31〜34のいずれか一項に記載の官能化ペイロード。
- LがpHに同調可能なリンカーである、請求項31〜34のいずれか一項に記載の官能化ペイロード。
- nが0である、請求項31〜36のいずれか一項に記載の官能化ペイロード。
- nが0超であり、少なくとも1つのR1が可容化置換基である、請求項31〜36のいずれか一項に記載の官能化ペイロード。
- 以下の式:
R1は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR1a、−NR1bR1c、−SR1d、−SO2R1e、−S(O)R1fおよび−P(O)OR1gR1h、
R2は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR2a、−NR2bR1c、−SR2d、−SO2R2e、−S(O)R2fおよび−P(O)OR2gR2h、
R3は各存在で、以下からなる群から独立して選択され:ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR3a、−NR3bR3c、−SR3d、−SO2R3e、−S(O)R3fおよび−P(O)OR3gR3h、
R4は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR4a、−NR4bR4c、−SR4d、−SO2R4e、−S(O)R4fおよび−P(O)OR4gR4h、
R5は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR5a、−NR5bR5c、−SR5d、−SO2R5e、−S(O)R5fおよび−P(O)OR5gR5h、
R6は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR6a、−NR6bR6c、−SR6d、−SO2R6e、−S(O)R6fおよび−P(O)OR6gR6h、
R7は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR7a、−NR7bR7c、−SR7d、−SO2R7e、−S(O)R7fおよび−P(O)OR7gR7h、
R8は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR8a、−NR8bR8c、−SR8d、−SO2R8e、−S(O)R8fおよび−P(O)OR8gR8h、
R10は各存在で、以下からなる群から独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
R11は各存在で、以下からなる群から独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
R12は各存在で、以下からなる群から独立して選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、−OR12a、−NR12bR12c、−SR12d、−SO2R12e、−S(O)R12fおよび−P(O)OR12gR12h、
R1a、R1b、R1c、R1d、R1e、R1f、R1g、R1h、R2a、R2b、R2c、R2d、R2e、R2f、R2g、R2h、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R4a、R4b、R4c、R4d、R4e、R4f、R4g、R4h、R5a、R5b、R5c、R5d、R5e、R5f、R5g、R5h、R6a、R6b、R6c、R6d、R6e、R6f、R6g、R6h、R7a、R7b、R7c、R7d、R7e、R7f、R7g、R7h、R8a、R8b、R8c、R8d、R8e、R8f、R8g、R8h、R12a、R12b、R12c、R12d、R12e、R12f、R12g、R12hは、以下からなる群からそれぞれ独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
Zは、O、N(Ra)、N(Rb)またはSからなる群から選択され、
Ra、Rb、Rc、RdおよびReは、水素、C1〜C6アルキルおよびC1〜C6ハロアルキルからなる群からそれぞれ独立して選択され、
L1はアルキレンであり、
nは0、1、2、3、4、5、6、7、8、9、10、11、12または13であり、
pは0、1、2、3または4であり、
qは0、1、2、3、4または5であり、
前記アルキル、アルキレン、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニルは各存在で、0個、1個、2個、3個、4個、5個、6個、7個、8個、9個または10個の置換基で独立して置換されており、前記置換基は、以下からなる群からそれぞれ独立して選択される:ハロゲン、=O、=S、シアノ、ニトロ、フルオロアルキル、アルコキシフルオロアルキル、フルオロアルコキシ、アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルコキシ、ヘテロアルキル、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、複素環、シクロアルキルアルキル、ヘテロアリールアルキル、アリールアルキル、ヒドロキシ、ヒドロキシアルキル、アルコキシ、アルコキシアルキル、アルキレン、アリールオキシ、フェノキシ、ベンジルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アミノアルキル、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、スルホニル、アルキルスルホニル、アリールスルホニル、アミノスルホニル、スルフィニル、−COOH、ケトン、アミド、カルバメート、シリル、置換シリル、t−ブチルジメチルシリル、アルキルスルファニル、スルファニルおよびアシル、
官能化ペイロード。 - 以下の式:
Gは
R9は各存在で、以下からなる群から独立して選択され:水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニル、
前記アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルおよびシクロアルケニルは各存在で、0個、1個、2個、3個、4個、5個、6個、7個、8個、9個または10個の置換基で独立して置換されており、前記置換基は、以下からなる群からそれぞれ独立して選択され:ハロゲン、=O、=S、シアノ、ニトロ、フルオロアルキル、アルコキシフルオロアルキル、フルオロアルコキシ、アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルコキシ、ヘテロアルキル、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、複素環、シクロアルキルアルキル、ヘテロアリールアルキル、アリールアルキル、ヒドロキシ、ヒドロキシアルキル、アルコキシ、アルコキシアルキル、アルキレン、アリールオキシ、フェノキシ、ベンジルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アミノアルキル、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、スルホニル、アルキルスルホニル、アリールスルホニル、アミノスルホニル、スルフィニル、−COOH、ケトン、アミド、カルバメート、シリル、置換シリル、t−ブチルジメチルシリル、アルキルスルファニル、スルファニルおよびアシル、
ZはOまたはNRaであり、
RaおよびRfはそれぞれ独立して、水素、C1〜C6アルキルまたはC1〜C6ハロアルキルである、
官能化ペイロード。 - 以下の式:
R20は、以下からなる群から選択され:水素、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキル、シクロアルケニル、CF3、CF2−R’、NO2、OR’、SR’、C(=O)R’、C(=S)R’、OC(=O)R’’’、SC(=O)R’’’、OC(=S)R’’’、SC(=S)R’’’、S(=O)R’、S(=O)2R’’’、S(=O)2NR’R”、C(=O)O−R’、C(=O)S−R’、C(=S)O−R’、C(=S)S−R’、C(=O)NR’R”、C(=S)NR’R”、NR’R”、NR’C(=O)R”、NR’C(=S)R”、NR’C(=O)OR”、NR’C(=S)OR”、NR’C(=O)SR”、NR’C(=S)SR”、OC(=O)NR’R”、SC(=O)NR’R”、OC(=S)R’R’’’、SC(=S)R’R”、NR’C(=O)NR”R”およびNR’C(=S)NR”R”、
R’およびR”は各存在で、水素、アリールおよびアルキルから独立して選択され、
R’’’は各存在で、アリールおよびアルキルから独立して選択され、
R30は、ハロゲン、シアノ、ニトロ、ヒドロキシ、アルキル、ハロアルキル;アルケニル、アルキニル、アルコキシ;ハルアルコキシ;ヘテロアルキル、アリール、ヘテロアリール、複素環、シクロアルキルまたはシクロアルケニルであり、
Ra、R31aおよびR31bはそれぞれ独立して、水素、C1〜C6アルキルまたはC1〜C6ハロアルキルであり、
tは0、1、2、3または4である、
治療用担体組成物。 - 前記担体組成物が粒子である、請求項43に記載の治療用担体組成物。
- 前記粒子がナノ粒子である、請求項44に記載の治療用担体組成物。
- 前記担体組成物がアルギン酸塩樹脂を含む、請求項43に記載の治療用担体組成物。
- 前記リンカーがC1〜C10アルキレン基である、請求項47に記載の治療用担体組成物。
- 前記リンカーがC1〜C10アルキレン基である、請求項49に記載の治療用担体組成物。
- 状態または障害を処置するまたは予防する方法であって、必要とする対象に請求項1〜50のいずれか一項に記載の官能化ペイロードおよび/または治療用担体組成物を投与することを含む方法。
- 前記状態または障害が癌である、請求項51に記載の方法。
- 前記癌が軟部組織肉腫である、請求項52に記載の方法。
- 前記癌が固形腫瘍である、請求項52に記載の方法。
- 前記癌が、黒色腫(例えば切除不能な転移性黒色腫)、腎癌(例えば腎細胞癌)、前立腺癌(例えば転移性の去勢抵抗性前立腺癌)、卵巣癌(例えば上皮性卵巣癌、例えば転移性の上皮性卵巣癌)、乳癌(例えば三種陰性乳癌)、膠芽腫、肺癌(例えば非小細胞肺癌)、軟部組織肉腫、線維肉腫、骨肉腫または膵癌である、請求項52に記載の方法。
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CN117567535A (zh) | 2024-02-20 |
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US20210015932A1 (en) | 2021-01-21 |
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