CN114430756A - 担载短链脂肪酸酯的亲水-疏水性共聚物 - Google Patents
担载短链脂肪酸酯的亲水-疏水性共聚物 Download PDFInfo
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Abstract
本发明提供短链脂肪酸的衍生物,该衍生物可发挥短链脂肪酸固有的生理功能。本发明提供嵌段或接枝共聚物,其含有:包含可被生物体内的酯酶水解的短链脂肪酸酯的重复单元的疏水性链段;以及包含聚(乙二醇)链的亲水性链段。这些共聚物对包括癌症在内的各种疾病或障碍的处置或治疗有效。
Description
技术领域
本发明涉及含有担载短链脂肪酸酯的疏水性部分和作为亲水性部的聚(乙二醇)链的嵌段共聚物或接枝共聚物及其作为纳米医学材料的应用。
背景技术
据报道,包括乙酸、丙酸、丁酸(或butyric acid)在内的短链脂肪酸根据其链长而具有免疫抑制能力、肝纤维化的抑制、肥胖抑制能力、抗癌能力等各种生理功能(例如参照非专利文献1)。具有上述生理功能的短链脂肪酸是通过肠道菌群由糖类产生的,但未必足够,期待足够的供给。
然而,短链脂肪酸不仅因其溶解性或气味而使给药方法受限,还因其为低分子而代谢快,而且通过缔合导致其生理功能发生变化等,难以处理。因此,以一部分补充剂等形式提供,但可以毫不夸张地说,不存在可发挥短链脂肪酸本质上具有的生理功能的有效的给药方法或制剂。
现有技术文献
非专利文献
非专利文献1:坂田隆、市川宏文, 短链脂肪酸的生理活性, 日本油化学杂志, 第46卷, 1205-1212 (1997)。
发明内容
发明所要解决的课题
本发明的目的在于提供:可向生物体内有效地给予、递送短链脂肪酸的方法。
用于解决课题的手段
一直以来,本发明人设计并提出了高分子化的药物系统,其是将被递送药物担载于具有缔合性、并且在水性介质中可进行自组装的高分子化合物,改变药物的递送特性(例如WO2009/133647、WO2016/052463)。本发明人假定:如果在达到上述目的方面也可成功地利用任何高分子化的药物系统,则有助于解决上述课题,并反复进行了研究。
其结果,确认到了:含有或担载一个或多个担载短链脂肪酸酯的疏水性部分和聚(乙二醇)链的嵌段共聚物或接枝共聚物或经由它们在水中的缔合进行自组装而形成的纳米颗粒或纳米尺寸的高分子胶束可治愈或矫正递送上述短链脂肪酸时的短处或缺陷。
因此,作为由本发明提供的主要方案,可列举:以下的方案。
方案1:亲水-疏水性共聚物,该亲水-疏水性共聚物包含下述的(1)和(2):
(1) 来自式I所表示的重复单元的疏水性链段,
式中,R为-(C=O)R1或氢原子,R1是未取代或取代的碳原子数为1~7个的直链或支链的烷基(被取代的情况下的取代基是未取代或取代的苯基,被取代的苯基的取代基是1个以上的卤素、羟基、甲氧基),这里,即使存在氢原子,其也为n的30%以下、优选20%以下、更优选10%以下、最优选为0%,n为5~1000、优选为10~1000、更优选为15~1000、30~1000的整数;以及
(2) 包含聚(乙二醇)链的亲水性链段,该亲水性链段为下述的(i)或(ii):
(i) 式IIa所表示的亲水性链段,
式中,A是未取代或取代的C1-C12烷氧基,被取代的情况下的取代基为甲酰基、式R’R”CH-基、苯基氨基或苯乙基氨基、苯基、甲氧基苯基,这里,R’和R”独立地为C1-C4烷氧基或R’和R”一起为-OCH2CH2O-、-O(CH2)3O-或-O(CH2)4O-,m为2~500、优选为10~300、更优选为20~200的整数;或
(ii) 来自式IIb所表示的重复单元的亲水性链段,
式中,Ra为氢原子或羧基,
当Ra为羧基时,X为C(=O)O或C(=O)NH,或者,当Ra为氢原子时,X为O或NH,
B为A-CH2CH2,A和m分别为如上述所定义,
y为1~300、优选为2~150、更优选为5~100的整数,
上述(1)的疏水性链段和(2) (i)的亲水性链段分别以嵌段形式存在,
包含上述(1)的疏水性链段和(2) (ii)的亲水性链段的各重复单元的每个成员彼此随机存在。
方案2:方案1的亲水-疏水性共聚物,其通过在水中缔合进行自组装而形成纳米颗粒或纳米尺寸的高分子胶束。
方案3:方案1或2的亲水-疏水性共聚物,该亲水-疏水性共聚物在于,
包含上述(1)的来自式(I)所表示的重复单元的疏水性链段和上述(2) (i)的式IIa的亲水性链段的共聚物为式BC所表示的嵌段共聚物:
式中,A、R、m、n分别为如上述所定义,L1表示直接键合或二价的连接基,Z为氢原子、SH、S(C=S)-Ph、S(=S)OCH2CH3、羟基、C1-C6烷氧基或芳基-C1-C2烷氧基,
包含上述(1)的来自式(I)所表示的重复单元的疏水性链段和上述(2) (ii)的式IIb的亲水性链段的共聚物为式GC所表示的接枝共聚物:
式中,R、Ra、B、X、m、n、y分别为如上述所定义。
方案4:纳米颗粒,其由方案1~3中任一项的亲水-疏水性共聚物在水性介质中形成。
方案5:药物制剂,其包含方案1~3中任一项的亲水-疏水性共聚物或方案4的纳米颗粒作为有效成分而形成。
方案6:方案5的药物制剂,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
方案7:方案1~3中任一项的亲水-疏水性共聚物,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
方案8:方案4的纳米颗粒,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
方案9:将方案1~3中任一项的亲水-疏水性共聚物给予至需要它们的患者,以用于进行癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗的方法。
方案10:将方案4的任一种亲水-疏水性共聚物给予至需要它们的患者,以用于进行癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗、糖尿病的预防或治疗(或肝纤维化的抑制)、放射线疗法中的放射线的增强、肝纤维化的抑制、或高氨血症的预防或治疗的方法。
发明效果
本发明的亲水-疏水性共聚物或其纳米颗粒或高分子胶束在给予至包括人类在内的哺乳动物时被递送至生物体局部,在其局部疏水性链段中的短链脂肪酸酯键进行酶水解而可缓慢释放所对应的短链脂肪酸,可消除或缓解给予短链脂肪酸其自身所随伴的问题。因此,可提供:可在哺乳动物的生物体局部或全身有效地发挥短链脂肪酸本质上具有的各种生理功能的共聚物、以及其纳米颗粒和药物制剂。
附图说明
[图1] 制造例3中得到的N684的1H NMR波谱。
[图2] 制造例4中得到的N731的1H NMR波谱。
[图3] 制造例5中得到的N721的1H NMR波谱。
[图4] 制造例6中得到的N741的1H NMR波谱。
[图5] 制造例7中得到的N684、N731、N721的各动态光散射光谱。
[图6] 制造例8中得到的N741的动态光散射光谱。
[图7] 试验例1的乙烯酯纳米颗粒(N684、N731、N721)的细胞毒性的图示。
[图8] 试验例2的乙烯酯纳米颗粒(N741)的细胞毒性的图示。
[图9] 试验例3的各试验组小鼠的体重变化的图示。数据从左起相当于5倍稀释、10倍稀释、20倍稀释、40倍稀释的样品的数据。
[图10] 试验例3的肺癌转移数的确认(肉眼观察)结果的图示。数据相当于水(对照)、5倍稀释、10倍稀释、20倍稀释、40倍稀释、80倍稀释、160倍稀释的样品的数据。
[图11] 在显微镜下测量在试验例3的肺癌转移数的确认中无法用肉眼观察的微小转移灶的数量的结果的图示。
[图12] 试验例3的肺组织图的H&E染色图的替代照片(左)和由图求得的转移癌的数量的图示(右)。
[图13] 试验例3的肺组织图的H&E染色图的替代照片(左)和由图求得的转移癌的面积的图示(右)。
[图14] 试验例3的血液中的ALT、AST、LDH和ALB水平的图示。
[图15] 试验例3的十二指肠的H&E染色图的替代照片(左)和各试验组的绒毛长度的图示(右)。
[图16] 试验例3的空肠的H&E染色图的替代照片(左)和各试验组的绒毛长度的图示(右)。
[图17] 试验例3的回肠的H&E染色图的替代照片(左)和各试验组的绒毛长度的图示(右)。
[图18] 试验例3的大肠组织的H&E染色图的替代照片(左)和各试验组的绒毛长度的图示(右)。
[图19] 试验例4的体重变化的图示。
[图20] 试验例5的疾病活动性评价指标(DAI)的图示。
[图21] 试验例5的各处置组(包括对照)中的各实验动物的白细胞数的图示。
[图22] 试验例6的各处置组(包括对照)中的各实验动物的肝脏和脾脏重量的图示。
[图23] 试验例7的试验中的样品消耗量和实验动物的体重变化的图示。
[图24] 试验例8的试验(1)的样品消耗量和实验动物的体重变化的图示。
[图25] 试验例8的试验(2)的葡萄糖耐量试验的结果的图示。
[图26] 试验例8的试验(3)的在试验结束时间点的器官重量的图示。
[图27] 显示试验例8的试验(4)的H和E染色肠道的组织学分析结果的图的替代照片。
[图28] 显示试验例8的试验(5)的H和E染色胰腺组织的组织学分析结果的图的替代照片。
[图29] 显示试验例9的试验(1)的放射线照射对体重变化体积变化的影响的图示。
[图30] 显示试验例9的试验(2)的放射线照射对癌症的体积变化的影响的图示。
[图31] 试验例10的试验(1)的癌症增殖曲线的数据的图示。
[图32] 试验例10的试验(2)的在试验结束时间点的癌症的重量的图示。
[图33] 显示试验例10的试验(3)的受试动物的体重变化的图示。
[图34] 显示与试验例11的放射线增强效果相关的球状体(球体)癌细胞的生长抑制效果的图的替代照片。
[图35] 试验例12的试验(1)的肝脏和脾脏的重量的图示。
[图36] 试验例12的试验(2)的经HE染色的肝脏的组织学分析结果的图示。
[图37] 试验例12的试验(3)的经MT染色的肝脏的组织学分析结果的图示。
[图38] 制造例9中得到的N821的1H NMR波谱。
[图39] 制造例10中得到的纳米颗粒(Ph-BNP、N832)的尺寸分布的表示。
[图40] 试验例13的试验(1)的血液的生化检验结果的图示。
[图41] 试验例13的试验(2)的血液的经HE染色的肝脏的组织学分析图的替代照片。
[图42] 试验例14的药物动力学试验(1)的结果的图示。
[图43] 试验例14的药物动力学试验(2)的结果的图示。
具体实施方式
只要没有特别提及,则关于本发明而阐述的术语等均作为具有该技术领域中常用的含义或内容的术语使用。通常,可对本发明进行以下的追加说明。
如上所述,短链脂肪酸可通过哺乳动物的肠道菌群由糖类产生,典型的是包含乙酸、丙酸、丁酸(或butyric acid),但根据情况包含:异丁酸或异戊酸这样的支链脂肪酸,该支链脂肪酸有时是由包含一定的支链氨基酸的蛋白质被降解而产生的;以及有时发挥与这些脂肪酸类似的功能的碳原子数达到7的直链或支链脂肪酸。因此,在本说明书所公开的共聚物中,在用于提供疏水性结构域的式I所表示的疏水性链段中的R为-(C=O)R1的情况下,对R1没有限定,可列举:甲基、乙基、丙基、异丙基、丁基、异丁基、庚基、戊基、3-甲基丁基等。这些基团可被取代,被取代的情况下的取代基优选为可与未键合末端的碳原子键合的未取代或取代的苯基,被取代的苯基的取代基可以是1个以上的卤素、羟基、甲氧基。另外,记作Cx-Cxx烷氧基等的烷基部分是指碳原子数为x个~xx个的直链或支链的烷基。R可以是氢原子,此时,其为n的重复单元总数的30%以下、优选为20%以下、更优选为10%以下、最优选为0%(不存在)。这样的优选程度是共聚物在水中缔合进行自组装时用于更可靠地形成疏水性结构域或区域的程度。
在本说明书所公开的共聚物中,用于提供亲水性链段的式IIa所表示的链段提供亲水性嵌段,另一方面,其可成为以式I所表示的疏水性链段为疏水性嵌段的亲水-疏水性嵌段共聚物的成员,或者,
提供亲水性链段的式IIb所表示的各重复单元可成为可与式I所表示的各疏水性链段彼此随机存在的亲水-疏水性无规共聚物的成员。彼此随机的说法在适当的情况下、例如在式I的n与式IIb的y为近似数值时可交替存在,另外,例如在式I的n:式IIb的y为30以上:1时,实质上疏水性链段可处于多个链段形成嵌段这样的形态。
这些嵌段共聚物和无规共聚物只要是多个共聚物在水中缔合并进行自组装而可形成核中包含疏水性链段、且壳中包含亲水性链段的所谓核-壳型纳米颗粒或高分子胶束的共聚物即可,可包括其他成员。并不限于这些,作为本说明书中公开的共聚物的典型例子,可列举:上述的式BC或式GC所表示的共聚物。例如,在式BC中的L1表示二价连接基的情况下,二价连接基通常是指最大34个、优选18个、更优选最大10个碳、以及任意含有氧和氮原子的基团。作为这样的连接基,具体而言,可列举以下的基团:
该基团选自下述结构式所表示的基团、或选自-(CH2)cS-、-CO(CH2)cS-、-(CH2)cNH-、-(CH2)cCO-、-CO-、-OCOO-、-CONH-,这里,可分别独立如下:b为2~6的整数,c为1~5的整数。
关于本发明,纳米颗粒或纳米尺寸的高分子胶束中所说的纳米或纳米尺寸是指,在水中进行纳米颗粒或高分子胶束的动态光散射测定(DLS)时,平均直径处于纳米范围,通常,平均直径处于约10nm~约2000nm、优选约10nm~约500nm、更优选约25nm~约200nm的尺寸。
上述的亲水-疏水性共聚物可参照所定义的化学结构,依据其自身已知的制造方法进行制造。可方便地按照以下的任一种方法。
方便的是,如上述(1)和上述(2) (i)所定义的典型的式BC所表示的共聚物参照上述的WO2009/133647、WO2016/052463如下进行制造。
可利用下述方法:首先,准备聚(乙二醇) (PEG)链段、即下述结构式所表示的PEG衍生物:
式A-1:
式A-2:
(上式中的A、L、m为如上述所定义),
然后,准备与式I的重复单元对应的乙烯醇的短链脂肪酸酯,通过由可逆的交换链转移介导的活性的自由基聚合反应,在前者的单元上加成后者。此时,若A-1中的L-S(C=S)Ph为后述的L-S(C=S)OCH2CH3,则可更高效地得到目标共聚物。需要说明的是,在A具有苯基氨基、苯乙基氨基作为取代基的情况下,可通过具有甲酰基作为取代基的式IIa所对应的化合物的甲酰基与对应的胺的还原氨基化反应引入该取代基。
典型的以式GC表示的接枝共聚物可如下进行制造:准备与式I的重复单元对应的乙烯醇的短链脂肪酸酯和担载羧基或其被保护的基团或卤原子(Cl、Br等)的聚合性不饱和单体、例如马来酸酐或氯乙烯,将它们在自由基引发剂的存在下进行自由基聚合,在所得的无规共聚物的酸酐单元或氯乙烯单元中,例如,将一个末端的羟基进行锂化等金属醇化,或者将该一个末端的羟基转化成氨基(NH2),使用所得的聚(乙二醇)衍生物,经由酯或酰胺键或醚(-O-)或-NH-接枝聚(乙二醇)链,从而即可制造。然而,在上述的聚合反应时,若并用甲基(苯基)氨基二硫代甲酸氰甲酯或氰甲基甲基(苯基)氨基二硫代甲酸酯这样的链转移剂,则可降低所合成的聚合物的分子量,可简化后续的接枝化反应的操作。当然,在不使用这样的链转移剂的情况下,也可制造目标共聚物。
上述的纳米颗粒或高分子胶束如下进行制作:依据本发明的共聚物是两亲性的,在调制含有水可溶性有机溶剂、例如N,N-二甲基甲酰胺(DMF)或二甲基亚砜(DMSO)的水溶液后,经由一定的截留分子量的透析膜在水中进行透析,使共聚物其本身缔合而形成胶束,从而即可制作。如此操作而形成的胶束或纳米颗粒例如可通过冷冻干燥、离心分离等进行分离,以所得的固态物的形式获取。
如此操作而提供的纳米颗粒和纳米尺寸的高分子胶束可在水性介质(根据需要为可包含生理盐水或pH调节剂的水溶液)中增溶或均匀地分散,以所得的溶液或液体制剂的形式提供,因此可制成包括胃肠外制剂在内的、处于各种形态的口服制剂。例如,在以口服制剂的形式提供的情况下,本发明的纳米颗粒还可利用其自身的该技术领域中常用的赋形剂、稀释剂,制成片剂、丸剂、颗粒剂来提供。对赋形剂或稀释剂没有限定,可以是该技术领域中常用的氯羧甲基纤维素钠、结晶纤维素、羟丙甲纤维素、十二烷基硫酸钠、硬脂酸镁、聚乙二醇(Macrogol) 4000、氧化钛等。
包含这样的纳米颗粒作为有效成分的药物制剂可在被递送该纳米颗粒的包括人类在内的哺乳动物的生物体局部发挥上述的短链脂肪酸其本身本质上具有的生理功能。这样的药物制剂的最适剂量根据以处置为目的的疾病或给药方法而变动,因此无法唯一地确定剂量,但剂量可根据通过小规模的临床试验等得到的数据等由专业医生进行确定。
具体实施方式
以下,为了避免说明变得繁杂,对本发明的典型示例进行具体地说明,但本发明并不限于这些示例。
制造例1:CH3O-(CH2CH2O)m-CH2PhCH2Br(N686)的合成
在100g (20mmol)市售的CH3O-(CH2CH2O)m-H (MW=5,000)中加入200mL四氢呋喃(THF)和14.4mL (23mmol)丁基锂(1.6M-己烷),之后加入25g (95mmol) α,α’-二溴二甲苯,在50℃下反应2天。在2-丙醇(IPA)中沉淀后,将沉淀物减压干燥。将所得的淡黄色聚合物溶于甲醇,进行离心分离,将α,α’-二溴二甲苯以沉淀的形式去除。向IPA中投入甲醇溶液,使所得的白色沉淀减压干燥,得到了目标物(N686) (收量104g)。
制造例2:CH3O-(CH2CH2O)m-CH2PhCH2S(=S)OCH2CH3(N717)的合成
将20g制造例1中合成的N686溶于100mL的乙醇,加入7g乙基黄原酸钾(CH3CH2OC(=S)SK),在室温下反应10分钟。离心分离出(分别)沉淀后,减压馏去乙醇。将残余物溶于氯仿,用水洗涤,分离出(分别)氯仿层,经无水硫酸钠脱水过滤后在IPA中沉淀,离心分离后减压干燥,得到了目标物(N717) (收量15g)。
制造例3:CH3O-(CH2CH2O)m-CH2PhCH2[CH2CH(OC(=O)CH3)]nS(=S) OCH2CH3(N684)的合成
将1g制造例2中合成的N717、15mg偶氮二异丁腈、6.6g乙酸乙烯酯加入到烧瓶中,充氮气5分钟后,在60℃下反应1天。将所得的目标物溶于THF,在IPA中沉淀,进行减压干燥,得到了2.6g目标物(N684)。N684的1H NMR波谱见图1。
制造例4:CH3O-(CH2CH2O)m-CH2PhCH2[CH2CH(OC(=O)CH2CH3)]nS (=S)OCH2CH3
(N731)的合成
将5g制造例2中合成的N717、75mg偶氮二异丁腈、7g丙酸乙烯酯加入到烧瓶中,充氮气5分钟后,在60℃下反应2天。将所得的目标物溶于THF,在IPA中沉淀,进行减压干燥,得到了9.3g目标物。N731的1H NMR波谱见图2。
制造例5:CH3O-(CH2CH2O)m-CH2PhCH2[CH2CH(OC(=O)CH2CH2 CH3)]nS(=S)OCH2
CH3(N721)的合成
将5g实施例2中合成的N717、75mg偶氮二异丁腈、10g丁酸乙烯酯加入到烧瓶中,充氮气5分钟后,在60℃下反应2天。将所得的目标物溶于THF,在IPA中沉淀,进行减压干燥,得到了12.3g目标物(N721)。N721的1H NMR波谱见图3。
制造例6:接枝共聚物(N741)的合成
将75mg偶氮二异丁腈、5.7g丁酸乙烯酯、100mg马来酸酐、200mg氰甲基甲基(苯基)氨基二硫代甲酸酯(PhN(CH3)C(=S)SCH2CN)加入到烧瓶中,充氮气5分钟后,在60℃下反应2天。将所得的目标物溶于THF,进行少量采样后,如下所述,加入另外调制的CH3O-(CH2CH2O)mOLi*的THF溶液,搅拌30分钟。将反应溶液倒入IPA中,将沉淀干燥,从而得到了6g目标物(N741)。N741的1H NMR波谱见图4。
*在20mLTHF中加入5g CH3O-(CH2CH2O)mOH (MW=5,000)和0.6mL丁基锂,制作CH3O-(CH2CH2O)mOLi的THF溶液。
制造例7:自组装颗粒的调制1
分别采集50mg上述中合成的聚合物(N684、N731、N721),溶于1mL的DMF,加入1mL水,装入透析膜(MWCO=3.5KDa)中,在2L水中进行透析。每半天交换3次透析水,之后进行动态光散射测定,确认形成了平均30-100nm的颗粒(参照图5)。
制造例8:自组装颗粒的调制2
除了使用制造例6中合成的接枝聚合物(N741)以外,重复制造例7的操作,确认形成了具有153nm的平均粒径的颗粒(参照图6)。
试验例1:细胞毒性1
在各接种了1×104个HepG2细胞的96孔板上添加制造例7中制作的自组装颗粒的各样品,培养24小时后添加WST溶液,在2小时后测定450nm的UV吸收,与对照进行比较时,确认了在测定的浓度下几乎均未产生毒性(图7:显示N684、N731、N721的各纳米颗粒的细胞毒性)。
试验例2:细胞毒性2
除了使用制造例8中制作的自组装颗粒以外,重复试验例1的操作,评价N741的细胞毒性。试验结果见图8。由图8判定:N741的纳米颗粒在该试验系统中未显示细胞毒性。
试验例3:癌症转移抑制效果
让1组5-7只的5周龄BALB/c小鼠(雄)自由摄取下述GP1~GP6的给药组中记载的各样品。2天后,尾静脉注射1×104个B16F10/B16F10黑色素瘤细胞(从理研细胞库获取),继续摄取样品水。在第11天进行解剖,通过肉眼观察确认粘附(正着)于肺部的癌症的个数,结果见图10,另外,试验中的实验动物的体重变化见图9。
根据图10,在短链脂肪酸中几乎完全没有发现癌症转移数抑制效果,相对于此,丙酸纳米颗粒的GP5组显示极高的癌症转移抑制。图11显示在显微镜下测量用肉眼无法观察到的微小转移灶的数量的结果。与图10同样,确认了丙酸纳米颗粒(图中,简记为PEG-b-PVPro)极度抑制癌症转移。
图12显示肺组织图的H&E染色图(左)和由图求得的转移癌的数量(右)。与对照相比,在丙酸纳米颗粒和丁酸纳米颗粒中观察到癌症的数量显著下降。图13显示肺组织图的H&E染色图(左)和由图求得的转移癌的面积(右)。与对照和低分子脂肪酸相比,在丙酸纳米颗粒和丁酸纳米颗粒中观察到癌症的面积显著减少。图14显示血液中的ALT、AST、LDH和ALB水平。确认到:在所有情况下对于肝脏或脏器几乎均未发现障碍。
图15~18显示小肠和大肠组织的H&E染色图。根据位置,在低分子脂肪酸组中发现了绒毛的缩短,确认到存在损伤。
样品给药组
GP1:健康组(n=5);
GP2:黑色素瘤给药组(n=7);
GP3:黑色素瘤给药组/30mM丙酸自由摄取组(n=7);
GP4:黑色素瘤给药组/30mM丁酸自由摄取组(n=7);
GP5:黑色素瘤给药组/30mM N731自由摄取组(n=7);
GP6:黑色素瘤给药组/30mM N721自由摄取组(n=7)。
试验例4:节食效果
对1组5只的4周龄C57BL/6J小鼠(雄)给予从EPS益新株式会社购入的固体饲料D12492 (60%脂肪、超高脂肪饲料),对下述GP1~GP3的各给药组给予所记载的各样品,测定体重。结果见图19。
由图19确认到:相对于自来水组和丙酸颗粒(N731),丁酸颗粒组(N721)显著抑制体重増加。
样品给药组
GP1:自来水自由摄取;
GP2:N731自由摄取(5mg/mL);
GP3:N721自由摄取(5mg/mL)。
试验例5:针对溃疡性大肠炎的效果
让1组7只的7周龄ICR小鼠(雄)自由摄取4%葡聚糖硫酸钠(DSS),通过Sonde一天一次口服给予下述样品。10天后测定疾病活动性评价指标(disease activity index(DAI)),对血液进行评价。如图20所示,针对溃疡性大肠炎模型,丁酸纳米颗粒(图中,记作BNP)使DAI显著下降,观察到治疗效果。另外,如图21所示,在溃疡性大肠炎模型中发现白细胞数的显著上升,相对于此,在BNP中显著抑制。
样品给药组
GP1:自来水自由摄取+自来水(0.65mL);
GP2:4% DSS摄取+自来水(0.65mL);
GP3:4% DSS摄取+丁酸(2.32mg/mL、0.65mL);
GP4:4% DSS摄取+CNP (PEG-b‐聚苯乙烯) (10mg/mL、0.65mL);
GP5:4% DSS摄取+BNP (PEG-b‐聚(丁酸乙烯酯) (10mg/mL、0.65mL)。
试验例6:针对非酒精性脂肪肝炎(NASH)的效果
对49只5周龄C57BL/6J小鼠(雄)通过自由摄取而给予从EPS益新株式会社购入的固体饲料A06071302 (胆碱缺乏高脂肪饲料、蛋氨酸减量、添加0.1%蛋氨酸),在4周后随机分成1组7只,通过自由摄取而给予下述GP1~GP7的各给药组中记载的各样品。在8周后进行数据分析。图22显示肝脏和脾脏重量。确认到:NASH组因炎症而发生肥大,相对于此,在丙酸颗粒给药组中肥大得到显著抑制。
样品给药组
GP1:普通固体饲料(东方酵母MF);
GP2:固体饲料A06071302;
GP3:固体饲料A06071302+丁酸(65mM);
GP4:固体饲料A06071302+丙酸(50mM);
GP5:固体饲料A06071302+丁酸纳米颗粒(10mg/mL、聚合物浓度1mM、丁酸换算计为65mM);
GP6:固体饲料A06071302+丙酸纳米颗粒(10mg/mL、聚合物浓度1mM、丙酸换算计为50mM);
GP7:固体饲料A06071302+聚苯乙烯纳米颗粒(10mg/mL)。
试验例7:癌症转移抑制效果之二
从Charles River Japan公司(横滨)获取1组5-7只的7-8周龄C57BL/6J小鼠(雄)。让这些小鼠在无病原性条件下、在12小时的暗/明循环中、在温度(23±1℃)和湿度(50±5%)可控下自由摄取标准固体饲料的同时进行饲养。将小鼠随机分成下述的GP1~GP6的给药组,自由摄取所记载的各样品。1天后,尾静脉注射每200μL生理盐水为2.5×105个的B16F10/B16F10黑色素瘤细胞(从理研细胞库获取)。从该尾静脉注射的1天前起到作为试验终点的11天为止,继续对小鼠以自由饮水形式给予各样品。在第11天采集血浆和其他脏器,为下述的进一步的各种分析做准备,适当地进行储存。
试验中的样品消耗量的变化和实验动物的体重变化见图23。对于其他试验,得到了与在试验例3中观察或确认到的试验结果实质上等价的试验结果。
样品给药组
GP1:健康组(n=5);
GP2:黑色素瘤给药组(n=7);
GP3:黑色素瘤给药组/30mM丙酸自由摄取组(n=7);
GP4:黑色素瘤给药组/30mM丁酸自由摄取组(n=7);
GP5:黑色素瘤给药组/30mM PNP (来自N731的颗粒:参照制造例7)自由摄取组(n=7);
GP6:黑色素瘤给药组/30mM BNP(来自N721的颗粒:参照制造例7)自由摄取组(n=7)。
试验例8:针对抗糖尿病试验的效果
关于该试验和本说明书中公开的所有的使用实验动物的试验中的动物的管理和使用,严格按照有关该管理等的筑波大学的指南来进行。
从Charles River Japan公司(横滨)获取1组7只的7-8周龄C57BL/6J小鼠(雄)。让这些小鼠在无病原性条件下、在12小时的暗/明循环中、在温度(23±1℃)和湿度(50±5%)可控下自由摄取标准固体饲料的同时进行饲养。将小鼠随机分成下述GP1~GP6的给药组,让其自由饮用、摄取所记载的各样品直至36天。1天后,进行葡萄糖耐量试验。试验中,每隔1天对各小鼠的体重和样品的消耗进行监测。之后,用饮料水置换样品直至试验的结束时间点(第40天)。
样品给药组
GP1:艾塞那肽(传统的抗糖尿病药)、1μg (第1-4天)、2μg (第5-36天)的每天皮下注射组;
GP2:60mM BNP (来自N721的颗粒:参照制造例7)自由摄取组;
GP3:60mM PNP (来自N721的颗粒:参照制造例7)自由摄取组;
GP4:30mM丁酸自由摄取组;
GP5:30mM丙酸自由摄取组;
GP6:对照组(水自由摄取)。
(1) 将该试验中的样品消耗量以每只小鼠的量(mL)计、将小鼠体重记作平均±SD值,分别见图24。
(2) 葡萄糖耐量试验是为了评价在控制所给予的葡萄糖的代谢时的短链脂肪酸的治疗效果而进行。在16小时的过夜约束后,对小鼠口服给予葡萄糖(2g/kg)。在给予葡萄糖的1小时前后,从尾静脉采集10μL血液,与含肝素(50单位/mL)的生理盐水以容量(v:v)比1:1混合。利用FUJI DRY-CHEM 7000V (富士胶片)测定稀释血液中的葡萄糖浓度。通过下式计算最终血中葡萄糖浓度。
最终葡萄糖浓度(mg/mL)=[葡萄糖]60分钟-[葡萄糖]0分钟
作为平均±SEM(n=7)值的数据见图25。
进行Student t-检验、尾(2)和类型(2),确定平均值间的统计误差(P<0.05在统计学上认为显著)。
对于糖尿病模型小鼠,丙酸给药组、丁酸给药组和丙酸纳米颗粒(PNP)给药组均未发现显著差异,相对于此,在糖尿病药艾塞那肽和BNP给药组中可使葡萄糖浓度显著下降,可知胰腺功能提高。
(3) 在试验的结束时间点的器官的重量
将小鼠解剖后,快速测定所取出的脾脏、肾脏和肝脏的重量,结果见图26,将这些脏器作为进一步的组织学分析用,保存在10%中性缓冲液中。Student t-检验同上。
该结果中,在丙酸给药组中发现脾脏重量上升,在丁酸给药组和艾塞那肽给药组中确认到肝脏重量上升。这显示脏器炎症。另一方面,在BNP给药组中脾脏、肾脏、肝脏均与对照相当,未显示毒性。
(4) H和E染色肠道的组织学分析
将解剖后所取出的小鼠的器官快速放入10%中性福尔马林溶液中,浸泡1天而进行固定。之后,置换成70%乙醇溶液以进行石蜡包埋。将石蜡包埋后的所有器官均加工成厚度5μm的组织切片,通过常规方法进行苏木精/伊红(H/E)染色。将组织切片用高浓度醇脱水,用二甲苯洗涤,之后进行显微镜检查(biorevo、BZ-9000、Keyence)。利用Image J软件(ImageJ software) (NIH)测定绒毛长度。结果见图29。定量数据的最小与最大范围的值、上限与下限的四分位数(quartile)、中央值:十二指肠(n=130-132)、空肠(n=96-185)、回肠(n=109-138)、结肠(n=37-47)以方框中的图表示。t-检验同上。
显示出:在艾塞那肽给药组中十二指肠、空肠、回肠、大肠的绒毛显著变短,显示强的副作用。丙酸和丁酸给药组也处于同样的倾向。另一方面,可知在BNP给药组、PNP给药组中未发现绒毛的缩短,对消化道没有损伤。
(5) H和E染色胰腺组织的组织学分析
将解剖后所取出的小鼠的器官快速放入10%中性福尔马林溶液中,浸泡1天而进行固定。之后,置换成70%乙醇溶液以进行石蜡包埋。按照常规方法,将石蜡包埋后的所有脏器均加工成厚度5μm的组织切片,利用常规方法进行苏木精/伊红(H/E)染色。将组织切片用高浓度醇脱水,用二甲苯洗涤后,进行固定,供于显微镜检查(biorevo、BZ-9000、Keyence)。利用Image J软件(Image J software) (NIH)确定朗格汉斯岛的区域。结果见图30。定量数据的最小与最大范围的值、上限与下限的四分位数(quartile)、中央值(n=10-20)以方框中的图表示。t-检验同上。
在糖尿病模型小鼠和丙酸给药组、丁酸给药组、PNP给药组中朗格汉斯岛尺寸缩小,而在BNP给药组和艾塞那肽给药组中未发现朗格汉斯岛的萎缩,显示出朗格汉斯岛的功能得以维持。
试验例9:作为放射线增强剂的效果之一
将与上述试验同样获取的一组5只的5-7周龄的C57BL/6J小鼠在同样的条件下进行饲养。在小鼠的右腿外侧部皮下注射每100μL (不含血清的DMEM)为0.076×106个的黑色素瘤B16F10细胞(照射前第7天)。在癌症增殖1周后,将小鼠随机分成下述给药组。在照射前1天和刚刚照射后对小鼠的腹腔内(i.p.)给予BNP (500mg/kg),确认放射线增强效果(分别为GP3和GP4)。照射条件设为10Gy、150kV、20mA、Al过滤、330mm间隔。
样品给药组
GP1:癌症对照组;
GP2:癌症+照射(IR:10Gy)组;
GP3:BNP 500mg/kg (照射前1天)组;
GP4:BNP 500mg/kg (照射后0天)组。
(1) 照射后,直至试验结束时间点(8天)对癌症增殖和体重进行追踪。结果见图31。0天是照射前的数据,8天是照射后(试验的结束时间点)的数据。
与未给药组同样,BNP给药组也没有体重变化、未发现毒性。
(2) 在试验的结束时间点采集血浆和其他器官,作为进一步的分析用,适当地进行保存。使用卡尺测定癌症的大小,利用下述等式算出癌症的体积。
癌症的体积=0.52×长度×宽度2
结果见图30。t-检验与试验8(2)相同。
在10Gy照射组中具有肿瘤生长抑制效果,即使在X射线照射之前和之后给予BNP,8天后的肿瘤尺寸与BNP未给药组相比也明显小,确认到放射线增强效果。
试验例10:作为放射线增强剂的效果之二
将与上述试验同样用于试验的一组5或7只的5-7周龄的C57BL/6J小鼠在同样的条件下进行饲养。在小鼠的右腿外侧部皮下注射每100μL (不含血清的DMEM)为0.076×106个的黑色素瘤B16F10细胞(照射前第9天)。当癌症的体积达到350-560mm3时,将小鼠随机分成下述给药组。照射条件设为10Gy、150kV、20mA、Al+Cu (0.5mm+0.1mm)过滤、330mm间隔。
与上述同样地算出癌症体积。
样品给药组
GP1:健康(生理盐水)组(n=5);
GP2:癌症对照组(n=7);
GP3:癌症+照射(IR(5Gy))组(n=7);
GP4:丁酸(i.p.;250mg/kg) (照射前6小时)+IR组(n=7);
GP5:丁酸(i.p.;500mg/kg) (照射前24小时)+IR组(n=7);
GP6:BNP (i.p.:500mg/kg) (照射前6小时)+IR组(n=7);
GP7:BNP (i.p.:500mg/kg) (照射前12小时)+IR组(n=7)。
(1) 在黑色素瘤异种移植模型中给予丁酸和NP后的基于5Gy照射的癌症增殖曲线的数据见图33。
在放射线照射前给予丁酸和BNP。肿瘤増殖抑制效果以照射组<6小时前丁酸给药组<6小时前BNP给药组=24小时前丁酸给药组<24小时前BNP给药组的顺序增加。
(2) 试验结束时间点(照射后第6天)的癌症的重量的数据以平均±SEM值(n=2-7)的形式见图32。t-检验与试验8(5)相同。
肿瘤重量的结果为:24小时前BNP给药组和6小时前丁酸给药组使肿瘤尺寸显著减小。(3) 将小鼠的体重变化作为平均±SD值(n=7)的数据见图35。t-检验同上。
在丁酸给药组中发现体重减少,产生毒性。另一方面,BNP给药组未见体重减少,没有产生毒性。
试验例11:通过球状体检验进行评价的BNP的放射线增强效果的体外评价
将黑色素瘤B16F10细胞用50mM的丁酸处理7小时后,照射2Gy (Al+Cu (0.5mm+0.1mm)过滤器)。在37℃下停止1小时,去除培养基,洗涤数次以去除样品,然后补充新鲜的培养基。将处理细胞培养24小时后,在0.6%的甲基纤维素和DMEM (1:1)中培养3天,形成球状体。通过直接镜检法拍摄图像,利用Image J软件(NIH)测定球状体。进行分组,然后将细胞在2Gy照射后用样品处理7小时。数据以平均±SEM值(n=32-37)的形式表示。这些结果见图38。t-检验同上。
细胞培养:
小鼠黑色素瘤B16F10细胞从细胞库(理研、日本)购入。将这些细胞株在补充了10%胎牛血清和100ng/mL的青霉素-链霉素-新霉素的抗生素混合物的Dulbecco改良Eagle培养基(DMEM;L-谷氨酰胺、1g/L的葡萄糖、碳酸氢钠、Sigma-Aldrich、St Louis、MO、USA)中,在5% CO2的加湿环境下于37℃进行保持。结果见图34。
在BNP给药组中明显地确认到球状体癌细胞的生长抑制效果。
试验例12:针对非酒精性脂肪肝炎(NASH)的效果之二
对42只5周龄C57BL/6J小鼠(雄)通过自由摄取而给予从EPS益新(株)购入的固体饲料A06071302 (胆碱缺乏高脂肪饲料、蛋氨酸减量、添加0.1%蛋氨酸),在4周后随机分成1组7只,对下述的健康组(Healthy) (未给予固体饲料A06071302)、NASH组、丁酸给药组(BA)、丙酸给药组(PA)、PNP给药组、BNP给药组这6组通过自由摄取而给予所记载的各样品(PA和PNP组的PA调制成65mM的浓度、BA和BNP组的BA调制成50mM的浓度)。在8周后进行数据分析。
(1) 肝脏和脾脏重量见图35。确认到:NASH组因炎症而发生肥大,相对于此,在丙酸颗粒给药组中肥大得到显著抑制。
这里,为了比较肝脏中蓄积的脂肪量的不同和与肝脏中的炎症相呼应的脾脏肿大的程度,测定在小鼠解剖后所取出的肝脏和脾脏的重量,求出各组的平均重量(各组n=7)。各组的平均肝脏重量值和平均脾脏重量值的误差棒采用标准偏差值(各组n=7)。为了研究平均值间在统计学上是否存在显著差异而进行t-检验,P<0.05,在统计学上存在显著差异。
关于肝脏重量(左图),相对于健康组,NASH组的肝脏重量明显重,引发了炎症。另一方面,与NASH组相比,PNP给药组的肝脏重量明显轻,抑制了炎症。
关于脾脏重量(左图)也同样,相对于健康组,在NASH组中显著上升,在PNP给药组中显著下降。
(2) 经HE染色的肝脏的组织学分析
将解剖后所取出的小鼠的肝脏快速放入10%中性缓冲福尔马林溶液中,浸泡1天而进行固定。之后,置换成70%乙醇溶液以进行石蜡包埋。石蜡包埋后所有的肝脏均加工成厚度5μm的组织切片,进行苏木精/伊红(HE)染色。染色后的所有组织切片均通过显微镜(All-in-One荧光显微镜、BZ-X710、Keyence)进行图像数据化,之后利用Image J (NIH)求出油滴组织面积与肝脏组织面积的比例(各组n=7)。结果见图36。图显示各组的油滴组织面积的平均值和标准偏差的误差棒。为了研究平均值间在统计学上是否存在显著差异而进行t-检验,P<0.05,在统计学上存在显著差异。
关于肝脏的油滴量,相对于健康组,在NASH组中大幅増加(脂肪肝状态)。另一方面,与NASH组相比,PNP给药组的油滴量明显少。
(3) 经MT染色的肝脏的组织学分析
将解剖后所取出的小鼠的肝脏快速放入10%中性缓冲福尔马林溶液中,浸泡1天而进行固定。之后,置换成70%乙醇溶液以进行石蜡包埋。石蜡包埋后所有的肝脏均加工成厚度5μm的组织切片,进行Masson三色(MT)染色。染色后的所有组织切片均通过显微镜(All-in-One荧光显微镜、BZ-X710、Keyence)进行图像数据化,之后利用Image J (NIH)求出纤维化组织面积与肝脏组织面积的比例(各组n=7)。结果见图42。图显示各组的纤维化组织面积的平均值和标准偏差的误差棒。为了研究平均值间在统计学上是否存在显著差异而进行T-检验,p<0.05,在统计学上存在显著差异。
关于肝纤维化量,相对于健康组,在NASH组中明显多。另一方面,与NASH组相比,PNP给药组的肝纤维化量明显少。
制造例9:CH3O-(CH2CH2O)m-CH2PhCH2[CH2CH2(OC(C=O)CH2CH2 CH2Ph)n]S(=S)
OCH2CH3(N821)的合成
将1.5g与制造例2 (本申请)中合成的N717同样地合成的N817、45mg偶氮二异丁腈、2g 4-苯基丁酸乙烯酯加入到烧瓶中,充氮气5分钟后,在60℃下反应1天。将所得的目标物溶于THF,在异丙醇(IPA)中沉淀,进行减压干燥,得到了2.8g目标物(N821)。N821的1HNMR波谱见图38。
制造例10:自组装颗粒(Ph-BNP)的调制
分别采集50mg制造例9中合成的聚合物(NN821),溶于1mL的DMF,加入1mL水,装入透析膜(MWCO=3.5KDa)中,在2L的水中进行透析。每半天交换3次透析水,之后进行动态光散射测定,可确认形成了平均67nm的颗粒。作为动态散射测定结果的PEG-b-聚(乙烯基4-苯基丁酸)纳米颗粒(Ph-BNP、N832)的尺寸分布见图44。
试验例13:抗氨血症效果
将24只6周龄的C57BL/6N小鼠(雄)随机分成4组,通过Sonde口服给予样品(1天1次、1.22mmol-4PBA/kg)达4天。在给药组2GP-4GP中,通过在第4天腹腔给予乙酰氨基酚(乙酰对氨基酚;APAP;300mg/kg)引起急性肝功能障碍和高氨血症,在第5天进行解剖,并进行评价。
样品给药组
1GP:生理盐水;
2GP:APAP+水;
3GP:APAP+4-苯基丁酸(200mg/kg、1.22mmol-4PBA/kg);
4GP:APAP+Ph-BNP (200mg/kg、1.22mmol-4PBA/kg)。
(1) 血液的生化检验
在试验开始第5天的刚刚心脏采血后,使用比色法载玻片,利用动物用生化自动分析装置分别测定血中氨浓度、作为肝功能指标的血浆天冬氨酸氨基转移酶(AST)、血浆丙氨酸氨基转移酶(ALT)水平。结果(Ph-BNP针对APAP急性肝障碍模型的口服给药效果)见图40。
由图可知:4-Ph-BNP显著降低血中氨浓度,另外,AST、ALT水平也显著降低,有助于肝功能的恢复。
(2) 经HE染色的肝脏的组织学分析
将解剖后所取出的小鼠的肝脏按照上述的器官或脏器的HE染色法进行染色。其结果见图41。由图可知:在APAP给药组中,肝脏中出现较强的障碍,但在Ph-BNP中损伤被抑制。图中,Healthy相当于健康组小鼠、APAP给药组小鼠,APAP+PBA相当于APAP和4-苯基丁酸的给药组,APAP+Ph-BNP相当于APAP和Ph-BNP (依照本发明的纳米颗粒)的给药组。
试验例15:药物动力学试验
依据上述的制造例1~8的方法,按照常规方法进行相应的改变,通过氯胺法向在PEG的α末端具有苯环的PEG-b-聚(乙烯基丁酸酯) (参照下式左)和PEG-b-聚(乙烯基4-苯基丁酸酯) (参照下式右)的苯基中引入125I,使用PD-10柱纯化2次,分离出(分别)未反应的碘。
(1)
将从供水瓶中自由摄取了N932的小鼠在24小时后采集血液、肝脏和消化道,使用闪烁检测器测定其γ射线强度。结果见图42 (左)。由图确认到:N932几乎完全局限于消化道内。
另一方面,通过Sonde强制口服给予N930,在24小时后测定主要脏器的γ射线强度。结果见图42(右)。由该图可确认到:除了消化道以外,还广泛分布于血液、肝脏、肾脏等,4-苯基丁酸在消化道中水解,被摄入到循环系统中。
(2)
将45只7周龄的ICR小鼠(雄)随机分成以下的3组,关于给药组:2GP和3GP的给药量,以所含的苯基丁酸达到200mg/kg (1.22mmol-4PBA/kg)的方式进行确定。对所有小鼠几乎同时给予各样品,之后按照各终点(endpoint,端点) (30分钟、1小时、2小时、4小时、12小时、16小时、24小时这7个终点)通过心脏穿刺采集1mL血液,并分离血浆。另外,由小鼠取出靶向脏器的肝脏,通过高效液相色谱法/质谱法(LC/MS)定量苯基丁酸单体的含量。测定结果见图43。由这些图可知:PBA在4小时以内完全从体内代谢,相对于此,4-Ph-BNP在血中和肝脏中持续地释放苯基丁酸单体,即使在经过了24小时的时间点其释放也未结束。另外,计算浓度-时间曲线下面积(AUC)也会发现:与PBA相比,4-Ph-BNP在血液中增加了约3倍、在肝脏中增加了约15倍。
样品给药组
1GP:生理盐水(对照、3只);
2GP:4-苯基丁酸 (30分钟、1小时、2小时、4小时、12小时、16小时、24小时这7个终点×3只);
3GP:Ph-BNP (30分钟、1小时、2小时、4小时、12小时、16小时、24小时这7个终点×3只)。
Claims (10)
1.亲水-疏水性共聚物,该亲水-疏水性共聚物包含下述的(1)和(2):
(1) 来自式I所表示的重复单元的疏水性链段,
式中,
R为-(C=O)R1或氢原子,R1是未取代或取代的碳原子数为1~7个的直链或支链的烷基,其中,被取代的情况下的取代基是未取代或取代的苯基,被取代的苯基的取代基是1个以上的卤素、羟基、甲氧基,这里,即使存在氢原子,其也为n的30%以下,n为5~1000的整数;以及
(2) 包含聚(乙二醇)链的亲水性链段,该亲水性链段为下述的(i)或(ii):
(i) 式IIa所表示的亲水性链段,
式中,A是未取代或取代的C1-C12烷氧基,被取代的情况下的取代基为甲酰基、式R’R”CH-基、或苯基氨基或苯乙基氨基,这里,R’和R”独立地为C1-C4烷氧基或R’和R”一起为-OCH2CH2O-、-O(CH2)3O-或-O(CH2)4O-,m为10~500的整数;或
(ii) 来自式IIb所表示的重复单元的亲水性链段,
式中,Ra为氢原子或羧基,
当Ra为羧基时,X为C(=O)O或C(=O)NH,或者,当Ra为氢原子时,X为O或NH,
B为A-CH2CH2,A和m分别为如上述所定义,
y为1~300的整数,
上述(1)的疏水性链段和(2) (i)的亲水性链段分别以嵌段形式存在,
包含上述(1)的疏水性链段和(2) (ii)的亲水性链段的各重复单元的每个成员彼此随机存在。
2.权利要求1的亲水-疏水性共聚物,其通过在水中缔合进行自组装而形成纳米颗粒或纳米尺寸的高分子胶束。
4.纳米颗粒,其由权利要求1~3中任一项的亲水-疏水性共聚物在水性介质中形成。
5.药物制剂,其包含权利要求1~3中任一项的亲水-疏水性共聚物或权利要求4的纳米颗粒作为有效成分而形成。
6.权利要求5的药物制剂,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
7.权利要求1~3中任一项的亲水-疏水性共聚物,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
8.权利要求4的纳米颗粒,其用于癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗。
9.将权利要求1~3中任一项的亲水-疏水性共聚物给予至需要它们的患者,以用于进行癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗(或肝纤维化的抑制)、糖尿病的预防或治疗、放射线疗法中的放射线的增强、或高氨血症的预防或治疗的方法。
10.将权利要求4的纳米颗粒给予至需要它们的患者,以用于进行癌症的预防或治疗、肥胖抑制、溃疡性大肠炎、非酒精性脂肪肝的预防或治疗、糖尿病的预防或治疗(或肝纤维化的抑制)、放射线疗法中的放射线的增强、肝纤维化的抑制、或高氨血症的预防或治疗的方法。
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AU2020324649A1 (en) | 2022-03-17 |
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