CN101460198A - 热敏性聚磷腈-生物活性分子缀合物、其制备方法及其用途 - Google Patents
热敏性聚磷腈-生物活性分子缀合物、其制备方法及其用途 Download PDFInfo
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Abstract
本发明涉及聚(有机磷腈)-生物活性分子缀合物,其中具有随温度变化显示溶液-凝胶相变的官能团的可生物降解和热敏聚(有机磷腈)与各种生物活性分子例如药物结合;其制备方法及其递送生物活性分子的用途。
Description
发明背景
(a)发明领域
本发明涉及聚(有机磷腈)-生物活性分子缀合物,其中具有随温度变化显示溶液-凝胶相变的官能团的可生物降解和热敏性聚(有机磷腈)与各种生物活性分子例如药物结合;其制备方法及其递送生物活性分子的用途。
(b)相关领域描述
热敏性聚合物水凝胶水溶液可在低温下保持溶液相,且可通过升温使其变为凝胶相。
这种溶液-凝胶相变可反向发生。据认为,由于其水溶液的优点在于可容易与治疗药物混合,故热敏性聚合物水凝胶是递送注射药物的有效物质。因此,可容易地将它注射到活体中,无需任何外科手术,且当注射到活体的需要的区域时,它在体温下形成具有3维结构的凝胶相,因而可实现药物的控释和缓释[Life Science,65,261(1999);J.Control.Rel,63,155(2000)]。
但是,具有小分子量或高亲水性的药物的问题是它们可容易地和迅速通过由热敏性聚合物水凝胶形成的凝胶的3维网络结构,致使30%或更多的大量药物在注射早期阶段释放。还存在另一个问题是,由于凝胶中的亲水性药物高速扩散到活体中致使在短时间内完成药物释放,因此无法实现药物缓释(Adv Drug Deliv Rev,31,197(1998))。
因此,需要其中生物活性分子或药物直接与水凝胶结合的可生物降解和热敏性聚合物。另外,因为细胞不能在凝胶中生长,所以需要与生物活性分子缀合的热敏性聚合物水凝胶,它可作为移植型细胞转运物质使用。
聚环氧乙烷和聚环氧丙烷的共聚物(泊咯沙姆)是熟知的热敏性聚合物水凝胶。但是,泊咯沙姆在体内不能降解[J.Pharm.Pharmacol,48,669(1996)]。近来,报道了可生物降解的聚环氧乙烷和聚交酯酸的共聚物()[Nature,388,860(1997)]。但是,的缺点是没有官能团,因而限制了与药物或生物活性分子的直接结合。
本发明发明人报道了通过用氨基酸酯和甲氧基聚乙二醇取代线性二氯磷腈制备的聚(有机磷腈)出现热敏性,该热敏性是在特定温度或更低温度下物质在水溶液中为溶液相,而当温度高于特定温度时,发生相变,溶液相变为3维结构的凝胶相。另外,它们在水溶液中逐渐水解[Macromolecules 32,2188(1999);Macromolecules 32,7820(1999);Macromolecules 35,3876(2002);韩国专利259,367和315,630号;和US专利6,319,984号]。
另外,本发明发明人还开发出具有随温度变化而显示溶液-凝胶相变的官能团的聚(有机磷腈)(韩国专利申请2006-0005579号)。
可通过化学键例如共价键或配位共价键,将药物或生物活性分子引入具有官能团的聚(有机磷腈)。可根据化学键的类型改变聚(有机磷腈)的性质,包括生物分布、生物降解、药效学、溶解度、抗原反应。
聚合物-药物缀合物可控制药物释放,减少药物毒性并增加药物的EPR作用(提高渗透和维持作用)[Bioconjugate Chem.3,351(1992)]。作为关于通过这种结合递药的代表性研究,已知环三磷腈-抗癌药物缀合物[J.Control.Release,161,55(1998)]。
可降解和热敏性聚(有机磷腈)-药物或生物活性分子缀合物是应用于热敏性聚合物的聚合物-药物缀合物。聚(有机磷腈)-药物或生物活性分子缀合物具有聚合物-药物缀合物和常规药物载体的优点,所以它可在体内有效递药、具有优良药物作用和适合植入型水凝胶,该水凝胶允许细胞在其中生长。
另外,将各种添加剂引入该聚合物水凝胶还可作为细胞转运物质或药物提高效率。当递送多肽或蛋白质药物时,引入添加剂可保持水凝胶中药物的稳定性、诱导添加剂和药物的离子键产生和控制水凝胶释放药物的速度。另外,当递送治疗性细胞时,递送到身体后,引入水凝胶的添加剂还可增加细胞的活性。
发明概述
本发明目的是提供聚(有机磷腈)-生物活性分子缀合物,其中随温度变化显示溶液-凝胶相变的聚(有机磷腈)与各种生物活性分子例如药物结合;及其制备方法。
本发明的另一个目的是提供含聚(有机磷腈)-生物活性分子缀合物的水凝胶。
本发明的再另一个目的是提供递送生物活性分子的组合物,该组合物含聚(有机磷腈)-生物活性分子缀合物和/或水凝胶和一种或多种选自其它药物和/或添加剂的物质。
图1是显示本发明聚(有机磷腈)-紫杉醇缀合物的溶液-凝胶相变的照片。
图2显示本发明聚(有机磷腈)-抗癌药物或生物活性分子缀合物随温度变化的粘度变化。
图3显示本发明聚(有机磷腈)-紫杉醇缀合物随时间变化的失重度。
图4显示本发明聚(有机磷腈)-抗癌药物或生物活性分子缀合物随时间变化的失重度。
图5显示本发明与抗癌药物缀合的聚(有机磷腈)水凝胶中抗癌药物随时间变化的释放行为。
图6显示本发明与紫杉醇缀合的聚(有机磷腈)水凝胶的体内抗癌活性。
图7显示本发明与多柔比星缀合的聚(有机磷腈)水凝胶的体内抗癌活性。
本发明涉及聚(有机磷腈)-生物活性分子缀合物,其中具有随温度变化显示溶液-凝胶相变的官能团的可生物降解和热敏性聚(有机磷腈)与各种生物活性分子例如药物结合;其制备方法及其递送生物活性分子的用途。
按照本发明,聚(有机磷腈)是可生物降解和热敏性磷酸肌酸基分子,因此发生随温度变化的溶液-凝胶相变。因此,当将它和生物活性分子例如药物给予活体时,聚(有机磷腈)在体温下形成凝胶相,允许生物活性分子控制释放。另外,聚(有机磷腈)具有与生物活性分子通过离子键、共价键或配位共价键化学结合的官能团,因其良好结合性质,故允许生物活性分子缓释。因此,聚(有机磷腈)可用作递送生物活性分子的物质。
本文中使用的术语“可生物降解”是指当物质注射到活体时,它在体内分解为无害物质,被排泄出,致使其不在体内停留,且无有害作用的性质。
术语“热敏性”是指物质发生溶液-凝胶相变的性质,其中通过升温,溶液相形式的溶液变为凝胶相,发生溶液-凝胶相变时的温度称为“胶凝温度”。
术语“生物活性分子”是指在体内具有有利作用的物质。例如,生物活性分子是选自以下的一种或多种分子:各种药物(如抗癌药物和血管发生抑制剂)、蛋白质、多肽、肽、疫苗、基因和激素。
在一个方面,本发明提供聚(有机磷腈)-生物活性分子缀合物,其中随温度变化显示溶液-凝胶相变的聚(有机磷腈)与一种或多种生物活性分子结合。
本发明聚(有机磷腈)-生物活性分子缀合物可由以下化学式1代表:
[化学式1]
其中,
p为乙二醇的重复单元数,为7-50的整数;
NHCH(R1)CO2R2为氨基酸酯,其中
R1选自H、HCH2、CH3、CH2SH、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C6H4OH、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、CH2CO2C2H5、(CH2)2CO2C2H5和HCONHCH(CH2C6H5),且
R2选自CH3、C3H7、C4H9、C2H5、CH2C6H5和CH2CHCH2;
NH(R3)(R4)(R5)为氨基酸、肽或缩肽酯,其中
R3为CH(W),
R4选自CO2、CO2CH2CO2、CO2CH(CH3)CO2和CONHCH(X)CO2,
R5选自H、CH3和C2H5,且
W和X独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH;
NH(R6)(R7)(R8)和NH(R6)(R7)(R9)是具有官能团的取代基,其中
R6为CH(Y),
R7选自C2H4、C3H6、C4H8、CH2C6H4、CH2CO2、O、CONHCH(Z)O、CO、CO2、S、CONHCH(Z)S、N、CONHCH(Z)N、CON、COCHNH(Z)CON、CONHCH(Z)CO和CONHCH(Z)CO2,
R8选自OH、SH、H、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2和下表1中所示保护基,
Y和Z独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R9选自OH、SH、H、NH2、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2、NHCH(SH)CO2H、NH(CH2)qSH、NH(CH2CH2NH)rH、[NHCH(C4H8NH2)CO]rOH、[NHCH[(CH2)3C(=NH)(NH2)]CO]rOH和鱼精蛋白,
q是亚甲基的重复单元数,为1-20的整数,
r是吖丙啶、赖氨酸或精氨酸的重复单元数,为1-18000的整数;
NH(R6)(R7)(R10)为具有官能团的取代基,其中
R6和R7与在NH(R6)(R7)(R8)和NH(R6)(R7)(R9)中的相同,
R10选自紫杉醇、多柔比星、喜树碱、表柔比星、5-氟尿嘧啶、10-羟基喜树碱、10-氨基喜树碱、7-乙基喜树碱、伊立替康、甲氨蝶呤、丝裂霉素C、紫杉烷、多西他赛、苯丁酸氮芥、加里刹霉素、美登醇、2-吡咯啉-1-基多柔比星(AN-201)、柔红霉素、丁酸、美法仑、4′-二甲基去氧鬼臼毒素、姜黄、鬼臼毒素、表鬼臼毒素、4-β-氨基-4′-O-去甲基表鬼臼毒素、太利苏霉素S10b、道诺霉素、duocarmycin A、duocarmycin SA、顺式-乌头道诺霉素、加里刹霉素、偶氮烯鎓二醇(diazeniumdiolate)、纺锤霉素、6-巯基嘌呤、glucuronidation、phosmidosine、链黑霉素、血卟啉、去铁胺(DFO)、去铁酮、阿西维辛、雌莫司汀、力达霉素、精氨酸-甘氨酸-天冬氨酸(aspatic acid)肽、神经肽(例如神经张力蛋白、速激肽、神经肽Y(NPY)、肽YY(PYY)、血管活性肠多肽(vascoactive intestinal polypeptide)(VIP)和垂体腺甘酸环化酶-激活多肽(PACAP))、白蛋白、牛血清白蛋白(BSA)、牛胰腺核糖核酸酶(RNA酶A)、牛精液核糖核酸酶(BS-RNA酶)、Bowman-birk蛋白酶抑制剂(BBI)、胶原蛋白、纤连蛋白、层粘连蛋白、红细胞生成素(EPO)、干扰素、蛭素、集落刺激因子(CSF)、胰岛素、去氨加压素、胰高血糖素样肽1(GLP1)、人生长激素拮抗剂、肿瘤坏死因子受体1(TNFR1)、天冬酰胺酶、腺苷脱氨酶、骨形态发生蛋白(BMPs)、生长因子(例如成纤维细胞生长因子(FGF)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)、神经生长因子(NGF)、血小板衍生生长因子(PDFG)、胰岛素样生长因子(IGF)、转化生长因子-β(TGF-β)、脑源神经营养因子(BDNF)、神经营养蛋白-2(NT-3)和神经营养蛋白-4/5(NT-4/5))、肿瘤坏死因子-相关凋亡-诱导配体(TRAIL)、细胞因子[例如干扰素-α 1a(IFN-α 1a)、干扰素-α 2a(IFN-α 2a)、干扰素-α 2b(IFN-α 2b)、干扰素-γ(IFN-γ)、白介素-1(IL-1)、白介素-2(IL-2)、白介素-3(IL-3)、白介素-4(IL-4)、白介素-5(IL-5)和白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和白血病抑制因子(LIF)]、茶氨酸地塞米松、肝素、壳聚糖、透明质烷、环糊精、淀粉、碳水化合物、糖类、荧光蛋白(例如绿荧光蛋白(GFP)和红荧光蛋白(RFP))、病毒样颗粒(VLP)和疫苗,
a、b、c、d、e和f分别代表各取代基的含量,其中a、b和f独立为0.01-1.9,c、d和e独立为0-1.9,和a+b+c+d+e+f=2.0;且
n是聚(有机磷腈)的聚合度,为5-100000。
用作R9的鱼精蛋白的分子量无限制,但优选分子量为4,000-10,000。
下表1中归纳了可用的保护基团,但不限于此:
[表1]
官能团 | 保护基(R’=R5) |
羧基(RCOOR’) | 芴基甲酯、甲氧基甲酯(CH2OCH3)、甲硫基甲酯(CH2SCH3)、四氢呋喃基酯、甲氧基乙氧基甲酯(CH2OCH2CH2OCH3)、2-(三甲基甲硅烷基)乙氧基甲基酯(CH2OCH2CH2Si(CH3)3)、苄氧基甲酯(CH2OCH2C6H5)、新戊酰氧基(Pivaloxyloxy)甲酯(CH2O2CC(CH3)3)、苯乙酰氧基甲酯(CH2O2CCH2Ph)、三异丙基甲硅烷基甲酯(CH2Si-i-Pr3)、氰基甲酯(CH2CN)、丙酮醇酯(CH2COCH3)、苯甲酰甲酯(CH2COC6H5)、对溴苯甲酰甲酯(CH2COC6H4-p-Br)、α-甲基苯甲酰甲酯(CH(CH3)COC6H5)、对甲氧基苯甲酰甲酯(CH2COC6H4-p-OCH3)、二苯乙酮基酯、酰胺基甲酯(CH2CONH2)、对偶氮苯酰胺基甲酯(CH2(O)CNHC6H4N=NC6H5)、N-苯二酰亚氨基甲酯、2,2,2-三氯乙酯(CH2CCl3)、2-卤乙酯(CH2CH2X,X=I,Br,Cl)、ω-氯烷基酯((CH2)nCl,n=4,5)、2-(三甲基甲硅烷基)乙酯(CH2CH2Si(CH3)3)、2-甲硫基乙酯(CH2CH2SCH3)、1,3-二噻烷基-2-甲酯、2-(对硝基苯硫基)乙酯(CH2CH2SC6H4-p-NO2)、2-(对甲苯磺酰基)乙酯(CH2CH2SO2C6H4-p-CH3)、2-(2′-吡啶基)乙酯(CH2CH2-2-C5H4N)、2-(对甲氧基苯基)乙酯(CH2CH2C6H4O-p-CH3)、2-(二苯基膦基)乙酯(CH2CH2P(C6H5)2)、1-甲基-1-苯基乙酯(C(CH3)2C6H5)、2-(4-乙酰基-2-硝基苯基)乙酯、2-氰基乙酯(CH2CH2CHN)、叔丁酯(C(CH3)3)、3-甲基-3-戊基酯(CCH3(C2H4)2)、二环丙基甲酯、2,4-二甲基-3-戊基酯(CH(i-Pr)2)、环戊基酯(c-C5H9)、环己基酯(c-C6H11)、烯丙基酯(CH2CH=CH2)、甲代烯丙酯(CH2(CH3)C=CH2)、2-甲基丁-3-烯-2-基酯(C(CH3)2CH=CH2)、3-甲基丁-2-烯酯(CH2CH=C(CH3)2)、3-丁烯-1-基酯(CH2CH2CH=CH2)、4-(三甲基甲硅烷基)-2-丁烯-1-基酯(CH2CH=CHCH2Si(CH3)3)、肉桂基酯(CH2CH=CHC6H5)、α-甲基肉桂基酯(CH(CH3)CH=CHC6H5)、丙-2-炔基酯(CH2C≡CH)、苯酯(C6H5)、2,6-二甲基苯酯、2,6-二异丙基苯酯、2,6-二-叔丁基-4-甲基苯酯、2,6-二-叔丁基-4-甲氧基苯酯、对-(甲硫基)苯酯(C6H4-p-SCH3)、五氟苯酯(C6F5)、苄酯(CH2C6H5)、三苯基甲酯(C(C6H5)3)、二苯基甲酯(CH(C6H5)2)二(邻硝基苯基)甲酯(CH(C6H4-o-NO2)2)、9-蒽基甲酯(CH2-9-蒽基)、2-(9,10-二氧代) |
蒽基甲基)酯、5-二苯并环庚酯、1-芘基甲酯、2-(三氟甲基)-6-色酮基甲酯、2,4,6-三甲基苄基酯(CH2C6H2-2,4,6-(CH3)3)、对-溴苄基酯(CH2C6H4-p-Br)、邻硝基苄酯(CH2C6H4-o-NO2)、对硝基苄酯(CH2C6H4-p-NO2)、对甲氧基苄酯(CH2C6H4-p-OCH3)、2,6-二甲氧基苄酯(CH2C6H3-2,6-(OCH3)2、4-(甲基亚硫酰基)苄酯(CH2C6H4(O)S-4-CH3)、4-磺基苄酯(CH2C6H4SO3 -Na+)、4-叠氮基甲氧基苄酯(CH2C6H4OCH2N3)、4-{N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基(methl)丁基]氨基}苄酯、哌酮基酯、4-吡啶甲酯(CH2-4-吡啶基)、对-P-苄基酯(CH2C6H4-p-P)、三甲基甲硅烷基酯(Si(CH3)3)、三乙基甲硅烷基酯(Si(C2H5)3)、叔丁基二甲基甲硅烷基酯(Si(CH3)2C(CH3)、异丙基二甲基甲硅烷基酯(Si(CH3)2CH(CH3)2)、苯基二甲基甲硅烷基酯(Si(CH3)2C6H5)、二叔丁基甲基甲硅烷基酯(SiCH3(t-Bu)2)、三异丙基甲硅烷基酯 | |
巯基(RSR’) | S-烷基硫醚(CnH2n+1)、S-苄基硫醚(CH2Ph)、S-对甲氧基苄基硫醚(CH2C6H4-p-OCH3)、S-邻-或对-羟基-或-乙酰氧基苄基硫醚(CH2C6H4-o-(或p-)-OR′,R′=H或Ac)、S-对硝基苄基硫醚(CH2C6H4-p-NO2)、S-2,4,6-三甲基苄基硫醚(CH2C6H2-2,4,6-Me3)、S-2,4,6-三甲氧基苄基硫醚(CH2C6H2-2,4,6-(OMe)3)、S-4-吡啶甲基硫醚(CH2-4-吡啶基)、S-2-喹啉基甲基硫醚、S-2-吡啶甲基N-氧化物硫醚(CH2-2-吡啶基N-氧化物)、S-9-蒽基甲基硫醚(CH2-9-蒽基(anthtyl))、S-9-芴基甲基硫醚、S-呫吨基硫醚、S-三茂铁基甲基硫醚、S-二苯基甲基硫醚(CH(C6H5)2)、S-二(4-甲氧基苯基)甲基硫醚(CH(C6H4-4-OCH3)2)、S-二(4-甲氧基苯基)苯基甲基硫醚、S-5-二苯并环庚基硫醚、S-三苯基甲基硫醚(C(C6H5)3)、S-二苯基-4-吡啶基甲基硫醚(C(C6H5)2-4-吡啶基)、S-苯基硫醚(C6H5)、S-2,4-二硝基苯基硫醚(C6H3-2,4-(NO2)2)、S-叔丁基硫醚(C(CH3)3)、S-1-金刚烷基硫醚、S-甲氧基甲基单缩硫醛(CH2OCH3)、S-异丁氧基甲基单缩硫醛(CH2OCH2CH(CH3)2)、S-苄氧基甲基单缩硫醛(CH2OBn)、S-2-四氢吡喃基单缩硫醛、S-苄硫基甲基二缩硫醛(CH2SCH2C6H5)、S-苯硫基甲基二缩硫醛(CH2SC6H5)、S-乙酰氨基甲基缩硫醛(CH2NHCOCH3)、S-三甲基乙酰氨基甲基缩硫醛(CH2NHCOC(CH3)3)、S-苯甲酰胺基甲基(缩硫醛CH2NHCOC6H5)、S-烯丙氧基羰基氨基甲基缩硫醛 |
(CH2NH(O)COCH2CH=CH2)、S-苯基乙酰氨基甲基缩硫醛(CH2NH(O)CCH2C6H5)、S-苯二酰亚氨基甲基缩硫醛、S-乙酰基-、S-羧基和S-氰基甲基硫醚(CH2X,X=-COCH3,-CO2H,-CN)、S-(2-硝基-1-苯基)乙基硫醚(CH(C6H5)CH2NO2)、S-2-(2,4-二硝基苯基)乙基硫醚、S-2-(4′-吡啶基)乙基硫醚(CH2CH2NC4H4)、S-2-氰基乙基硫醚(CH2CH2CN)、S-2-(三甲基甲硅烷基)乙基硫醚(CH2CH2TMS)、S-2,2-二(乙氧基羰基(carboethoxy))乙基硫醚(CH2CH(COOC2H5)2)、S-(1-间硝基苯基-2-苯甲酰基)乙基硫醚(CH(C6H4-m-NO2)CH2COC6H5)、S-2-苯磺酰基乙基硫醚(CH2CH2SO2Ph)、S-1-(4-甲基苯基磺酰基)-2-甲基丙-2-基硫醚(C(CH3)2CH2SO2C6H4-4-CH3)、三异丙基甲硅烷基硫醚、S-乙酰基衍生物(COCH3)、S-苯甲酰基衍生物(COC6H5)、S-三氟乙酰基衍生物(COCF3)、S-2,2,2-三氯乙氧基羰基衍生物(COOCH2CCl3)、S-叔丁氧基羰基衍生物(COOC(CH3)3)、S-苄氧基羰基衍生物(COOCH2C6H5)、S-对甲氧基苄氧基羰基衍生物(COOCH2C6H4-p-OCH3)、S-(N-乙基氨基甲酸酯)(CONHC2H5)、S-(N-甲氧基甲基氨基甲酸酯)(CONHCH2OCH3)、S-乙基联硫基(SC2H5)、S-叔丁基联硫基(SC(CH3)3) | |
羟基(ROR′) | 甲醚(CH3)、甲氧基甲基醚(CH2OCH3)、甲硫基甲基醚(CH2SCH3)、(苯基二甲基甲硅烷基)甲氧基甲基醚(CH2OCH2Si(CH3)2C6H5)、苄氧基甲基醚(CH2OCH2Ph)、对甲氧基苄氧基甲基醚(CH2OCH2C6H4O-p-Me)、对硝基苄氧基甲基醚(CH2OCH2C6H4-4-NO2)、邻硝基苄氧基甲基醚(CH2OCH2C6H4-2-NO2)、(4-甲氧基苯氧基)甲基醚(CH2OC6H4-4-OCH3)、愈创木酚甲基醚(CH2OC6H4-2-OMe)、叔丁氧基甲基醚(CH2O-t-Bu)、4-戊烯氧基甲基醚(CH2OCH2CH2CH2CH=CH2)、甲硅烷氧基甲基醚(CH2OSiR′R",R′=t-Bu,R"=Me;R′=Thexyl,R"=Me;R′=t-Bu,R"=Ph)、2-甲氧基乙氧基甲基醚(CH2OCH2CH2OCH3)、2,2,2-三氯乙氧基甲基醚(CH2OCH2CCl3)、二(2-氯乙氧基)甲基醚(CH(OCH2CH2Cl)2)、2-(三甲基甲硅烷基)乙氧基甲基醚(CH2OCH2CH2SiMe3)、甲氧基(Memthoxy)甲基醚、四氢吡喃醚、3-溴四氢吡喃醚、四氢噻喃醚、1-甲氧基环己醚、4-甲氧基四氢吡喃醚、4-甲氧基四氢噻喃醚、 |
1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基醚、1-(2-氟苯基)-4-甲氧基哌啶-4-基醚、1,4-二噁烷-2-基醚、四氢呋喃醚、四氢噻吩醚、2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-亚甲基苯并呋喃-2-基醚、1-乙氧基乙醚(CH(OC2H5)CH3)、1-(2-氯乙氧基)乙醚(CH(CH3)OCH2CH2Cl)、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、1-甲基-1-甲氧基乙醚(C(OCH3)(CH3)2)、1-甲基-1-苄氧基乙醚(C(OBn)(CH3)2)、1-甲基-1-苄氧基-2-氟乙醚(C(OBn)(CH2F)(CH3)、1-甲基-1-苯氧基乙醚(C(OPh)(CH3)2)、2,2,2-三氯乙醚(CH2CCl3)、1,1-二茴香基-2,2,2-三氯乙醚、1,1,1,3,3,3-六氟-2-苯基异丙醚(C(CHF3)2Ph)、2-三甲基甲硅烷基乙醚(CH2SiMe3)、2-(苄硫基)乙醚(CH2CH2SBn)、2-(苯基硒基)乙醚(CH2CH2SePh)、叔丁醚、烯丙醚(CH2CH=CH2)、丙炔醚(CH2C≡CH)、对甲氧基苯醚(C6H4O-p-Me)、对硝基苯醚(C6H4-p-NO2)、2,4-二硝基苯醚(C6H3-2,4-(NO2)2)、2,3,5,6-四氟-4-(三氟甲基)苯醚(C6F4CF3)、苄醚(CH2Ph)、对甲氧基苄醚(CH2C6H4-p-OMe)、3,4-二甲氧基苄醚(CH2C6H3-3,4-(OMe)2)、邻硝基苄醚(CH2C6H4-o-NO2)、对硝基苄醚(CH2C6H4-p-NO2)、对卤苄醚(CH2C6H4-p-X,X=Br,Cl)、2,6-二氯苄醚(CH2C6H3-2,6-Cl2)、对氰基苄醚(CH2C6H4-p-CN)、对苯基苄醚(CH2C6H4-p-C6H5)、2,6-二氟苄醚(CH2C6H3F2)、对酰基氨基苄醚(CH2C6H3-p-NHCOR′)、对叠氮基苄醚(CH2C6H4-4-N3)、4-叠氮基-3-氯苄醚(CH2C6H3-3-Cl-4-N3)、2-三氟甲基苄醚(CH2C6H4-2-CF3)、对-(甲基亚硫酰基)苄醚(CH2C6H4-p-(MeS(O))、2-和4-吡啶甲基醚(CH2C5H4N)、3-甲基-2-吡啶甲基N-氧化物(Oxido)醚、2-喹啉基甲基醚、1-芘基甲基醚、二苯基甲基醚(CHPh2)、对,对′-二硝基二苯甲基醚(CH(C6H4-p-NO2)2)、5-二苯并环庚基醚、三苯基甲基醚、对甲氧基苯基二苯基甲基醚(C(Ph)2C6H4-p-OMe)、二(对甲氧基苯基)苯基甲基醚(CPh(p-MeOC6H4)2)、三(对甲氧基苯基)甲基醚(C(p-MeOC6H4)3)、4-(4′-溴苯甲酰甲氧基)苯基二苯基甲基醚(C(Ph)2C6H4-p-(OCH2(O)CC6H4-p-Br)、4,4′,4"-三(4,5-二氯苯二酰亚氨基苯基)甲基醚、4,4′,4"-三(乙酰丙酰基氧基苯基)甲基)醚、4,4′4"-三(苯甲酰氧基苯基)甲基)醚、4,4′-二甲氧基-3"-[N-(咪唑基甲基)]三苯甲基醚、4,4′-二甲氧基、3"-[N-(咪唑基乙基)氨基甲酰 |
基)三苯甲基醚、1,1-二(4-甲氧基苯基)-1-pytenyl甲基醚、4-(17-四苯并[a,c,g,i]芴基甲基)-4’,4"-二甲氧基三苯甲基醚、9-蒽基醚、9-(9-苯基)呫吨基醚、三苯甲酮醚、1,3-苯并二硫戊环-2-基醚、苯并异噻唑基-S,S-二氧化物(dioxido)醚、三甲基甲硅烷基(Si(CH3)3)醚、三乙基甲硅烷基(SiEt3)醚、三异丙基甲硅烷基(Si(i-Pr)3)醚、二甲基异丙基甲硅烷基(SiMe2-i-Pr)醚、二乙基异丙基甲硅烷基(SiEt2-i-Pr)醚、二甲基甲硅烷基(thesilyl)醚((CH3)2Si(CH3)2CCH(CH3)2)、叔丁基二甲基甲硅烷基醚(SiMe2-t-Bu)、叔丁基二苯基甲硅烷基醚(SiPh2-t-Bu)、三苄基甲硅烷基醚(Si(CH2C6H5)3)、三-对二甲苯基甲硅烷基醚(Si(CH2C6H4-p-CH3)3)、三苯基甲硅烷基醚(SiPh3)、二苯基甲基甲硅烷基醚(SiMePh2)、二-叔丁基甲基甲硅烷基醚(SiMe(t-Bu)2)、三(三甲基甲硅烷基)甲硅烷基醚([Si[Si(CH3)3]3)、(2-羟基苯乙烯基)二甲基甲硅烷基醚、(2-羟基苯乙烯基)二异丙基(propul)甲硅烷基醚、叔丁基甲氧基苯基甲硅烷基醚(SiPh(OCH3)-t-Bu)、叔丁氧基二苯基甲硅烷基醚(Si(t-OBu)Ph2)、甲酸酯(CHO)、苯甲酰基甲酸酯(COCOPh)、乙酸酯(COCH3)、氯乙酸酯(COCH2Cl)、二氯乙酸酯(COCHCl2)、三氯乙酸酯(COCCl3)、三氟乙酸酯(COCF3)、甲氧基乙酸酯(COCH2OMe)、三苯基甲氧基乙酸酯(COCH2OCPh3)、苯氧基乙酸酯(COCH2OPh)、对氯苯氧基乙酸酯(COCH2OC6H4-p-Cl)、苯乙酸酯(COCH2Ph)、对-P-苯乙酸酯(COCH2C6H4-p-P)、二苯基乙酸酯(COCHPh2)、烟酸酯、3-苯基丙酸酯(COCH2CH2Ph)、4-戊烯酸酯(COCH2CH2CH=CH2)、4-氧代戊酸酯(COCH2CH2COCH3)、4,4-(亚乙基联硫)戊酸酯、5-[3-二(4-甲氧基苯基)羟基甲基苯氧基]乙酰丙酸酯、新戊酸(COC(CH3)3)酯、巴豆酸酯(COCH=CHCH3)、4-甲氧基巴豆酸酯(COCH=CHCH2OCH3)、苯甲酸酯(COPh)、苯甲酸对苯基酯(COC6H4-p-C6H5)、2,4,6-三甲基苯甲酸酯(COC6H2-2,4,6-Me3)、碳酸烷基酯甲酯(CO2CH3)、碳酸甲氧基甲酯(CO2CH2OCH3)、碳酸烷基酯9-芴基甲酯(metyl)、碳酸烷基酯乙酯(CO2Et)、碳酸烷基酯2,2,2-三氯乙酯(CO2CH2CCl3)、碳酸1,1-二甲基-2,2,2-三氯乙酯(CO2C(CH3)2CCl3)、碳酸烷基酯2-(三甲基甲硅烷基)乙酯(CO2CH2CH2SiMe3)、碳酸烷基酯2-(苯基磺酰基)乙酯 |
(CO2CH2CH2SO2Ph)、碳酸烷基酯异丁酯(CO2CH2CH(CH3)2)、碳酸烷基酯乙烯酯(CO2CH=CH2)、碳酸烷基酯烯丙基酯(CO2CH2CH=CH2)、碳酸烷基酯对硝基苯酯(CO2C6H4-p-NO2)碳酸烷基酯苄酯(CO2Bn)、碳酸烷基酯对甲氧基苄酯(CO2CH2C6H4-p-OMe)、碳酸烷基酯3,4-二甲氧基苄酯(CO2CH2C6H3-3,4-(OMe)2)、碳酸烷基酯邻硝基苄酯(CO2CH2C6H4-o-NO2)、碳酸烷基酯对硝基苄酯(CO2CH2C6H4-p-NO2)、碳酸2-丹酰乙酯、碳酸2-(4-硝基苯基)乙酯(CO2CH2CH2C6H4-4-NO2)、碳酸2-(2,4-二硝基苯基)乙酯(CO2CH2CH2C5H3-2,4-(NO2)2)、碳酸2-氰基-1-苯基乙酯(CO2(C6H5)CHCH2CN)、硫代碳酸烷基酯S-苄酯(COSCH2Ph)、碳酸烷基酯4-乙氧基-1-萘基酯、二硫代碳酸烷基酯甲酯(SCSCH3)、2-碘苯甲酸酯(COC6H4-2-I)、4-叠氮基丁酸酯(CO(CH2)3N3)、4-硝基-4-甲基戊酸酯、邻-(二溴甲基)苯甲酸酯(COC6H4-o-(CHBr2))、2-甲酰基苯磺酸酯、碳酸烷基酯2-(甲硫基甲氧基)乙酯(CO2CH2CH2OCH2SCH3)、4-(甲硫基甲氧基)丁酸酯(CO(CH2)3OCH2SCH3)、2-(甲硫基甲氧基甲基)苯甲酸酯(COC6H4-2-(CH2OCH2SCH3))、2-(氯乙酰氧基甲基)苯甲酸酯(benzioate)、2-[(2-氯乙酰氧基)乙基]苯甲酸酯、2-[2-(苄氧基)乙基]苯甲酸酯、2-[2-(4-甲氧基苄氧基)乙基]苯甲酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-二(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、异丁酸酯、琥珀酸单酯、(E)-2-甲基-2-丁烯酸酯、邻-(甲氧基羰基)苯甲酸酯)、对-P-苯甲酸酯、α-萘甲酸酯、硝酸酯、N,N,N′,N’-四甲基二氨基磷酸烷基酯、2-氯苯甲酸酯、4-溴苯甲酸酯、4-硝基苯甲酸酯、碳酸3,5-二甲氧基苯偶姻酯、对光极不(wild andwoolly)稳定的荧光酯、N-苯基氨基甲酸烷基酯、硼酸酯、二甲基硫膦基酯((S)P(CH3)2)、次磺酸烷基酯2,4-二硝基苯酯(SC6H3-2,4-(NO2)2)、硫酸酯、磺酸烯丙酯(SOCH2CH=CH2)、甲磺酸酯(SO2Me)、磺酸苄酯(SO2Bn)、甲磺酸酯(SO2C6H4CH3)、2-[(4-硝基苯基)乙基]磺酸酯(SO2CH2CH2C6H4-4-NO2) | |
氨基(RNR’) | 甲酰胺(Fromamide)(CHO)、乙酰胺(Ac)、氯乙酰胺(COCH2Cl)、三氯乙酰胺(COCCl3)、三氟乙酰胺(COCF3)、苯乙酰胺 |
(COCH2C6H5)、3-苯丙酰胺(COCH2CH2C6H5)、戊-4-烯酰胺((O)CH2CH2CH=CH2)、吡啶酰胺(CO-2-吡啶基)、3-吡啶基酰胺(CO-3-吡啶基)、N-苯甲酰基苯基丙氨酰衍生物(COCH(NHCOC6H5)CH2C6H5)、苯甲酰胺(COC6H5)、对-苯基苯甲酰胺(COC6H4-p-C6H5) | |
酰胺基(CORNR’) | N-烯丙基酰胺(CH2CH=CH2)、N-叔丁酰胺(t-Bu)、N-二环丙基甲酰胺(CH(C3H5)2)、N-甲氧基甲酰胺(CH2OCH3)、N-甲硫基甲酰胺(CH2SCH3)、N-苄氧基甲酰胺(CH2OCH2C6H5)、N-2,2,2-三氯乙氧基甲酰胺(CH2OCH2CCl3)、N-叔丁基二甲基甲硅烷氧基甲酰胺(CH2OSi(CH3)2-y-C4H9)、N-新戊酰氧基甲酰胺(CH2CO2C(CH3)3)、N-氰基甲酰胺(CH2CHN)、N-吡咯烷-1-基甲酰胺、N-甲氧基酰胺(OMe)、N-苄氧基酰胺(OCH2C6H5)、N-甲硫基酰胺(SMe)、N-三苯基甲基硫代酰胺(SCPh3)、N-叔丁基二乙基甲硅烷基酰胺(Si(CH3)2-t-C4H9)、N-三异丙基甲硅烷基酰胺(Si(i-Pr)3)、N-4-甲氧基苯基酰胺(C6H4-4-OCH3)、N-4-(甲氧基甲氧基)苯基酰胺(C6H4(OCH3)2)、N-2-甲氧基-1-萘基酰胺(C10H6-2-OCH3)、N-苯甲酰胺(CH2C6H5)、N-4-甲氧基苯甲酰胺(CH2C6H4-4-OCH3)、N-2,4-二甲氧基苯甲酰胺N-3,4-二甲氧基苯甲酰胺(CH2C6HH3-2,4(3,4)-(OCH3)2)、N-2-乙酰氧基-4-甲氧基苯甲酰胺(CH2C6HH3-4-OMe-2-Ac)、N-邻硝基苯甲酰胺(CH2C6H4-2-NO2)、N-二(4-甲氧基苯基)甲酰胺(CH(C6H4-4-OMe)2)、N-二(4-(甲氧基苯基)苯甲酰胺(CPh-(C6H4-4-OMe)2)、N-二(4-甲基亚硫酰基苯基)甲酰胺(CH(C6H4(O)S-4-Me)2)、N-三苯基甲酰胺(C(C6H5)3)、N-9-苯基芴基酰胺、N-叔丁氧基羰基酰胺(CO-t-OC4H9)、N-苄氧基羰基酰胺、N-甲氧基羰基酰胺(COOMe)、N-乙氧基羰基酰胺(COOEt)、N-对甲苯磺酰基酰胺、N-丁烯基酰胺(CH=CHCH2CH3)、N-[(E)-2-(甲氧基羰基)乙烯基]酰胺(CH=CCO2Me)、N-二乙氧基甲基酰胺(CH(OEt)2)、N-(1-甲氧基-2,2-二甲基丙基)酰胺、N-2-(4-甲基苯基磺酰基)乙酰胺(CH2CH2SO2C6H4-4-CH3) |
在一个本发明聚(有机磷腈)实施方案中,将分子量为350-2,500的疏水性氨基酸酯和亲水性甲氧基-聚乙二醇引入二氯磷腈的线性聚合物中,以使该聚合物可出现热敏性和生物降解能力。另外,还可将可控制聚合物降解速度的氨基酸、肽和缩肽酯部分引入该聚合物中。
在另一个本发明实施方案中,可用各种方法例如通过将侧链上的含官能团例如羟基、酰胺、氨基、硫醇基或羧基的取代基直接引入主链,将官能团引入聚(有机磷腈),或引入取代的氨基酸酯或肽酯,其中将所述官能团用保护基保护后引入聚合物的主链,然后将保护基团除去。
在另一个本发明实施方案中,可使赖氨酸、精氨酸、半胱氨酸、巯基烷基胺、聚氮丙啶、聚赖氨酸、聚精氨酸或具有各种分子量的鱼精蛋白与聚(有机磷腈)和羧酸反应,作为官能团引入聚合物。
可通过可控制降解速度的这种疏水性氨基酸酯、这种氨基酸、肽或缩肽、具有官能团的这种取代基、甲氧基聚乙二醇的链长、所有取代基的组成、聚(有机磷腈)的分子量、多分散指数、聚(有机磷腈)溶液的浓度等控制本发明聚(有机磷腈)发生溶液-凝胶相变时的胶凝温度、凝胶硬度和/或生物降解速度。
例如,当疏水性氨基酸的含量增加时,胶凝温度下降。当聚(有机磷腈)溶液浓度增加时,胶凝温度下降,凝胶硬度增加。当甲氧基聚乙二醇链长增加时,胶凝温度升高,凝胶硬度增加。含缩肽酯的聚(有机磷腈)的生物降解速度显示比不含缩肽酯的聚(有机磷腈)的高。具有羧酸官能团的聚(有机磷腈)的生物降解速度显示比无羧酸官能团的聚(有机磷腈)的高。
在另一个方面,本发明提供制备聚(有机磷腈)-生物活性分子缀合物的方法,其中使随温度变化显示溶液-凝胶相变的聚(有机磷腈)与由化学式1代表的生物活性分子结合。
本发明制备方法可包括以下步骤:
(1)使由以下化学式2代表的磷腈三聚体热聚合,制备由以下化学式3代表的二氯磷腈的线性聚合物
[化学式2]
[化学式3]
(其中n为7-100,000的整数);
(2)使在步骤(1)中制备的化学式3化合物与0.01-1.9当量的由以下化学式4代表的氨基酸酯或其盐反应
[化学式4]
NH2CH(R1)CO2R2;
(3)使在步骤(2)中制备的化合物与0-1.9当量的物质反应,所述物质选自由以下化学式5代表的氨基酸、肽和缩肽酯及其盐,
[化学式5]
NH2(R3)(R4)(R5);
(4)使在步骤(3)中制备的化合物与0.01-1.9当量的具有由以下化学式6代表的官能团的取代基或其盐反应,
[化学式6]
NH2(R6)(R7)(R8);和
(5)使在步骤(4)中制备的化合物与0.01-1.9当量的由以下化学式7代表的氨基甲氧基聚乙二醇或其盐反应,
[化学式7]
NH2(CH2CH2O)PCH3;和
当化学式6中的R8为CH2C6H5或CH2CHCH2时,本发明制备方法还可包括使在步骤(5)中制备的聚合物脱氢(当R8为CH2C6H5时)或脱烯丙酯化(当R8为CH2CHCH2时)的步骤(5-1),制备聚(有机磷腈),其中R8具有氢官能团。
另外,本发明制备方法还可包括使步骤(5)或(5-1)产物与赖氨酸、精氨酸、半胱氨酸、巯基烷基胺、聚氮丙啶、聚赖氨酸、聚精氨酸或各种分子量的鱼精蛋白反应的步骤(5-2),制备聚(有机磷腈),其中R9具有选自以下的各种官能团:NHCH(SH)CO2H、NH(CH2)qSH、NH(CH2CH2NH)rH、[NH(CH2)4CH(NH2)CO]rOH、[NHC(=NH)(CH2)3CH(NH2)CO]rOH和鱼精蛋白。
另外,本发明制备方法可包括使在步骤(5)、步骤(5-1)或步骤(5-2)中制备的化合物与生物活性分子(R10)反应的步骤(6)。R10选自紫杉醇、多柔比星、喜树碱、表柔比星、5-氟尿嘧啶、10-羟基喜树碱、10-氨基喜树碱、7-乙基喜树碱、伊立替康、甲氨蝶呤、丝裂霉素C、紫杉烷、多西他赛、苯丁酸氮芥、加里刹霉素、美登醇、2-吡咯啉-1-基-多柔比星(AN-201)、柔红霉素、丁酸、美法仑、4′-二甲基去氧鬼臼毒素、姜黄、鬼臼毒素、表鬼臼毒素、4-β-氨基-4′-O-去甲基表鬼臼毒素、太利苏霉素S10b、道诺霉素、duocarmycin A、duocarmycin SA、顺式-乌头-道诺霉素、加里刹霉素、偶氮烯鎓二醇、纺锤霉素、6-巯基嘌呤、glucuronidation、phosmidosine、链黑霉素、血卟啉、去铁胺(DFO)、去铁酮、阿西维辛、雌莫司汀、力达霉素、精氨酸-甘氨酸-天冬氨酸肽、神经肽[例如神经张力蛋白、速激肽、神经肽Y(NPY)、肽YY(PYY)、血管活性肠多肽(VIP)和垂体腺甘酸环化酶-活化多肽(PACAP)]、白蛋白、牛血清白蛋白(BSA)、牛胰腺核糖核酸酶(RNaseA)、牛精液核糖核酸酶(BS-RNase)、Bowman-birk蛋白酶抑制剂(BBI)、胶原蛋白、纤连蛋白、层粘连蛋白、红细胞生成素(EPO)、干扰素、蛭素、集落刺激因子(CSF)、胰岛素、去氨加压素、胰高血糖素样肽1(GLP1)、人生长激素拮抗剂、肿瘤坏死因子受体1(TNFR1)、天冬酰胺酶、腺苷脱氨酶、生长因子[例如骨形态发生蛋白(BMPs)、成纤维细胞生长因子(FGF)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)、神经生长因子(NGF)、血小板衍生生长因子(PDFG)、胰岛素样生长因子(IGF)、转化生长因子-β(TGF-β)、脑源神经营养因子(BDNF)、神经营养蛋白-2(NT-3)和神经营养蛋白-4/5(NT-4/5)]、肿瘤坏死因子-相关凋亡-诱导配体(TRAIL)、细胞因子[例如干扰素-α 1a(IFN-α 1a)、干扰素-α 2a(IFN-α 2a)、干扰素-α 2b(IFN-α 2b)、干扰素-γ(IFN-γ)、白介素-1(IL-1)、白介素-2(IL-2)、白介素-3(IL-3)、白介素-4(IL-4)、白介素-5(IL-5)和白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和白血病抑制因子(LIF)]、茶氨酸地塞米松、肝素、壳聚糖、透明质烷、环糊精、淀粉、碳水化合物、糖类、荧光蛋白[例如绿荧光蛋白(GFP)和红荧光蛋白(RFP)]、病毒样颗粒(VLP)和疫苗,
按照步骤(6),可通过本发明制备方法得到聚(有机磷腈)-生物活性分子缀合物,其中生物活性分子与聚(有机磷腈)直接化学结合。
以上聚(有机磷腈)-药物或化学式1生物活性分子缀合物的制备方法归纳在反应式1中:
[反应式1]
在化学式4、5、6和7和反应式1中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、a1、a2、b、c、d、e、f、n和p定义同化学式1。
化学式1聚(有机磷腈)-生物活性分子缀合物的制备方法在下文中更详细地说明,但该方法不限于此。
所有制备反应方法可优选使用真空和/或氮气线(line),以防止水分流入。另外,还优选通过常规方法将其中的水分充分除去后,再使用用于反应的所有溶剂。
首先,可通过将化学式2化合物和0.1-10%(重量)AlCl3放入玻璃反应试管,将试管密封后,在200-250℃下反应4-8小时,同时按1rpm(圈/分钟)搅拌,进行步骤(1)。
可通过在0.01-1.9当量的化学式4氨基酸酯或其盐和4当量三乙胺的存在下,使1当量的步骤(1)产物反应,进行步骤(2)。优选,化学式4氨基酸酯的盐可以是硫酸盐或水合氯化物(chlorohydrate)。反应溶剂可选自但不限于四氢呋喃、二噁烷、氯仿和甲苯。反应可在-60℃至50℃下进行约8-72小时。
可在0-1.9当量的由化学式5代表的氨基酸、肽、缩肽酯或其盐和4当量三乙胺的存在下,通过使1当量的步骤(2)产物反应,进行步骤(3)。优选,所述化学式5化合物的盐可以是草酸盐、水合氯化物或三氟酸盐。反应溶剂可选自但不限于乙腈、四氢呋喃、二噁烷、氯仿和甲苯。反应可在0℃-50℃下进行约1-72小时。
可在0.01-1.9当量的具有官能团的化学式6取代基或其盐和4当量三乙胺的存在下,通过使1当量的步骤(3)产物反应,进行步骤(4)。优选,所述化学式6取代基的盐可以是草酸盐、水合氯化物或三氟酸盐。反应溶剂可选自但不限于乙腈、四氢呋喃、二噁烷、氯仿和甲苯。反应可在25℃-50℃下进行约12-72小时。
可在2当量(按残余氯基量计)化学式6氨基甲氧基聚乙二醇和4当量三乙胺的存在下,使步骤(4)产物反应,将所有残余氯基取代,进行步骤(5),其中按残余氯基计算当量。反应溶剂可选自但不限于四氢呋喃、二噁烷、氯仿和甲苯。反应可在25℃-50℃下进行约24-72小时。
当化学式6中的R8为CH2C6H5时,可在50-90%(重量)钯/碳或钯黑和氢气(在30-80psi压力)存在下,通过使步骤(5)产物脱氢,用羧基取代,进行步骤(5-1)。反应溶剂可以是但不限于甲醇或乙醇。反应可在10℃-35℃下进行约1-24小时。
当化学式6中的R8为CH2CHCH2时,可在10-20mol%四(三苯基膦)合钯(O)和10-20当量吗啉存在下,使步骤(5)产物脱烯丙酯,用羧基取代,进行步骤(6)。反应溶剂可以选自但不限于四氢呋喃、二噁烷、氯仿和甲苯。反应可在0℃-25℃下进行约1-24小时。
可在1-3当量二环己基碳二亚胺和1-3当量羟基琥珀酰亚胺的存在下,通过使在步骤(5)或步骤(5-1)中得到的具有羧酸的产物与一种或多种选自以下的化合物反应,制备具有各种官能团的聚(有机磷腈),进行步骤(5-2):赖氨酸、精氨酸、半胱氨酸、巯基烷基胺、聚氮丙啶、聚赖氨酸、聚精氨酸和各种分子量的鱼精蛋白。反应溶剂可以是但不限于四氢呋喃或氯仿。反应可在0℃-25℃下进行约1-48小时。
可在1-3当量二环己基碳二亚胺和1-3当量二甲基氨基吡啶的存在下,通过使在步骤(5)、步骤(5-1)或步骤(5-2)中得到的具有羧酸的产物与生物活性分子包括具有羟基的药物反应,制备聚(有机磷腈)-生物活性分子缀合物,其中使生物活性分子例如药物与聚(有机磷腈)化学结合,可进行步骤(6)。反应溶剂可以为但不限于二氯甲烷。反应可在0℃-25℃下进行约1-48小时。
另外,还可在1-3当量三丁胺和1-3当量氯甲酸异丁酯的存在下,通过使在步骤(5)、步骤(5-1)或步骤(5-2)中得到的具有羧酸的产物与包括具有胺基的药物在内的生物活性分子反应,制备聚(有机磷腈)-生物活性分子缀合物,其中使生物活性分子例如药物与聚(有机磷腈)化学结合,进行步骤(6)。反应溶剂可以是但不限于四氢呋喃。反应可在0℃-25℃下进行约1-48小时。
对于步骤(6),可通过硫酸化结合[Int.J.Cancer,73,859-864(1997)]、氨基甲酸酯化(cabamite)结合[I.Biochem.Pharmacol,34,289(1985)]或腙键[J.Control Release,73,89-102(2001)],使具有特定官能团的生物活性分子与步骤(5)、步骤(5-1)或步骤(5-2)中具有各种官能团的产物上的官能团结合。
在所述步骤(1)-(5-2)中,各步骤中的产物在后续步骤中使用时无需纯化。可通过如下纯化方法,由步骤(6)反应混合物收集纯产物:
先将反应混合物离心或过滤,将其中的沉淀(例如氯化三乙铵、草酸三乙铵盐等)除去。然后,进行减压浓缩直至仅剩少量溶剂。将得到的浓缩物溶于四氢呋喃和过量乙醚、己烷,或加入乙醚和己烷的混合溶剂,诱发沉淀。然后,将沉淀过滤2或3次,除去无活性的取代基。将通过这些处理得到的化合物再次溶于少量甲醇或乙醇。然后,在25℃下,将反应产物在甲醇或乙醇中透析3-10天,然后在4℃-25℃下,在蒸馏水透析3-10天。然后,将反应产物在低温下干燥,得到由化学式1代表的纯化合物。
在另一方面,本发明提供聚合物溶液(水凝胶),该溶液含由化学式1代表的聚(有机磷腈)-生物活性分子缀合物溶液,该聚合物溶液发生随温度变化的溶液-凝胶相变。
由化学式1代表的聚(有机磷腈)-生物活性分子缀合物在溶于合适溶剂的溶液状态下,显示随温度变化的明显溶液-凝胶相变,处于体温范围时呈现凝胶相,并开始体内注射液中的凝胶3D形成。
具有生物降解能力和取决于温度变化的溶液-凝胶相变的本发明水凝胶可以是溶液,其中将1-50%(重量),优选3-20%(重量)化学式1聚(有机磷腈)-生物活性分子缀合物溶于选自以下的溶剂:水、缓冲液、酸溶液、碱性溶液、盐溶液、盐水溶液、注射用水和葡萄糖盐溶液。
本发明聚(有机磷腈)-生物活性分子缀合物在10℃-60℃温度下发生溶液-凝胶相变。因此,本发明聚(有机磷腈)可在体温下为凝胶相,因此可在体内用作递送各种生物活性分子的物质。
在另一方面,本发明提供递送生物活性分子的含一种或多种选自聚(有机磷腈)-生物活性分子缀合物的化合物的组合物,和含聚(有机磷腈)-生物活性分子缀合物的水凝胶。递送生物活性分子的组合物可含一种或多种添加剂。
在另一方面,本发明提供生物活性分子递药系统,该系统含有一种或多种选自聚(有机磷腈)-生物活性分子缀合物的化合物,和含聚(有机磷腈)-生物活性分子缀合物的水凝胶;和一种或多种选自以下的物质:其它生物活性分子、用于递送至需要细胞或药物的部位的细胞和添加剂,因此提供优良的药物作用和细胞活性。
可通过加入各种盐控制聚(有机磷腈)-生物活性分子缀合物或聚(有机磷腈)水凝胶的溶液-凝胶相变,达到需要的凝胶硬度和胶凝温度(Macromolecules 32,7820,1999)。
当递送多肽或蛋白药物时,加入合适的添加剂可保持水凝胶中药物稳定性。另外,引入添加剂与药物之间的包括离子键在内的化学键,以控制水凝胶释放药物的速度。另外,当递送治疗性细胞时,因添加剂引入水凝胶,故递送到身体后细胞活性可增加。
即添加剂可引起聚(有机磷腈)-生物活性分子缀合物或聚(有机磷腈)水凝胶和生物活性分子例如药物之间包括离子键在内的化学键的各种相互作用,控制生物活性分子释放和/或增加体内的生物活性分子例如药物或治疗性细胞活性。
添加剂可为一种或多种选自以下的物质:阳离子型聚合物(分子量为200-750,000例如聚-L-精氨酸、聚-L-赖氨酸、聚(乙二醇)、聚吖丙啶、壳聚糖、鱼精蛋白等;阴离子型聚合物例如聚(N-乙烯基-2-吡咯烷酮)、聚乙酸乙烯酯(PVA)、透明质酸、硫酸软骨素、肝素、藻酸盐等;可生物利用的物质例如阿米洛利、普鲁卡因胺、乙酰基-β-甲基胆碱、精胺、亚精胺、溶菌酶、纤维蛋白(丝心蛋白)、白蛋白、胶原蛋白、转化生长因子-β(TGF-β)、骨形态发生蛋白(BMPs)、成纤维细胞生长因子(bFGF)、地塞米松、血管内皮生长因子(VEGF)、纤连蛋白、纤维蛋白原、凝血酶、蛋白质、佑雷佐生、亚叶酸、蓖麻油酸、磷脂、小肠粘膜下层、维生素E、聚脂肪酸甘油酯、Labrafil、LabrafilM1944CS、柠檬酸、谷氨酸、羟丙基甲基纤维素、明胶、肉豆寇酸异丙酯、丙烯酸树脂、tego甜菜碱、二肉豆蔻酰卵磷脂、菌核葡聚糖等;
有机溶剂例如聚氧乙烯蓖麻油、乙醇、二甲亚砜等;防腐剂例如尼泊金甲酯等;糖例如淀粉、环糊精及其衍生物、乳糖、葡萄糖、右旋糖苷、甘露糖、蔗糖、海藻糖、麦芽糖、聚蔗糖等;多元醇例如肌醇(innositol)、甘露醇、山梨醇等;含多元醇的糖例如蔗糖-甘露醇、葡萄糖-甘露醇(mannitoal)等;氨基酸例如丙氨酸、精氨酸、甘氨酸等;含多元醇的聚合物例如海藻糖-PEG、蔗糖-PEG、蔗糖-右旋糖苷等;含糖氨基酸例如山梨醇-甘氨酸、蔗糖-甘氨酸等;表面活性剂例如各种分子量的泊洛沙姆、吐温20、吐温80、triton X-100、十二烷基硫酸钠(SDS)、苄泽等;含糖离子例如海藻糖-ZnSO4、麦芽糖-ZnSO4等,和生物上可接受的盐例如硅酸盐、NaCl、KCl、NaBr、NaI、LiCl、n-Bu4NBr、n-Pr4NBr、Et4NBr、Mg(OH)2、Ca(OH)2、ZnCO3、Ca3(PO4)2、ZnCl2、(C2H3O2)2Zn、ZnCO3、CdCl2、HgCl2、CoCl2、(CaNO3)2、BaCl2、MgCl2、PbCl2、AlCl3、FeCl2、FeCl3、NiCl2、AgCl、AuCl3、CuCl2、十四烷基硫酸钠、十二烷基三甲基溴化铵、十二烷基三甲基氯化铵、十四烷基三甲基溴化铵等。
在一个本发明实施方案中,添加剂的含量占生物活性分子递药组合物或生物活性分子递药系统总重为约1×10-6-30%(重量),优选约1×10-3-10%(重量)。如果添加剂含量低于上述范围,则添加剂不出现需要的作用。在另一方面,如果添加剂含量高于上述范围,则本发明热敏聚合物的作用和/或性质可受到破坏。
另外含有的生物活性分子是一种或多种选自以下的物质:蛋白、多肽、肽、疫苗、基因、激素、抗癌药物和血管发生抑制剂。
蛋白、多肽和肽可以是一种或多种选自以下的物质:红细胞生成素(EPO)、干扰素-α、干扰素-β、干扰素-γ、生长激素(人、猪、牛等)、生长激素释放因子、神经生长因子(NGF)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、巨噬细胞-集落刺激因子(M-CSF)、凝血因子、胰岛素、催产素、血管升压素、促肾上腺皮质激素、表皮生长因子、血小板衍生生长因子(PDGF)、催乳素、促黄体素释放素、黄体激素释放因子(LHRH)、LHRH激动剂、LHRH拮抗剂、促生长素抑制素、胰高糖血素、白介素-2(IL-2)、白介素-11(IL-11)、胃泌素、四肽胃泌素、五肽胃泌素、尿抑胃素、胰泌素、降钙素、脑啡肽、内啡肽、血管紧张肽、促甲状腺素释放激素(TRH)、肿瘤坏死因子(TNF)、肿瘤坏死因子相关凋亡诱导配体(TRAIL)、肝素酶、骨形态发生蛋白(BMP)、人心房促尿钠排泄肽(hANP)、胰高血糖素样肽(GLP-1)、肾素、缓激肽、杆菌肽、多粘菌素、粘菌素、短杆菌酪肽、短杆菌肽、环胞菌素及其合成类似物、单克隆抗体、抗体、改善或显示相同药物作用的物质、酶和细胞因子。
疫苗可以是一种或多种选自肝炎疫苗的疫苗。
基因可以是选自以下的一种或多种基因:小干扰(smallinterference)RNA(siRNA)、质粒DNA和反义寡脱氧核苷酸(AS-ODN)。
激素可以是一种或多种选自以下的激素:睾酮、雌二醇、孕酮、前列腺素及其合成类似物,和改善或显示相同药物作用的物质。
抗癌药物可以是一种或多种选自以下的药物:紫杉醇、多柔比星、5-氟尿嘧啶、顺铂、卡铂、奥沙利铂、替加氟、伊立替康、多西他赛、环磷酰胺、吉西他滨(cemcitabine)、异环磷酰胺、丝裂霉素C、长春新碱、依托泊苷、甲氨蝶呤、托泊替康、他莫昔芬、长春瑞滨、喜树碱、道诺霉素、苯丁酸氮芥、苔鲜抑素-1、加里刹霉素、美登素(mayatansine)、左旋咪唑、DNA重组干扰素α-2a、米托蒽醌、尼莫司汀、干扰素α-2a、去氧氟尿苷、福美坦、醋酸亮丙立德、醋酸甲地孕酮、卡莫氟、替尼泊苷、博来霉素、卡莫司汀、庚铂、依西美坦、阿那曲唑、雌莫司汀、卡培他滨、醋酸戈舍瑞林、海藻酸钾、醋酸甲羟孕酮、表柔比星、来曲唑、吡柔比星、托泊替康、六甲蜜胺、柠檬酸托瑞米芬、BCNU、泰索帝、放线菌素D、蛋白质-聚乙二醇缀合物及其合成类似物,改善或显示相同药物作用的物质。
血管发生抑制剂可以是一种或多种选自以下的物质:BMS-275291、氯膦酸盐、6-脱氧-6-去甲基-4-脱二甲基氨基四环素、强力霉素、马立马司他、2-甲氧基雌二醇、角鲨胺、SU5164、沙利度胺、TNP-470、考布他汀A4、大豆异黄酮、Enzastaurin、CC 5013、塞来考昔、ZD 6474、氢溴酸卤夫酮、干扰素-α、贝伐单抗、AE-941、白介素-12、VEFG-trap、西妥昔单抗及其合成类似物,和改善或显示相同药物作用的物质。
另外含的生物活性分子可以是治疗性细胞例如选自以下的一种或多种细胞:早幼成骨细胞、软骨细胞、脐静脉内皮细胞(UVEC)、成骨细胞、成熟干细胞、神经鞘细胞、少突神经胶质细胞、肝细胞、壁细胞(与UVEC联用)、成肌细胞、分泌胰岛素细胞、内皮细胞、平滑肌细胞、成纤维细胞、β-细胞、内胚层细胞、肝干细胞、球旁(juxraglomerular)细胞、骨骼肌细胞、角质细胞、黑素细胞、郎氏细胞、梅克尔细胞、成皮细胞和早幼脂肪细胞。
如果含本发明聚(有机磷腈)-生物活性分子缀合物的组合物含有作为生物活性分子的药物,则药物含量占总体积约1×10-8-50%(体积),优选约1×10-4-20%(体积)。如果药物含量低于上述范围,则不能得到需要的药物作用。在另一方面,如果药物含量高于上述范围,热敏聚合物的性质可能被破坏。
可通过选自以下的给药途径给予含本发明聚(有机磷腈)-生物活性分子缀合物的组合物至活体内:肠道外给药、经眼给药;注射到软膏组织、骨组织、脂肪组织或癌组织;吸入、经皮给药、阴道给药、尿道给药、直肠给药、鼻给药、口服给药、肺部给药、耳给药、肌肉给药、皮下给药和静脉内给药,尤其优选局部给药,例如皮下注射、肌肉注射、经皮给药或肿瘤内给药。
因为具有在室温下聚(有机磷腈)以溶液相存在的特性,可容易地注射各种形式的本发明组合物。尤其是,可将本发明组合物局部涂在特定的需要位置,且可容易地控制缀合的生物活性分子释放,因为当所述组合物注射到体内时,体温造成生物活性分子的溶液-凝胶相变。
以下实施例可使本领域技术人员更清楚地理解如何实施本发明。可以理解,虽然结合其优选的具体实施方案描述了本发明,但是这些实施方案用于举例说明而非限制本发明范围。本发明的其它方面对本发明所属领域的技术人员而言是显而易见的。
[实施例]
在以下实施例中,由Korea Institute of Science and Technology下属高级分析中心(Advanced Analysis Center),用Perkin-Elmer C,H,N分析仪对产物进行碳、氢和氮元素分析。
用Varian Gemini-300分别测量氢和磷的核磁共振波谱,通过凝胶渗透色谱,用Waters 1515泵和2410差示折射计测量平均分子量(Mw)。
在制备反应进行期间,在50℃下,将在真空条件和氮气线下干燥反应物2天,以最大限度除去水分。另外,在真空条件下,将烧瓶干燥多次。在制备期间,通过套管加入(dipped)溶剂和添加剂。
实施例1:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰紫杉醇)磷腈],[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlyCOOH)0.22(GlyGlyPTX)0.02]n的制备
将干燥异亮氨酸乙酯水合氯化物(4.22g,21.58mmol)溶于100ml无水四氢呋喃(THF),加入三乙胺(6.55g,64.74mmol)。然后,在-60℃下,将溶液滴加到含聚(二氯磷腈)(2.00g,17.26mmol)的四氢呋喃溶液(50ml)的干冰-丙酮浴中,然后使混合物在室温下反应48小时。
按31P-NMR数据确证反应速率后,将干燥甘氨酰甘氨酸烯丙酯三氟乙酸盐(1.19g,4.14mmol)在50ml无水THF中熔化。加入三乙胺(1.26g,12.42mmol),然后使混合物反应8小时。
按31P-NMR数据再次确证反应速率后,将在无水THF(50ml)中熔化的干燥氨基甲氧基聚乙二醇(9.68g,17.61mmo,Mw=550)溶液滴加到反应物中。使混合物在室温下反应12小时,然后在40℃-50℃下反应24小时。
将反应溶液过滤,将生成的三乙胺盐酸盐除去。将滤液减压浓缩至除去大部分溶剂。将得到的浓缩物溶于THF(10ml),加入过量己烷,形成沉淀。将该过程重复进行2或3次,将得到的沉淀再次溶于少量甲醇。在室温下,用甲醇将得到的溶液通过MWCO 12000膜(SpectrumLaboratories,Inc.)透析5天,然后用蒸馏水透析5天。然后,将得到的产物在低温下干燥,得到聚(二氯磷腈)[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlyOAll)0.24]n(14.21g)。
将得到的[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlyOAll)0.24]n(14.21g)在无水THF(200ml)中熔化,然后用15mol%四(三苯基膦)合钯(O)(0.56g)和20当量吗啉(4.23g),在室温下反应8小时。在室温下,将得到的溶液用甲醇通过MWCO6-8000膜(Spectrum Laboratories,Inc.)透析5天,然后在4℃下,用蒸馏水透析5天。然后,将得到的产物在低温下干燥,得到中间体产物[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlCOOH)0.24]n(13.78g)。
将得到的[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlyCOOH)0.24]n(13.78g)在无水二氯甲烷(100ml)中熔化,用0.02当量紫杉醇(0.39g)、0.04当量二环己基碳二亚胺(0.16g)和0.04当量二甲基氨基吡啶(0.01g),在0℃下反应24小时。在室温下,将得到的溶液用甲醇通过MWCO6-8000膜(Spectrum Laboratories,Inc.)透析5天,然后用蒸馏水在4℃下透析5天。然后,将得到的产物在低温下干燥,得到终产物[NP(IleOEt)1.25(AMPEG550)0.51(GlyGlyCOOH)0.22(GlyGlyPTX)0.02]n(13.02g,收率89%)。
实验式:C25H43N3O8P
元素分析数据:C,55.27;H,7.83;N,7.63
理论值:C,55.45;H,7.72;N,7.71
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),0.11(s,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),1.86(s,CH3),2.18(s,CH3),2.30(s,CH3),3.30(s,CH3),3.42 to 3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2),4.65(t,CH),4.78(s,OH),4.99(t,CH),5.22(s,CH),5.48(d,CH),5.64(d,CH),5.96(t,CH),6.26(d,CH),6.36(s,OH),
7.28-8.04(m,芳族化合物),9.00(d,NH)。
磷核磁共振图谱(DMSO-d6,ppm):δ 17.9
平均分子量(Mw):45000
实施例2:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰紫杉醇)磷腈],[NP(IleOEt)1.25(AMPEG550)0.55(GlyGlyCOOH)0.18(GlyGlyPTX)0.02]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.22g,21.58mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.99g,3.45mmol)、分子量为550的氨基甲氧基聚乙二醇(10.44g,18.99mmol)、四(三苯基膦)合钯(0)(0.61g)、吗啉(4.85g)、紫杉醇(0.40g)、二环己基碳二亚胺(0.17g)、二甲基氨基吡啶(0.10g)、三乙胺(7.59g)、四氢呋喃(550ml)和二氯甲烷(100ml)外,按与实施例1相同的方法,进行合成,得到6.95g终产物[NP(IleOEt)1.25(AMPEG550)0.55(GlyGlyCOOH)0.18(GlyGlyPTX)0.02]n(收率77%)。
实验式:C30H68N8O14P
元素分析数据:C,47.80;H,9.20;N,9.60
理论值:C,48.21;H,8.97;N,9.58
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),0.11(s,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),1.86(s,CH3),2.18(s,CH3),2.30(s,CH3),3.30(s,CH3),3.42 to 3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2),4.65(t,CH),4.78(s,OH),4.99(t,CH),5.22(s,CH),5.48(d,CH),5.64(d,CH),5.96(t,CH),6.26(d,CH),6.36(s,OH),7.288.04(m,芳族化合物),9.00(d,NH)。
磷核磁共振图谱(DMSO-d6,ppm):δ 18.2
平均分子量(Mw):31000
实施例3:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰多柔比星)磷腈],[NP(IleOEt)1.20(AMPEG550)0.60(GlyGlyCOOH)0.10(GlyGlyDOX)0.04]n的制备
除用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.22g,21.58mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.99g,3.45mmol)、分子量550的氨基甲氧基聚乙二醇(10.44g,18.99mmol)、四(三苯基膦)合钯(0)(0.62g)、吗啉(4.95g)和三乙胺(7.60g)、四氢呋喃(550ml)外,按与实施例1相同的方法,进行合成,得到中间体产物[NP(IleOEt)1.20(AMPEG550)0.60(GlyGlyCOOH)0.14]n(11.23g)。
将得到的[NP(IleOEt)1.20(AMPEG550)0.60(GlyGlyCOOH)0.14]n(11.23g)在无水四氢呋喃(100ml)中熔化,然后在0℃下,在30分钟内,滴加0.08当量三丁胺(0.22g)和0.08当量氯甲酸异丁酯(0.16g)。然后,将0.04当量多柔比星(0.44g)在少量水中熔化,将多柔比星溶液滴加到上述活化溶液中,使反应在0℃下进行1小时,然后在室温下进行24小时。
在室温下,将得到的溶液用甲醇通过MWCO6-8000膜(SpectrumLaboratories,Inc.)透析5天,然后在4℃下用蒸馏水透析5天。然后,将得到的产物在低温下干燥,得到终产物[NP(IleOEt)1.20(AMPEG550)0.60(GlyGlyCOOH)0.10(GlyGlyDOX)0.04]n(10.02g,收率82%)。
实验式:C29H70N5O14P
元素分析数据:C,47.01;H,9.38;N,9.59
理论值:C,46.98;H,8.97;N,8.98
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),2.16(m,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.56(m,CH),4.68(d,CH),4.85(m,CH),4.94(m,CH),5.21(s,CH),5.45(s,CH),6.63(d,NH),7.65(m,CH),7.92(d,CH),4.08(b,CH).
磷核磁共振图谱(DMSO-d6,ppm):δ 17.9
平均分子量(Mw):392000
实施例4:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰多柔比星)磷腈],[NP(IleOEt)1.24(AMPEG550)0.57(GlyGlyCOOH)0.14(GlyGlyDOX)0.05]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.19g,21.40mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.94g,3.28mmol)、分子量550的氨基甲氧基聚乙二醇(10.82g,19.68mmol)、四(三苯基膦)合钯(0)(0.63g)、吗啉(5.05g)、多柔比星(0.51g)、氯甲酸异丁酯(0.19g)、三丁胺(0.26g)、三乙胺(7.49g)和四氢呋喃(650ml)外,按与实施例3相同的方法,进行合成,得到11.25g终产物[NP(IleOEt)1.24(AMPEG550)0.57(GlyGlyCOOH)0.14(GlyGlyDOX)0.05]n(收率81%)。
实验式:C25H57N5O11P
元素分析数据:C,48.12;H,9.30;N,11.26
理论值:C,49.41;H,9.63;N,10.91
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),2.16(m,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.56(m,CH),4.68(d,CH),4.85(m,CH),4.94(m,CH),5.21(s,CH),5.45(s,CH),6.63(d,NH),7.65(m,CH),7.92(d,CH),4.08(b,CH).
磷核磁共振图谱(DMSO-d6,ppm):δ 18.1
平均分子量(Mw):91800
实施例5:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰多柔比星)磷腈],[NP(IleOEt)1.22(AMPEG550)0.66(GlyGlyCOOH)0.06(GlyGlyDOX)0.06]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.12g,21.06mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.59g,2.07mmol)、分子量550的氨基甲氧基聚乙二醇(12.53g,22.78mmol)、四(三苯基膦)合钯(0)(0.53g)、吗啉(4.78g)、多柔比星(0.80g)、氯甲酸异丁酯(0.29g)、三丁胺(0.40g)、三乙胺(7.02g)和四氢呋喃(650ml)外,按与实施例3相同的方法,进行合成,得到13.38g终产物[NP(IleOEt)1.22(AMPEG550)0.66(GlyGlyCOOH)0.06(GlyGlyDOX)0.06]n(收率87%)。
实验式:C26H63N5O12P
元素分析数据:C,46.95;H,9.48;N,10.74
理论值:C,46.21;H,8.95;N,10.13
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),2.16(m,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.56(m,CH),4.68(d,CH),4.85(m,CH),4.94(m,CH),5.21(s,CH),5.45(s,CH),6.63(d,NH),7.65(m,CH),7.92(d,CH),4.08(b,CH).
磷核磁共振图谱(DMSO-d6,ppm):δ 19.0
平均分子量(Mw):88500
实施例6:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇750)(甘氨酰甘氨酸)(甘氨酰甘氨酰多柔比星)磷腈],[NP(IleOEt)1.27(AMPEG750)0.57(GlyGlyCOOH)0.23(GlyGlyDOX)0.05]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.29g,21.92mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(1.38g,4.83mmol)、分子量750的氨基甲氧基聚乙二醇(14.76g,19.68mmol)、四(三苯基膦)合钯(0)(0.71g)、吗啉(5.98g)、多柔比星(0.67g)、氯甲酸异丁酯(0.24g)、三丁胺(0.34g)、三乙胺(8.12g)和四氢呋喃(650ml)外,按与实施例3相同的方法合成,得到14.95g终产物[NP(IleOEt)1.27(AMPEG750)0.57(GlyGlyCOOH)0.23(GlyGlyDOX)0.05]n(收率73%)。
实验式:C20H40N3O7P
元素分析数据:C,50.65;H,8.64;N,8.98
理论值:C,49.49;H,8.55;N,8.79
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65 to 1.79(b,CH),2.16(m,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.56(m,CH),4.68(d,CH),4.85(m,CH),4.94(m,CH),5.21(s,CH),5.45(s,CH),6.63(d,NH),7.65(m,CH),7.92(d,CH),4.08(b,CH).
磷核磁共振图谱(DMSO-d6,ppm):δ 19.1
平均分子量(Mw):87400
实施例7:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(peptied))磷腈],[NP(IleOEt)1.30(AMPEG550)0.53(GlyGlyCOOH)0.07(GlyGlyGRGDS)0.10]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.39g,22.44mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.84g,2.93mmol)、分子量550的氨基甲氧基聚乙二醇(10.06g,18.30mmol)、四(三苯基膦)合钯(0)(0.48g)、吗啉(4.23g)、甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(0.87g)、氯甲酸异丁酯(0.06g)、三丁胺(0.62g)、三乙胺(7.70g)和四氢呋喃(650ml)外,按与实施例3相同的方法合成,得到10.87g终产物[NP(IleOEt)1.30(AMPEG550)0.53(GlyGlyCOOH)0.07(GlyGlyGRGDS)0.10]n(收率72%)。
由Korea Basic Science Institute(KBSI)所属proteomic分析室,用蛋白分析计算终产物中GRGDS含量
实验式:C22H44N3O9P
元素分析数据:C,50.54;H,8.50;N,8.03
理论值:C,50.50;H,8.23;N,7.98
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65-1.79(b,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2).
磷核磁共振图谱(DMSO-d6,ppm):δ 18.9
平均分子量(Mw):108100
实施例8:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],[NP(IleOEt)1.13(AMPEG550)0.50(GlyGlyCOOH)0.04(GlyGlyGRGDS)0.15]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(3.81g,19.50mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.94g,3.28mmol)、分子量550的氨基甲氧基聚乙二醇(9.49g,17.26mmol)、四(三苯基膦)合钯(0)(0.43g)、吗啉(4.12g)、甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(2.61g)、氯甲酸异丁酯(0.18g)、三丁胺(1.86g)、三乙胺(6.92g)和四氢呋喃(650ml)外,按与实施例3相同的方法合成,得到11.21g终产物[NP(IleOEt)1.13(AMPEG550)0.50(GlyGlyCOOH)0.04(GlyGlyGRGDS)0.15]n(收率81%).
实验式:C24H50N3O10P
元素分析数据:C,51.25;H,8.71;N,7.21
理论值:C,50.98H,8.50N,7.92
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65-1.79(b,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2).
磷核磁共振图谱(DMSO-d6,ppm):δ 19.2
平均分子量(Mw):98300
实施例9:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸乙酯)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],[NP(IleOEt)1.19(AMPEG550)0.52(GlyGlyCOOH)0.10(GlyGlyGlyOEt)0.02(GlyGlyGRGDS)0.10]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(3.81g,19.50mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.94g,3.28mmol)、分子量550的氨基甲氧基聚乙二醇(9.49g,17.26mmol)、四(三苯基膦)合钯(0)(0.61g)、吗啉(5.32g)、甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(1.74g)、氯甲酸异丁酯(0.12g)、三丁胺(1.24g)、三乙胺(7.70g)和四氢呋喃(650ml)外,按与实施例3相同的方法合成,得到中间体产物[NP(IleOEt)1.19(AMPEG550)0.52(GlyGlyCOOH)0.20(GlyGlyGRGDS)0.10]n(13.78g)。
将得到的[NP(IleOEt)1.19(AMPEG550)0.52(GlyGlyCOOH)0.20(GlyGlyGRGDS)0.10]n在无水四氢呋喃(150ml)中熔化,在0℃下,使得到的溶液与三丁胺(0.16g)和熔化在少量水中的甘氨酰乙酯(0.08g)溶液反应1小时。在室温下,将得到的溶液用甲醇通过MWCO6-8000膜(Spectrum Laboratories,Inc.)透析5天,然后在4℃下用蒸馏水透析5天。然后将得到的产物在低温下干燥,得到终产物[NP(IleOEt)1.19(AMPEG550)0.52(GlyGlyCOOH)0.10(GlyGlyGlyOEt)0.10(GlyGlyGRGDS)0.10]n(13.64g,收率91%)。
实验式:C25H52N3O10P
元素分析数据:C,51.54;H,8.77;N,7.10
理论值:C,51.87H,8.51N,6.89
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65-1.79(b,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2).
磷核磁共振图谱(DMSO-d6,ppm):δ 19.1
平均分子量(Mw):27200
实施例10:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酰乙酯)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],[NP(IleOEt)1.13(AMPEG550)0.65(GlyGlyGlyOEt)0.17(GlyGlyGRGDS)0.05]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.36g,22.27mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.84g,2.93mmol)、分子量550的氨基甲氧基聚乙二醇(10.25g,18.64mmol)、四(三苯基膦)合钯(0)(0.57g)、吗啉(4.98g)、甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(0.79g)、甘氨酰乙酯(0.13g)、氯甲酸异丁酯(0.07g)、三丁胺(0.61g)、三乙胺(7.64g)和四氢呋喃(800ml)外,按与实施例3相同的方法合成,得到12.29g终产物[NP(IleOEt)1.29(AMPEG550)0.54(GlyGlyGlyOEt)0.12(GlyGlyGRGDS)0.05]n(收率80%)。
实验式:C24H47N3O9P
元素分析数据:C,51.65;H,8.48;N,7.60
理论值:C,50.91;H,8.30;N,7.86
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65-1.79(b,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2).
磷核磁共振图谱(DMSO-d6,ppm):δ 20.0
平均分子量(Mw):86500
实施例11:聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],[NP(IleOEt)1.29(AMPEG550)0.54(GlyGlyCOOH)0.12(GlyGlyGRGDS)0.05]n的制备
除使用聚(二氯磷腈)(2.00g,17.26mmol)、异亮氨酸乙酯(4.36g,22.27mmol)、甘氨酰甘氨酸烯丙酯三氟乙酸盐(0.84g,2.93mmol)、分子量550的氨基甲氧基聚乙二醇(10.25g,18.64mmol)、四(三苯基膦)合钯(0)(0.51g)、吗啉(4.28g)、甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽(0.81g)、氯甲酸异丁酯(0.071g)、三丁胺(0.63g)、三乙胺(7.65g)和四氢呋喃(650ml)外,按与实施例3相同的方法合成,得到16.12g终产物[NP(IleOEt)1.29(AMPEG550)0.54(GlyGlyCOOH)0.12(GlyGlyGRGDY)0.05]n(收率82%)。
实验式:C23H45N3O9P
元素分析数据:C,50.63;H,8.52;N,7.79
理论值:C,49.47;H,8.49;N,7.70
氢核磁共振图谱
(DMSO-d6,ppm):δ 0.92(b,CH3),1.25(b,CH2),1.57(s,CH3),1.65-1.79(b,CH),3.42-3.50(b,CH2),3.56(s,CH2),4.08(b,CH),4.15(b,CH2).
磷核磁共振图谱(DMSO-d6,ppm):δ 19.1
平均分子量(Mw):87400
实施例12:聚(有机磷腈)-药物或生物活性分子缀合物随温度变化的溶液-凝胶相变的观察
在4℃下,将在实施例1-11中得到的聚(有机磷腈)-药物或生物活性分子缀合物分别溶于磷酸盐缓冲盐水(pH7.4),以制备浓度为10%(重量)溶液。将溶液放入配备恒温浴(TC-501)的Brookfield DV-III+流变计的室中。按0.04℃/min速度升温和在0.1-1.7/秒剪切速度下,观察溶液-凝胶相变。
以上观察到的取决于温度的本发明热敏聚(有机磷腈)-药物或生物活性分子缀合物的凝胶性质在下表2中列出。
[表2]
图1是显示本发明聚(有机磷腈)-紫杉醇缀合物随温度改变的溶液-凝胶相变的照片。其中显示,在低于初始胶凝温度时,聚合物溶液为流体溶液相,而在高于初始胶凝温度的最大胶凝温度时,它变为凝胶相。
图2显示本发明聚(有机磷腈)-抗癌药物或生物活性分子缀合物随温度变化的粘度变化。
可通过调节取代聚合物的疏水性氨基酸酯的种类;可控制降解速度的氨基酸、肽或缩肽的种类;具有官能团的氨基酸或肽的种类;甲氧基聚乙二醇的链长;和所有取代基的组成,确认具有最大胶凝温度和最大凝胶硬度的聚(有机磷腈)(韩国专利申请2006-0005579号)。
另外,还可根据官能团中取代的药物、生物活性分子的种类和取代度,控制最大凝胶强度。可制备聚(有机磷腈)-药物或生物活性分子缀合物,该缀合物在室温下为溶液状态而在体温下为凝胶相。
实施例13:聚(有机磷腈)-紫杉醇缀合物分子的失重度随时间变化的观察
将在本发明实施例1和2中得到的聚(有机磷腈)-紫杉醇缀合物溶于磷酸盐缓冲盐水(pH 7.4),制备浓度为10%(重量)溶液。将溶液(0.5ml)在37℃下放入单孔悬挂式插入式细胞培养皿(millicell),制备水凝胶,然后将其浸泡在磷酸盐缓冲盐水(10ml,pH 7.4)中,其中含SDS(0.1%(体积)),然后将溶液放入37℃浴中,按50rpm搅拌。达到预定时间后,将单孔悬挂式插入式细胞培养皿取出,然后冻干,测量聚(有机磷腈)-紫杉醇缀合物的重量。
聚(有机磷腈)-紫杉醇缀合物的失重度与时间变化的关系见下图3。如图3所示,在水溶液条件(37℃)下,聚(有机磷腈)水凝胶在10天内发生50%,在30天内发生20%失重。
按照在一定时间内分解的聚合物溶液的成分分析,检测到(depected)聚合物溶液中的紫杉醇、磷酸盐、氨、乙醇等。因此,可认为聚(有机磷腈)-紫杉醇缀合物应该分解为对活体无害的成分例如磷酸盐、氨、乙醇等。
实施例14:聚(有机磷腈)-多柔比星或RGD肽缀合物的失重度随时间变化的观察
将在本发明实施例3和4中得到的聚(有机磷腈)-多柔比星缀合物和在本发明实施例9中得到的聚(有机磷腈)-RGD肽缀合物分别溶于磷酸盐缓冲盐水(pH 7.4),制备浓度为10%(重量)溶液,然后将溶液放入37℃浴中,按50rpm搅拌。按通过凝胶渗透色谱(GPC)测得的随时间变化的聚合物分子量的减少程度,确定随时间变化的聚合物水解程度。
聚(有机磷腈)-多柔比星或RGD肽缀合物的失重度与时间变化的关系见下图4。如图4所示,在37℃下粘度最低的聚(有机磷腈)-RGD肽缀合物(实施例9)水解最快。而在37℃下粘度最高的聚(有机磷腈)-多柔比星缀合物(实施例3)水解最慢。
因此在本发明中,可通过控制聚(有机磷腈)在37℃时的粘度,控制聚(有机磷腈)-药物和生物活性分子缀合物的水解速度。
实施例15:与紫杉醇缀合的聚(有机磷腈)水凝胶中紫杉醇的体外释放行为的观察
将实施例3中的聚(有机磷腈)溶于磷酸盐缓冲盐水,制备浓度为7%(重量)溶液。将0.1%(体积)紫杉醇溶于得到的溶液。将含0.5ml紫杉醇的溶液放入在37℃的单孔悬挂式插入式细胞培养皿,形成水凝胶。
将得到的含紫杉醇的聚(有机磷腈)水凝胶加入100ml释放溶液。用含0.1%(体积)SDS的磷酸盐缓冲盐水(pH 7.4)作为释放溶液。
将得到的含含紫杉醇的聚(有机磷腈)水凝胶释放溶液放入37℃浴中,按50rpm搅拌。在如图4中所示固定时间间隔内,吸取(correct)5(5)ml释放溶液,通过HPLC测量紫杉醇的释放量。吸取5ml释放液后,补加等量新制释放液。
聚(有机磷腈)水凝胶中紫杉醇随时间变化的释放行为见图5。如图5所示,含紫杉醇的聚(有机磷腈)水凝胶中紫杉醇的释放完全受到控制和维持,紫杉醇可释放至少50天。
实施例16:与多柔比星缀合的聚(有机磷腈)水凝胶中多柔比星的体外释放行为的观察
将实施例4聚(有机磷腈)溶于水,制备浓度为10%(重量)溶液。将0.1%(体积)多柔比星溶于得到的溶液。将含0.5ml多柔比星的溶液放入在37℃的单孔悬挂式插入式细胞培养皿,形成水凝胶。将得到的含多柔比星的聚(有机磷腈)水凝胶加入作为释放溶液用的10ml磷酸盐缓冲盐水(pH 7.4)。将得到的含含多柔比星的聚(有机磷腈)水凝胶的释放溶液放入37℃浴中,按50rpm搅拌。
然后,将单孔悬挂式插入式细胞培养皿转移到新制释放液中。用UV-VIS光谱(激发波长:495nm)测量其中发生多柔比星释放的释放溶液中多柔比星释放量。
聚(有机磷腈)水凝胶中多柔比星释放行为与时间的关系见图5。如图5所示,含多柔比星的聚(有机磷腈)水凝胶中多柔比星的释放完全控制和维持,多柔比星可释放至少60天。
实施例17:聚(有机磷腈)-抗癌药物缀合物的体外抗癌活性的观察
为证实本发明聚(有机磷腈)-抗癌药物缀合物的体外抗癌活性,在人乳腺癌(MCF-7,the Korea Cell Line Bank)和人宫颈腺癌(Hela,theKorea Cell Line Bank)上进行以下试验。
对于体外细胞实验,为测量聚(有机磷腈)-抗癌药物缀合物对癌细胞的半数生殖制止浓度(IC50),使用溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓(MTT)的分析方法[T.Mosmann,J.Immunol.Method,65,(1985)55]。
将测量用物质在少量DMSO(二甲亚砜)中熔化,将它们用蒸馏水稀释200倍。将该物质溶液加入MCF-7癌细胞(the Korea Cell LineBank)和Hela(the Korea Cell Line Bank)。然后,将它们加入96孔微量滴定板至浓度1.0×104细胞/ml(癌细胞浓度)。在37℃下,在5% CO2条件下,将它们分别培养2、3、4天。
将MTT溶液(20μl)与培养的细胞混合,在37℃下,在5% CO2条件下,将它们再培养4小时。将各细胞的上层培养基除去后,将DMSO(100μl)加入孔中,在室温下,用板摇床将它们振摇20分钟,从而将通过MTT减少产生的甲结晶溶解。
本发明聚(有机磷腈)-抗癌药物缀合物的体外抗癌活性的测量结果列于表3。
[表3]
如表3所示,紫杉醇-聚(有机磷腈)缀合物显示与紫杉醇相似的体外抗癌活性。聚(有机磷腈)-多柔比星缀合物显示与多柔比星相似的体外抗癌活性。
实施例18:与紫杉醇缀合的聚(有机磷腈)水凝胶的体内抗癌活性观察
通过以下方法测定按实施例1方法制备的与紫杉醇缀合的聚(有机磷腈)水凝胶的体内抗癌活性。
用裸小鼠(OrientalBio,Balb/C,雌性,5周龄,20g)作为动物体内试验的动物模型。将胃癌细胞,SNU-601(1×107细胞,0.2ml,the KoreanCell Line Bank)注射到小鼠背部。制备聚合物溶液,该溶液含10%(重量)实施例1的聚(有机磷腈)-紫杉醇缀合物的磷酸盐缓冲盐水(pH 7.4)溶液。将0.1ml和0.2ml该溶液分别注射到癌细胞中,测量细胞大小变化。
当溶液的注射量多达0.1ml时,紫杉醇的注射量为10mg/l kg小鼠体重。当溶液的注射量多达0.2ml时,紫杉醇的注射量为30mg/l kg小鼠体重。
作为对照组,分别测量按60mg紫杉醇/l kg小鼠重量量注射到癌细胞后的癌大小变化和用盐水代替抗癌药物给予癌细胞后的癌大小变化。所用的小鼠数分别为10只。
按上述测量的癌细胞大小变化见图6。
如图6所示,用盐水代替抗癌药物给予对照组癌细胞26天后,细胞体积增加94%,34天后增加134%。
但给予0.1ml量与紫杉醇缀合的聚(有机磷腈)水凝胶26天后,该组癌细胞体积减少至60%,34天后减少至57%。给予0.2ml与紫杉醇缀合的聚(有机磷腈)水凝胶26天后,该组癌细胞的体积减少至81%,34天后减少至81%。
用按60mg/kg浓度注射紫杉醇组作为对照组,10天后,由于紫杉醇毒性,8只小鼠死亡。
实施例19:与多柔比星缀合的聚(有机磷腈)水凝胶的体内抗癌活性观察
通过以下方法测定按实施例5方法制备的与多柔比星缀合的聚(有机磷腈)水凝胶的体内抗癌活性。
用裸小鼠(OrientalBio,Balb/C,雌性,5周龄,20g)作为动物体内试验的动物模型。将胃癌细胞,SNU-601(1x107细胞,0.2ml,the KoreanCell Line Bank)注射到小鼠背部。制备聚合物溶液,该溶液含10%(重量)实施例5的聚(有机磷腈)-多柔比星缀合物的磷酸盐缓冲盐水(pH7.4)溶液。将0.1ml和0.2ml该溶液分别注射到癌细胞中,测量癌细胞大小变化。
当溶液的注射量为0.1ml时,多柔比星的注射量为30mg/l kg小鼠体重。当溶液的注射量为0.2ml时,多柔比星的注射量为60mg/l kg小鼠体重。
作为对照组,分别测量按30mg多柔比星/l kg小鼠重量量注射到癌细胞后的癌细胞大小变化和用盐水代替抗癌药物给予癌细胞后的癌细胞大小变化。所用小鼠数目分别为10只。
按上述测量的癌细胞大小变化见图7。
如图7所示,用盐水代替抗癌药物给予对照组癌细胞14天后,该组细胞体积增加至70%,28天后增加至223%。
但给予0.1ml量与多柔比星缀合的聚(有机磷腈)水凝胶14天后,该组癌细胞体积减至68%,26天后减至173%,28天后减至168%。给予0.2ml与多柔比星缀合的聚(有机磷腈)水凝胶14天后,该组癌细胞的体积减至155%,22天后减至195%,28天后减至182%。
用按30mg/kg浓度注射多柔比星组作为对照组,14天后,由于紫杉醇毒性,所有小鼠死亡。但是,在注射多柔比星浓度为30mg/kg和60mg/kg与多柔比星缀合的聚(有机磷腈)水凝胶的小鼠组,无小鼠死亡。
如上所述,本发明递药系统中的药物在药物组合物中具有优良的药物稳定性、长时间持续药物释放和优良生物活性。因此,预计本发明递药系统可用作药物载体,同时可用于与组织技术(histotechnology)有关的各种生物材料领域。
Claims (14)
1.一种由以下化学式1代表的聚(有机磷腈)-生物活性分子缀合物,其中具有官能团的可生物降解和热敏性聚(有机磷腈)和由以下取代基R10代表的生物活性分子结合:
[化学式1]
其中,
p为7-50的整数;
R1选自H、HCH2、CH3、CH2SH、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C6H4OH、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、CH2CO2C2H5、(CH2)2CO2C2H5和HCONHCH(CH2C6H5),
R2选自CH3、C3H7、C4H9、C2H5、CH2C6H5和CH2CHCH2,
R3为CH(W),
R4选自CO2、CO2CH2CO2、CO2CH(CH3)CO2和CONHCH(X)CO2,
R5选自H、CH3和C2H5,
W和X独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R6为CH(Y),
R7选自C2H4、C3H6、C4H8、CH2C6H4、CH2CO2、O、CONHCH(Z)O、CO、CO2、S、CONHCH(Z)S、N、CONHCH(Z)N、CON、COCHNH(Z)CON、CONHCH(Z)CO和CONHCH(Z)CO2,
R8选自OH、SH、H、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2和在本发明说明书详述部分所述表1中定义的保护基团,
Y和Z独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R9选自OH、SH、H、NH2、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2、NHCH(SH)CO2H、NH(CH2)qSH、NH(CH2CH2NH)rH、[NHCH(C4H8NH2)CO]rOH、[NHCH[(CH2)3C(=NH)(NH2)]CO]rOH和鱼精蛋白,
q为1-20的整数,
r为1-18000的整数;
R10选自紫杉醇、多柔比星、喜树碱、表柔比星、5-氟尿嘧啶、10-羟基喜树碱、10-氨基喜树碱、7-乙基喜树碱、伊立替康、甲氨蝶呤、丝裂霉素C、紫杉烷、多西他赛、苯丁酸氮芥、加里刹霉素、美登醇、2-吡咯啉-1-基-多柔比星(AN-201)、柔红霉素、丁酸、美法仑、4′-二甲基去氧鬼臼毒素、姜黄、鬼臼毒素、表鬼臼毒素、4-β-氨基-4′-O-去甲基表鬼臼毒素、太利苏霉素S10b、道诺霉素、duocarmycin A、duocarmycin SA、顺式-乌头-道诺霉素、加里刹霉素、偶氮烯鎓二醇、纺锤霉素、6-巯基嘌呤、glucuronidation、phosmidosine、链黑霉素、血卟啉、去铁胺(DFO)、去铁酮、阿西维辛、雌莫司汀、力达霉素、精氨酸-甘氨酸-天冬氨酸肽、神经肽、白蛋白、牛血清白蛋白(BSA)、牛胰腺核糖核酸酶(RNase A)、牛精液核糖核酸酶(BS-RNase)、Bowman-birk蛋白酶抑制剂(BBI)、胶原蛋白、纤连蛋白、层粘连蛋白、红细胞生成素(EPO)、干扰素、蛭素、集落刺激因子(CSF)、胰岛素、去氨加压素、胰高血糖素样肽1(GLP1)、人生长激素拮抗剂、肿瘤坏死因子受体1(TNFR1)、天冬酰胺酶、腺苷脱氨酶、转化生长因子-β(TGF-β)、骨形态发生蛋白(BMPs)、生长因子、肿瘤坏死因子-相关凋亡-诱导配体(TRAIL)、细胞因子、茶氨酸地塞米松、肝素、壳聚糖、透明质烷、环糊精、淀粉、碳水化合物、糖类、荧光蛋白(例如绿荧光蛋白(GFP)、红荧光蛋白(RFP))、病毒样颗粒(VLP)和疫苗,
a、b、c、d、e和f分别代表各取代基的含量,其中a、b和f独立为0.01-1.9,c、d和e独立为0-1.9,和
a+b+c+d+e+f=2.0,和
n为5-100000。
2.权利要求1的聚(有机磷腈)-生物活性分子缀合物,所述缀合物选自
1)聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰紫杉醇)磷腈],
2)聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰多柔比星)磷腈],
3)聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],
4)聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-乙酯)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-蜡酸肽)磷腈],和
5)聚[(异亮氨酸乙酯)(氨基甲氧基聚乙二醇550)(甘氨酰甘氨酸)(甘氨酰甘氨酰甘氨酸-精氨酸-甘氨酸-天冬酰胺-酪氨酸肽)磷腈]。
3.一种权利要求1的聚(有机磷腈)-生物活性分子缀合物的制备方法,所述方法包括以下步骤:
(1)使由以下化学式2代表的磷腈三聚体热聚合,制备由以下化学式3代表的二氯磷腈的线性聚合物
[化学式2]
[化学式3]
(其中n为7-100,000的整数);
(2)使在步骤(1)中制备的化学式3化合物与0.01-1.9当量的由以下化学式4代表的氨基酸酯或其盐反应
[化学式4]
NH2CH(R1)CO2R2;
(3)使在步骤(2)中制备的化合物与0-1.9当量的一种由以下化学式5代表的化合物反应,所述化学式5代表的化合物选自氨基酸、肽和缩肽酯及其盐,
[化学式5]
NH2(R3)(R4)(R5);
(4)使在步骤(3)中制备的化合物与0.01-1.9当量的以下化学式6代表的具有官能团的取代基或其盐反应
[化学式6]
NH2(R6)(R7)(R8);
(5)使在步骤(4)制备的化合物与0.01-1.9当量的由以下化学式7代表的氨基甲氧基聚乙二醇或其盐反应
[化学式7]
NH2(CH2CH2O)pCH3;和
(6)使在步骤(5)中制备的化合物与选自以下的生物活性分子反应:蛋白、多肽、肽、疫苗、基因、激素、抗癌药物和血管发生抑制剂,
其中,
p为7-50的整数;
R1选自H、HCH2、CH3、CH2SH、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C6H4OH、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、CH2CO2C2H5、(CH2)2CO2C2H5和HCONHCH(CH2C6H5),和
R2选自CH3、C3H7、C4H9、C2H5、CH2C6H5和CH2CHCH2;
R3为CH(W),
R4选自CO2、CO2CH2CO2、CO2CH(CH3)CO2和CONHCH(X)CO2,
R5选自H、CH3和C2H5,
W和X独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R6为CH(Y),
R7选自C2H4、C3H6、C4H8、CH2C6H4、CH2CO2、O、CONHCH(Z)O、CO、CO2、S、CONHCH(Z)S、N、CONHCH(Z)N、CON、COCHNH(Z)CON、CONHCH(Z)CO和CONHCH(Z)CO2,
R8选自OH、SH、H、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2和在本发明说明书详述部分所述表1中定义的保护基团,
Y和Z独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R9选自OH、SH、H、NH2、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2、NHCH(SH)CO2H、NH(CH2)qSH、NH(CH2CH2NH)rH、[NHCH(C4H8NH2)CO]rOH、[NHCH[(CH2)3C(=NH)(NH2)]CO]rOH和鱼精蛋白,
q为1-20的整数,
r为1-18000的整数;
R10选自紫杉醇、多柔比星、喜树碱、表柔比星、5-氟尿嘧啶、10-羟基喜树碱、10-氨基喜树碱、7-乙基喜树碱、伊立替康、甲氨蝶呤、丝裂霉素C、紫杉烷、多西他赛、苯丁酸氮芥、加里刹霉素、美登醇、2-吡咯啉-1-基-多柔比星(AN-201)、柔红霉素、丁酸、美法仑、4′-二甲基去氧鬼臼毒素、姜黄、鬼臼毒素、表鬼臼毒素、4-β-氨基-4′-O-去甲基表鬼臼毒素、太利苏霉素S10b、道诺霉素、duocarmycin A、duocarmycin SA、顺式-乌头-道诺霉素、加里刹霉素、偶氮烯鎓二醇、纺锤霉素、6-巯基嘌呤、glucuronidation、phosmidosine、链黑霉素、血卟啉、去铁胺(DFO)、去铁酮、阿西维辛、雌莫司汀、力达霉素、精氨酸-甘氨酸-天冬氨酸肽、神经肽、白蛋白、牛血清白蛋白(BSA)、牛胰腺核糖核酸酶(RNase A)、牛精液核糖核酸酶(BS-RNase)、Bowman-birk蛋白酶抑制剂(BBI)、胶原蛋白、纤连蛋白、层粘连蛋白、红细胞生成素(EPO)、干扰素、蛭素、集落刺激因子(CSF)、胰岛素、去氨加压素、胰高血糖素样肽1(GLP1)、人生长激素拮抗剂、肿瘤坏死因子受体1(TNFR1)、天冬酰胺酶、腺苷脱氨酶、转化生长因子-β(TGF-β)、骨形态发生蛋白(BMPs)、生长因子、肿瘤坏死因子-相关凋亡-诱导配体(TRAIL)、细胞因子、茶氨酸地塞米松、肝素、壳聚糖、透明质烷、环糊精、淀粉、碳水化合物、糖类、荧光蛋白、病毒样颗粒(VLP)和疫苗,
a、b、c、d、e和f分别代表各取代基的含量,其中a、b和f独立为0.01-1.9,c、d和e独立为0-1.9,和a+b+c+d+e+f=2.0,且
n为5-100000。
4.权利要求3的方法,当所述步骤(5)产物在化学式6中含选自CH2C6H5和CH2CHCH2的R8时,所述方法还包括在所述步骤(5)和步骤(6)之间使所述步骤(5)的产物脱氢或脱烯丙酯化的步骤(5-1)。
5.权利要求3或权利要求4的方法,所述方法还包括在所述步骤(5)和步骤(6)之间或所述步骤(5-1)和步骤(6)之间使所述步骤(5)或步骤(5-1)产物与一种或多种选自以下的物质反应的步骤(5-2):赖氨酸、精氨酸、半胱氨酸、巯基烷基胺、聚氮丙啶、聚赖氨酸、聚精氨酸和鱼精蛋白。
6.一种聚(有机磷腈)水凝胶,所述水凝胶含随温度变化显示溶液-凝胶相变的以下化学式1的聚(有机磷腈)-生物活性分子缀合物:
(化学式1-1)
其中,
p为7-50的整数;
R1选自H、HCH2、CH3、CH2SH、CH(CH3)2、CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C6H4OH、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、CH2CO2C2H5、(CH2)2CO2C2H5和HCONHCH(CH2C6H5),
R2选自CH3、C3H7、C4H9、C2H5、CH2C6H5和CH2CHCH2,
R3为CH(W),
R4选自CO2、CO2CH2CO2、CO2CH(CH3)CO2和CONHCH(X)CO2,
R5选自H、CH3和C2H5,
W和X独立选自H、HCH2、CH3、CH(CH3)2、CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R6为CH(Y),
R7选自C2H4、C3H6、C4H8、CH2C6H4、CH2CO2、O、CONHCH(Z)O、CO、CO2、S、CONHCH(Z)S、N、CONHCH(Z)N、CON、COCHNH(Z)CON、CONHCH(Z)CO和CONHCH(Z)CO2,
R8选自OH、SH、H、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2,和在本发明说明书详述部分所述表1中定义的保护基团,
Y和Z独立选自H、HCH2、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)C2H5、CH2CH2SCH3、CH2C6H5、CH2C2NH2C6H4、OCOC4N+H9、CO2C2H5、(CH2)2CO2C2H5、CH2OH、CH(CH3)OH、CH2C6H4OH、CH2COOH、CH2CH2COOH、CH2CONH2、C4H8NH2、C3H6NHC(=NH)NH2、CH2C3N2H3和CH2SH,
R9选自OH、SH、H、NH2、CH3、C2H5、C3H7、C4H9、CH2C6H5、CH2CHCH2、NHCH(SH)CO2H、NH(CH2)qSH、NH(CH2CH2NH)rH、[NHCH(C4H8NH2)CO]rOH、[NHCH[(CH2)3C(=NH)(NH2)]CO]rOH和鱼精蛋白,
q为1-20的整数,
r为1-18000的整数,
R10选自紫杉醇、多柔比星、喜树碱、表柔比星、5-氟尿嘧啶、10-羟基喜树碱、10-氨基喜树碱、7-乙基喜树碱、伊立替康、甲氨蝶呤、丝裂霉素C、紫杉烷、多西他赛、苯丁酸氮芥、加里刹霉素、美登醇、2-吡咯啉-1-基-多柔比星(AN-201)、柔红霉素、丁酸、美法仑、4′-二甲基去氧鬼臼毒素、姜黄、鬼臼毒素、表鬼臼毒素、4-β-氨基-4′-O-去甲基表鬼臼毒素、太利苏霉素S10b、道诺霉素、duocarmycin A、duocarmycin SA、顺式-乌头-道诺霉素、加里刹霉素、偶氮烯鎓二醇、纺锤霉素、6-巯基嘌呤、glucuronidation、phosmidosine、链黑霉素、血卟啉、去铁胺(DFO)、去铁酮、阿西维辛、雌莫司汀、力达霉素、精氨酸-甘氨酸-天冬氨酸肽、神经肽、白蛋白、牛血清白蛋白(BSA)、牛胰腺核糖核酸酶(RNase A)、牛精液核糖核酸酶(BS-RNase)、Bowman-birk蛋白酶抑制剂(BBI)、胶原蛋白、纤连蛋白、层粘连蛋白、红细胞生成素(EPO)、干扰素、蛭素、集落刺激因子(CSF)、胰岛素、去氨加压素、胰高血糖素样肽1(GLP1)、人生长激素拮抗剂、肿瘤坏死因子受体1(TNFR1)、天冬酰胺酶、腺苷脱氨酶、转化生长因子-β(TGF-β)、骨形态发生蛋白(BMPs)、生长因子、肿瘤坏死因子-相关凋亡-诱导配体(TRAIL)、细胞因子、茶氨酸地塞米松、肝素、壳聚糖、透明质烷、环糊精、淀粉、碳水化合物、糖类、荧光蛋白、病毒样颗粒(VLP)和疫苗,
a、b、c、d、e和f分别代表各取代基的含量,其中a、b和f独立为0.01-1.9,c、d和e独立为0-1.9,且a+b+c+d+e+f=2.0,且
n为5-100000。
7.权利要求6的水凝胶,其中将所述聚(有机磷腈)-生物活性分子缀合物溶于一种或多种溶液,所述溶液选自水、缓冲液、酸溶液、碱性溶液、盐溶液、盐水溶液、注射用水和葡萄糖盐溶液,且所述聚(有机磷腈)-生物活性分子缀合物浓度为1-50%(重量)。
8.一种递送生物活性分子的组合物,所述组合物含一种或多种选自以下的物质:权利要求1或2的聚(有机磷腈)-生物活性分子缀合物,和含权利要求6或7的聚(有机磷腈)-生物活性分子缀合物的水凝胶。
9.权利要求8的递送生物活性分子的组合物,所述组合物还包含一种或多种选自其它生物活性分子、细胞和添加剂的物质。
10.权利要求9的递送生物活性分子的组合物,其中所述添加剂的含量占组合物总重1×10-6-30%(重量),且
所述添加剂选自分子量为200-750,000的阳离子聚合物、聚(N-乙烯基-2-吡咯烷酮)、聚乙酸乙烯酯(PVA)、透明质酸、硫酸软骨素、肝素、藻酸盐、阿米洛利、普鲁卡因胺、乙酰基-β-甲基胆碱、精胺、亚精胺、溶菌酶、丝心蛋白、白蛋白、胶原蛋白、生长因子、骨形态发生蛋白(BMPs)、地塞米松、纤连蛋白、纤维蛋白原、凝血酶、蛋白、聚氧乙烯蓖麻油EL、佑雷佐生、亚叶酸、蓖麻油酸、磷脂、小肠粘膜下层、维生素E、聚脂肪酸甘油酯、Labrafil、Labrafil M1944CS、柠檬酸、谷氨酸、羟丙基甲基纤维素、明胶、肉豆寇酸异丙酯、丙烯酸树脂、tego甜菜碱、二肉豆蔻酰卵磷脂、菌核葡聚糖、乙醇、二甲亚砜、防腐剂、糖、多元醇、含多元醇的糖、氨基酸、含多元醇的聚合物、含氨基酸的糖、表面活性剂、含糖离子、硅酸盐、NaCl、KCl、NaBr、NaI、LiCl、n-Bu4NBr、n-Pr4NBr、Et4NBr、Mg(OH)2、Ca(OH)2、ZnCO3、Ca3(PO4)2;ZnCl2、(C2H3O2)2Zn、ZnCO3、CdCl2、HgCl2、CoCl2、(CaNO3)2、BaCl2、MgCl2、PbCl2、AlCl3、FeCl2、FeCl3、NiCl2、AgCl、AuCl3、CuCl2、十四烷基硫酸钠、十二烷基三甲基溴化铵、十二烷基三甲基氯化铵和十四烷基三甲基溴化铵。
11.权利要求9的递送生物活性分子的组合物,其中所述其它生物活性分子选自蛋白、多肽、肽、疫苗、基因、激素、抗癌药物和血管发生抑制剂,且所述其它生物活性分子的含量占所述组合物总体积1×10-8-50%(体积)。
12.权利要求9的递送生物活性分子的组合物,其中所述蛋白、多肽或肽是一种或多种选自以下的物质:红细胞生成素(EPO)、干扰素-α、干扰素-β、干扰素-γ、生长激素(人、猪、牛等)、生长激素释放因子、神经生长因子(NGF)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、巨噬细胞-集落刺激因子(M-CSF)、凝血因子、胰岛素、催产素、血管升压素、促肾上腺皮质激素、表皮生长因子、血小板衍生生长因子(PDGF)、催乳素、促黄体素释放素、黄体激素释放激素(LHRH)、LHRH激动剂、LHRH拮抗剂、促生长素抑制素、胰高糖血素、白介素-2(IL-2)、白介素-11(IL-11)、胃泌素、四肽胃泌素、五肽胃泌素、尿抑胃素、胰泌素、降钙素、脑啡肽、内啡肽、血管紧张肽、促甲状腺素释放激素(TRH)、肿瘤坏死因子(TNF)、肿瘤坏死因子相关凋亡诱导配体(TRAIL)、肝素酶、骨形态发生蛋白(BMP)、人心房促尿钠排泄肽(hANP)、胰高血糖素样肽(GLP-1)、肾素、缓激肽、杆菌肽、多粘菌素、粘菌素、短杆菌酪肽、短杆菌肽、环胞菌素及其合成类似物、单克隆抗体、抗体、改善或显示相同药物作用的物质、酶和细胞因子;
所述疫苗是肝炎疫苗;
所述基因是一种或多种选自以下的物质:小干扰RNA(siRNA)、质粒DNA和反义寡脱氧核苷酸(AS-ODN);
所述激素是一种或多种选自以下的物质:睾酮、雌二醇、孕酮、前列腺素及其合成类似物;
所述抗癌药物是一种或多种选自以下的物质:紫杉醇、多柔比星、5-氟尿嘧啶、顺铂、卡铂、奥沙利铂、替加氟、伊立替康、多西他赛、环磷酰胺、吉西他滨、异环磷酰胺、丝裂霉素C、长春新碱、依托泊苷、甲氨蝶呤、托泊替康、他莫昔芬、长春瑞滨、喜树碱、道诺霉素、苯丁酸氮芥、苔鲜抑素-1、加里刹霉素、美登素、左旋咪唑、DNA重组干扰素α-2a、米托蒽醌、尼莫司汀、干扰素α-2a、去氧氟尿苷、福美坦、醋酸亮丙立德、醋酸甲地孕酮、卡莫氟、替尼泊苷、博来霉素、卡莫司汀、庚铂、依西美坦、阿那曲唑、雌莫司汀、卡培他滨、醋酸戈舍瑞林、海藻酸钾、醋酸甲羟孕酮、表柔比星、来曲唑、吡柔比星、托泊替康、六甲蜜胺、柠檬酸托瑞米芬、BCNU、泰索帝、放线菌素D、聚乙二醇-蛋白缀合物及其合成类似物;和
所述血管发生抑制剂是一种或多种选自以下的物质:BMS-275291、氯膦酸盐、6-脱氧-6-去甲基-4-脱二甲基氨基四环素、强力霉素、马立马司他、2-甲氧基雌二醇、角鲨胺、SU5164、沙利度胺、TNP-470、考布他汀A4、大豆异黄酮、Enzastaurin、CC5013、塞来考昔、ZD 6474、氢溴酸卤夫酮、干扰素-α、贝伐单抗、AE-941、白介素-12、VEFG-trap、西妥昔单抗及其合成类似物。
13.权利要求9的递送生物活性分子的组合物,其中所述细胞是一种或多种选自以下的细胞:早幼成骨细胞、软骨细胞、脐静脉内皮细胞(UVEC)、成骨细胞、成熟干细胞、神经鞘细胞、少突神经胶质细胞、肝细胞、壁细胞(与UVEC联用)、成肌细胞、胰岛素-分泌细胞、内皮细胞、平滑肌细胞、成纤维细胞、β-细胞、内胚层细胞、肝干细胞、球旁细胞、骨骼肌细胞、角质细胞、黑素细胞、郎氏细胞、梅克尔细胞、成皮细胞和早幼脂肪细胞。
14.权利要求9的递送生物活性分子的组合物,所述组合物通过选自以下的给药途径给予:肠道外给药、经眼给药;注射到软骨组织、骨组织、脂肪组织或癌组织;吸入、经皮给药、阴道给药、尿道给药、直肠给药、含服给药、口服给药、肺部给药、经耳给药、肌肉给药、皮下给药和静脉内给药。
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- 2006-11-03 EP EP06812411.4A patent/EP2001513B1/en not_active Not-in-force
- 2006-11-03 US US11/568,852 patent/US8287888B2/en active Active
- 2006-11-03 WO PCT/KR2006/004574 patent/WO2007114549A1/en active Application Filing
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Cited By (15)
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CN103554507B (zh) * | 2013-10-23 | 2015-10-14 | 上海交通大学 | 一种可用于腰椎间盘突出手术的聚膦腈医用支架的制备方法 |
CN103554507A (zh) * | 2013-10-23 | 2014-02-05 | 上海交通大学 | 一种可用于腰椎间盘突出手术的聚膦腈医用支架的制备方法 |
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CN106065079A (zh) * | 2016-06-08 | 2016-11-02 | 江苏华昌织物有限公司 | 一种用于药物缓释的聚磷腈高分子的制备方法 |
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CN109771658A (zh) * | 2017-11-14 | 2019-05-21 | 博瑞生物医药(苏州)股份有限公司 | 靶向多臂偶联物 |
CN108096630A (zh) * | 2018-01-29 | 2018-06-01 | 暨南大学 | 一种载淫羊藿苷和去铁胺的聚乳酸基骨组织支架及制备方法和应用 |
CN108096630B (zh) * | 2018-01-29 | 2020-09-04 | 暨南大学 | 一种载淫羊藿苷和去铁胺的聚乳酸基骨组织支架及制备方法和应用 |
CN109762150A (zh) * | 2018-12-14 | 2019-05-17 | 华南理工大学 | 一种具有内在荧光特性可降解生物医用材料及其制备方法 |
CN109432051A (zh) * | 2018-12-25 | 2019-03-08 | 浙江大学 | 一种具有抗卵巢癌活性的靶向纳米粒及制备和应用 |
CN111494711A (zh) * | 2019-01-31 | 2020-08-07 | 华东理工大学 | 干细胞发生器产生的干细胞用于治疗造血损伤 |
CN111494711B (zh) * | 2019-01-31 | 2023-06-23 | 华东理工大学 | 干细胞发生器产生的干细胞用于治疗造血损伤 |
CN111297799A (zh) * | 2019-04-12 | 2020-06-19 | 浙江大学 | 一种多肽蛋白类药物的缓释组合物制剂及其制备方法 |
CN111297799B (zh) * | 2019-04-12 | 2021-12-03 | 浙江大学 | 一种多肽蛋白类药物的缓释组合物制剂及其制备方法 |
Also Published As
Publication number | Publication date |
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CN101460198B (zh) | 2013-08-07 |
EP2001513A4 (en) | 2013-02-13 |
WO2007114549A1 (en) | 2007-10-11 |
JP2009532554A (ja) | 2009-09-10 |
EP2001513B1 (en) | 2016-06-01 |
JP5124561B2 (ja) | 2013-01-23 |
US8287888B2 (en) | 2012-10-16 |
EP2001513A1 (en) | 2008-12-17 |
KR100746962B1 (ko) | 2007-08-07 |
US20090181088A1 (en) | 2009-07-16 |
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