CN114409887B - 一种氟化端基两亲性聚合物、其制备方法及应用 - Google Patents
一种氟化端基两亲性聚合物、其制备方法及应用 Download PDFInfo
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- CN114409887B CN114409887B CN202111533789.3A CN202111533789A CN114409887B CN 114409887 B CN114409887 B CN 114409887B CN 202111533789 A CN202111533789 A CN 202111533789A CN 114409887 B CN114409887 B CN 114409887B
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Classifications
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及纳米生物材料领域,公开一种氟化端基两亲性聚合物、其制备方法及应用,聚合物如式(I)或式(II)所示,其制备方法包括:在催化剂作用下将两亲性聚合物与氟化物反应得到。该两亲性聚合物能够在水溶液中自组装形成胶束,具有更低的CMC、与白蛋白作用时更好的稳定性等特性。作为药物载体包封脂溶性抗肿瘤药物后,能够达到药物缓释的效果,减少药物在体内的突释,同时在体内能够延长药物的血液循环时间,有助于肿瘤部位的蓄积,从而达到更好的治疗效果。
Description
技术领域
本发明涉及纳米生物材料领域,具体涉及一种氟化端基两亲性聚合物、其制备方法及应用。
背景技术
癌症是由突变细胞产生的疾病,这种突变细胞具有无限增殖和逃避细胞凋亡的能力,最终导致肿瘤形成并侵入周围组织(也称为转移)。2018年癌症仍然是全球第二大死亡原因,约有960万人死亡,占六分之一。目前,临床上治疗癌症除手术治疗外还是很大程度上依赖于放疗和化疗。
近年来,随着纳米技术的发展,聚合物纳米胶束作为纳米药物输送体系已成为增加化疗药物靶向性、降低毒副作用、提高疗效的有效途径之一。纳米胶束载药系统显示出了很多优点,包括:1)可以高剂量输送治疗药物;2)延长药物半衰期;3)可以针对细胞或组织以特定的方式靶向递送药物;4)实现可控释放、按需释放;5)可以同时递送多种类型的药物或诊断试剂进行联合治疗。然而,胶束载体进入体内后会经历一系列内环境变化,包括血液稀释效应、血液中的pH与离子浓度的变化对其影响等,这些都有可能导致胶束的解体,药物提前释放,从而减弱药物富集效果,导致严重的毒副作用,因此纳米胶束的稳定性是最终实现其药物富集能力的关键因素之一。
两亲性聚合物是较为常见的制备载药胶束的材料,具有良好的生物相容性,可再生来源,低水平的免疫原性和毒性,有多种材料作为载体的药物已被FDA批准进入临床,例如Genexol-PM为PEG-PLA包载紫杉醇形成的胶束,用于治疗多种的癌症;由多西他赛与PEG-PLA组成的BIND-014纳米粒子系统,靶向前列腺特异性膜抗原(PSMA),显著提高药物在体内的循环时间。但是,与小分子药物相比,聚合物胶束载药系统在临床上的治疗效果并没有得到提高,其原因是胶束作为聚合物链的动态聚集体,进入血液系统会很快解离,释放所携载的药物,使得到达肿瘤部位的胶束/药物较少,因此提高胶束在血液中的稳定性是纳米胶束临床转化的迫切需求。
CN103156811 A公开了一种具有磷酸钙壳的两亲性聚合物载药胶束的制备方法,该方法在两亲性聚合物载药胶束外包载钙离子,提高胶束的稳定性并改善药物突释现象,但其存在包载钙离子易脱落,包覆不完全,稳定性提升不高的问题;CN105801873A公开,该发明采用两亲性二元分子刷聚合物构筑稳定的pH响应性单分子纳米胶束,解决了多分子纳米胶束因为其浓度,剪切力等其他因素的作用而解体的问题,但其对两亲性聚合物的结构存在很大限制。
发明内容
本发明目的在于解决纳米胶束易解离的缺陷,采用氟化端基修饰两亲性聚合物,增强聚合物胶束在血液中的稳定性,得到的聚合物胶束具有更低的临界胶束浓度,包封脂溶性抗肿瘤药物后,能够达到药物缓释的效果,减少药物在体内的突释。
为实现上述目的,本发明采用的技术方案是:
一种氟化端基两亲性聚合物,如式(I)或式(II)所示:
其中,为两亲性聚合物,A为亲水聚合物链段,B为疏水聚合物链段;所述氟化端基如式(I-1)或(II-1)所示:
其中R为任一取代基,z为1-10的整数;(II)中R取代基数与F取代数之和为5;X为连接含氟基团到疏水链端基的功能基团。
本发明在两亲性聚合物的疏水端引入氟化端基,由于氟原子较大的电负性,在粒径相同的情况下,氟化端基修饰后的两亲性聚合物能够在水溶液中自组装形成胶束,相较于原材料形成的胶束具有更低的临界胶束浓度(CMC)、与白蛋白作用时更好的稳定性等特性。作为药物载体包封脂溶性抗肿瘤药物后,能够达到药物缓释的效果,减少药物在体内的突释,同时在体内能够延长药物的血液循环时间,有助于肿瘤部位的蓄积,从而达到更好的治疗效果。
进一步地,所述X包括但不限于酯基,酰胺基,碳酸酯基,醚基,硫醚基中任一种。
进一步地,所述亲水聚合物链段选自聚乙二醇(mPEG)、聚乙烯基吡咯烷酮(PVP)、聚乙烯醇(PVA)或聚丙烯酸(PAA)等中的一种或多种的组合,其分子量为2000-20000,优选2000-5000。
进一步地,所述疏水聚合物链段选自聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚己内酯(PCL)、聚乙醇酸(PGA)或聚谷氨酸苄酯(PBLG)等中的一种或者多种的组合,其分子量为2000-20000,优选2000-5000。
进一步地,所述两亲性聚合物包括PEG-PLA、PAA-PLGA、PVP-PLA其中的一种。
优选地,所述氟化端基的来源包括七氟丁酸酐、七氟丁酸、七氟丁酰氯、五氟丙酸酐、五氟丙酸、五氟丙酰氯、九氟戊酸酐、九氟戊酸、九氟戊酰氯、3,4-二氟苯甲酸、3,4,5-三氟苯甲酸、2,3,4,5-四氟苯甲酸、2,3,4,5,6-五氟苯甲酸其中至少一种。
另一方面,本发明还提供所述的氟化端基两亲性聚合物的制备方法,包括:在催化剂作用下,将两亲性聚合物与氟化物反应得到如式(I)或式(II)所示的聚合物。
所述氟化物包括七氟丁酸酐、七氟丁酸、七氟丁酰氯、五氟丙酸酐、五氟丙酸、五氟丙酰氯、九氟戊酸酐、九氟戊酸、九氟戊酰氯、3,4-二氟苯甲酸、3,4,5-三氟苯甲酸、2,3,4,5-四氟苯甲酸、2,3,4,5,6-五氟苯甲酸其中至少一种;
所述催化剂包括4-二甲氨基吡啶、三乙胺、二异丙基乙胺、N-甲级吗啉中至少一种。
进一步地,反应在有机溶剂中进行,所述有机溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、二氧六环、二甲基亚砜、四氢呋喃中任一种或多种的组合。
进一步地,所述两亲性聚合物与催化剂的摩尔比为1:0.1-2;两亲性聚合物与氟化物的摩尔比为1:2-10,包括1:2.5、1:3、1:4、1:5、1:5.5、1:6、1:7、1:8、1:9等;反应时间为12-24h,包括14h、16h、18h、20h、22h,反应温度为室温。
另一方面,本发明还提供一种纳米胶束,由包括所述的氟化端基两亲性聚合物在水中自组装形成。在形成纳米胶束过程中,可添加治疗抗肿瘤药物。优选地,纳米胶束的粒径为50-250nm。
第三方面,本发明还提供所述氟化端基两亲性聚合物作为药物载体的应用,由于两亲性聚合物端基经氟化物改性,其具有较强的疏水/疏油性,在粒径相同的情况下,具有更低的CMC、与白蛋白作用时更好的稳定性等特性。
进一步地,所述氟化端基两亲性聚合物在制备抗肿瘤药物中的应用。
另一方面,本发明还提供一种药物,包括所述氟化端基两亲性聚合物;其制备过程包括:将聚合物和脂溶性抗肿瘤药物混合,溶剂挥干成膜,在超声状态下加入去离子水,超声时间为0.5-1h,即得所述药物。该聚合物包封脂溶性抗肿瘤药物后,能够达到药物缓释的效果,减少药物在体内的突释,同时在体内能够延长药物的血液循环时间,有助于肿瘤部位的蓄积,从而达到更好的治疗效果。
所述脂溶性抗肿瘤药物包括阿霉素、5-氟尿嘧啶、紫杉醇(PTX)、姜黄素、甲氨蝶呤其中的一种。
与现有技术相比,本发明具有以下有益效果:
(1)本发明提供的氟化端基两亲性聚合物能够在水溶液中自组装形成胶束,相较于原材料形成的胶束,由于氟原子较大的电负性,在粒径相同的情况下,具有更低的CMC、与白蛋白作用时更好的稳定性等特性。作为药物载体包封脂溶性抗肿瘤药物后,能够达到药物缓释的效果,减少药物在体内的突释,同时在体内能够延长药物的血液循环时间,有助于肿瘤部位的蓄积,从而达到更好的治疗效果。
(2)本发明提供的氟化端基两亲性聚合物的制备方法条件温和、操作简单、产率较高,能够扩大量生产,可有效应用于工业生产中。
(3)本发明提供的两亲性聚合物能够有效应用于抗肿瘤领域,尤其适用于作为载体实现肿瘤化疗药物的递送。
附图说明
图1为实施例1-3制备的氟化端基两亲性聚合物核磁氟谱图;
图2为应用例1中空载胶束的粒径分布图;
图3为应用例2中P3空载胶束与BSA孵育后的胶束粒径随不同时间变化图;
图4为应用例2中P3-HFA空载胶束与BSA孵育后的胶束粒径随不同时间变化图;
图5为应用例2中P3与BSA孵育后荧光发射光谱随时间的变化图;
图6为应用例2中P3-HFA与BSA孵育后荧光发射光谱随时间的变化图;
图7为应用例3中载药胶束的粒径分布图;
图8为应用例3中P3与P3-HFA的细胞生存曲线图;
图9为应用例3中载药胶束在不同条件下的体外释放PTX曲线;
图10为应用例3中载药胶束的血药清除百分比趋势线。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。本领域技术人员在理解本发明的技术方案基础上进行修改或等同替换,而未脱离本发明技术方案的精神和范围,均应涵盖在本发明的保护范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
制备氟化端基两亲性聚合物P1-HFA
其中,x嵌段为PAA,分子量为3000,m和n为PLGA的嵌段,PLGA分子量为3000。
在单口烧瓶中加入1g的PAA-PLGA和0.1g 4-二甲氨基吡啶(DMAP)和10mL二氯甲烷,在冰浴的条件下搅拌使其溶解。在恒压滴液漏斗中加入10mL二氯甲烷和0.15g的五氟丙酰氯,在冰浴条件下,缓慢滴入烧瓶中。滴加完毕后,恢复至常温反应12h。反应结束后将反应液用无水乙醚沉淀洗涤三次,过滤得到最终产物P1-HFA。
实施例2
制备氟化端基两亲性聚合物P2-HFA
其中,x嵌段为分子量2000的PVP,y嵌段为分子量5000的PLA。
在单口烧瓶中加入1.2g的PVP-PLA和0.06g DMAP、1.0g二环己基碳二亚胺和10mL乙腈,在冰浴的条件下搅拌使其溶解。在恒压滴液漏斗中加入10mL乙腈和0.20g的九氟戊酸(HFAA),在冰浴条件下,缓慢滴入烧瓶中。滴加完毕后,恢复至常温反应24h。反应结束后将反应液用无水乙醚沉淀洗涤三次,过滤得到最终产物P2-HFA。
实施例3
制备氟化端基两亲性聚合物P3-HFA
其中,x嵌段为PEG,分子量5000,y嵌段为PLA,分子量3000,z为2。
在单口烧瓶中加入0.8g的mPEG-PLA和0.05g DMAP和10mL四氢呋喃,在冰浴的条件下搅拌使其溶解。在恒压滴液漏斗中加入10mL四氢呋喃和0.26g的七氟丁酸酐(HFAA),在冰浴条件下,缓慢滴入烧瓶中。滴加完毕后,恢复至常温反应24h。反应结束后将反应液用无水乙醚沉淀洗涤三次,过滤得到最终产物P3-HFA。
将实施例1-3制备的三种聚合物分别取10mg溶解于氘代氯仿中,用于19F NMR测定分析,实验结果如图1所示,核磁氟谱中的峰,全都成功归属,表明氟化端基的成功修饰。
应用例1
空载胶束的制备及表征
分别取10mg将实施例1-3制备的聚合物(P1-HFA、P2-HFA、P3-HFA)及未修饰前的聚合物(P1-P3)在1.5mL离心管中,用1mL N,N’-二甲基甲酰胺(DMF)在超声状态下使其充分溶解,缓慢将其滴入到超声状态下的5mL超纯水中。滴加完毕后继续搅拌2h,随后用滴管将溶液滴入3500KD透析袋在超纯水中透析,除去DMF,透析48h。透析结束后,用0.22μm滤膜过滤,4℃保存。
胶束的粒径大小通过动态光散射仪(DLS)进行测定:取聚合物胶束样品在测试温度25℃下预热2min,然后进行测试,结果如图2所示。可见修饰前后的不同分子量的聚合物形成的胶束粒径大都分布在100nm左右,说明氟化端基的修饰对胶束的粒径影响不大。
应用例2
①空载胶束与白蛋白(BSA)孵育后的粒径变化
将应用例1中P3和P3-HFA制备的胶束浓缩后与BSA溶液混合,使最终胶束浓度与BSA浓度均为8mg/ml,将混合溶液置于常温搅拌孵育,分别在不同时间点用动态光散射仪(DLS)检测粒径变化情况。P3的结果如图3所示,端基未修饰的胶束在30min时峰型变宽,说明胶束结构出现不稳定,可能是胶束与白蛋白之间的相互结合,在60min时在1000nm左右出现第二个峰,说明胶束发生解离。而修饰上氟化端基的P3-HFA(如图4所示)则在孵育的6h内基本保持较好的单一峰。实验结果说明修饰氟化端基后,由于氟原子较大的电负性,增强了胶束疏水核中的相互作用力,有效减少了胶束与BSA的结合导致的胶束解离。
②CMC测定
取30ul溶于二氯甲烷的尼罗红于菌种瓶中,无盖避光条件下使其挥发,在各菌种瓶中分别加入不同浓度的胶束水溶液3ml,使尼罗红的终浓度为10-6M,搅拌过夜,在酶标仪上以540nm为激发波长,检测发射波长630nm处的荧光强度。绘图拟合得到两条直线,二者的交点即为聚合物的CMC。在各组中加入BSA,的最终浓度为40mg/ml,测试胶束的CMC。
结果如表1所示,修饰了氟化端基的各聚合物CMC均明显降低,其中P3胶束更是从41.70μg/ml降低至4.87μg/ml,使聚合物在更低浓度下就能以胶束形式存在,明显提高胶束的稳定性。所有聚合物与BSA孵育后CMC均有提高,这说明BSA与胶束的相互结合,导致需要更高浓度的聚合物链段相互作用才能形成胶束。而修饰了氟化端基后的聚合物的CMC则基本保持不变,这归功于氟原子较强的电负性,明显增加了胶束疏水核内部的相互作用力,减少了胶束与BSA之间的结合,增加了胶束在血液中的稳定性。
表1 各两亲性聚合物的临界胶束浓度
聚合物 | CMC(ug/mL) | 与BSA作用后CMC(ug/mL) |
P1 | 31.94 | 49.80 |
P1-HFA | 19.73 | 23.58 |
P2 | 11.91 | 24.66 |
P2-HFA | 8.53 | 9.51 |
P3 | 41.70 | 73.55 |
P3-HFA | 19.73 | 23.58 |
③荧光共振能量转移
P3-Cy5、P3-HFA-Cy5的制备
在圆底烧瓶中依次加入P3或P3-HFA(0.25mmol)、戊二酸酐(1.2mmol)。随后,加入THF溶液10ml,吡啶2ml,在40℃下搅拌反应12h,反应结束后,用乙醚沉淀三次,离心并真空干燥得到产物P3-COOH或P3-HFA-COOH。
将P3-COOH或P3-HFA-COOH溶解在20ml THF溶液中,再加入NHS(2.6mmol)、DCC(1.9mmol),400C搅拌反应12h。随后,再加入乙二胺(1.5mmol)40℃继续反应12h。反应结束后,过滤溶液,在大量乙醚中沉淀洗涤3次,离心干燥后得到产物P3-NH2或P3-HFA-NH2。
将P3-NH2或P3-HFA-NH2(2.5mmol)溶解在1ml THF溶液中,加入100μl Cy5-NHS(1mg/ml)的DMSO溶液,避光搅拌反应过夜。所得溶液透析并冷冻干燥冻干,得到蓝色粉末P3-Cy5或P3-HFA-Cy5。
P3-Cy5、P3-HFA-Cy5分别与BSA-Cy5.5混合,使BSA的最终浓度为40mg/ml。将混合溶液避光常温搅拌孵育,在不同时间点使用酶标仪以640nm为激发光,记录640-800nm的发射光光谱。
实验结果如图5-6所示,P3胶束在与白蛋白孵育1h时发生荧光共振能量转移,说明胶束与白蛋白之间确实存在相互作用,使得Cy5与Cy5.5之间的距离小于10nm,同时随着孵育时间的推移,Cy5.5的荧光越来越强,说明两者间的相互作用越来越多。反之,修饰了氟化端基的聚合物胶束P-HFA在4h时荧光发射光谱在710nm也仅出现了一个小峰,说明仅有一小部分胶束与白蛋白结合解离,大部分聚合物仍保持胶束状态存在,这与上述粒径测试的结果相符。进一步说明了氟化端基的修饰明显减少了聚合物与白蛋白的相互作用,提高了胶束的稳定性。
应用例3
载药胶束的制备与表征
以PTX为模型药物作为实施例。采用薄膜水化法包载化疗药物PTX:将聚合物(10mg)和PTX(1mg)溶于1ml乙腈中,40℃减压旋转蒸发,使溶剂挥干成膜,缓慢加入等温的3ml去离子水,加入完毕后,持续超声30min,超声结束后将胶束放入4℃静置过夜,第二天用0.22μm滤膜过滤,4℃冷藏保存。胶束的粒径大小通过DLS进行测定,结果如图7所示。修饰前后的P2和P3形成的载药胶束粒径大都分布在100-200nm左右,证明氟化端基的修饰对载药胶束的粒径基本无影响。
性能测试
①载药胶束的细胞毒性
将4T1细胞培养至生长对数期,用0.25%胰酶-EDTA将细胞全部消化,使用血细胞计数板计算细胞数量后,以5000细胞/孔的密度铺96孔板,置于二氧化碳培养箱中培养24h后,以培养基作为溶剂配置浓度梯度为1024nΜ-4nM不等的胶束溶液,按从低到高的浓度每孔加入100μL含药培养液,每种药物做6个平行组,给药培养24h。采用MTT细胞毒性检测试方法。用酶标仪在570nm处测定吸光度OD值,计算细胞存活率,并计算IC50值。
结果如图8所示,P3与氟化端基修饰后P3-HFA的聚合物的细胞生存曲线不存在显著差异,同时根据存活曲线计算可得IC50分别为529.30nM和442.60nM,两者相差并不明显,说明氟化端基的修饰不会改变胶束对癌细胞的杀伤能力。
②载药胶束的药物释放曲线
配置PBS缓冲液(0.01M,PH 7.4和PH 5.4),并加入0.5%的吐温-80,将2ml载药胶束溶液P3和P3-HFA置于Mw=3500的透析袋内,释放介质体积为20ml,置于37℃的恒温摇床中孵育,转速为100rpm,在实验设定时间点分别取样1ml,并补加等体积释放介质,所取样品冷冻干燥后,超声溶解于1ml乙腈中,离心后取上清液用0.22μm滤膜过滤,HPLC法定量分析PTX的含量,计算药物累积释放百分率,绘制释放曲线。
结果如图9所示,P3胶束在PH 7.4的PBS溶液中,在6h内快速释放超过50%的药物,6h后趋于平稳释放,48h时释放60%左右的药物。在PH 5.4的PBS中6h后进一步加快释放,48h释放70%的药物。修饰了氟化端基的P3-HFA胶束释放明显减缓,在PH 7.4的PBS缓冲溶液中6h时仅释放30%左右药物,12h达到释放最高值,累计释放50%的药物。在PH 5.4的PBS缓冲溶液中也是相同的释放规律。上述实验结果充分说明了,修饰氟化端基可以有效增加载药胶束的稳定性,减少PTX的突释,缓慢释放药物,减少药物在非靶标器官的非特异性释放。
③血液清除实验
PTX纳米药物的药物代谢动力学研究是以周龄6-7周(体重约20g)的ICR小白鼠为动物模型,每组设三只动物做平行实验。纳米胶束溶液(PTX当量浓度为10mg/kg)给药后2min、10min、0.5h、1h、2h、4h、6h后分别取样,立即5000rpm,4℃条件下离心10min,取血浆上清保存于-20℃冰箱直至HPLC检测。
本实验釆用两倍血浆体积的乙腈沉淀蛋白,振荡5min,然后10000rpm,4℃条件下离心5min,然后取上清液置于-80℃冰箱中冷冻处理半小时,取出融化后再10000rpm,4℃条件下离心2分钟,取上清液直接用于HPLC进样检测。检测条件为C18柱(4.6×250mm,Waters,Ireland),流动相为色谱级纯乙腈:水=60:40(v/v),柱温35℃,检测波长为227nm,流速为1.0ml/min。最后根据定量得到血液中药物浓度。
实验结果如图10所示,与P3载药胶束相比,氟化端基修饰的P3-HFA载药胶束的体内循环时间更长。采用二室模型计算药代动力学参数,汇总于表2。药代动力学参数显示,氟化端基修饰的载药胶束P3-HFA的血液分布相半衰期(T1/2 alpha)延长了2.4倍,消除相半衰期(T1/2 beta)延长了约1.3倍,AUC增加了1.3倍。因此,氟化端基修饰的载药胶束体内清除速率较慢,具有优于P3载药胶束的药物代谢动力学特征。P3-HFA载药胶束具有相似的载药量和粒径,可能通过氟化端基与药物间的相互作用和氢键形成包覆更紧密的内核,增强体内稳定性,较长的循环时间有助于肿瘤部位的蓄积,从而达到更好的治疗效果。
表2 药代动力学参数
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,所述氟化端基两亲性聚合物如式(I)所示:
其中,为两亲性聚合物,A为亲水聚合物链段,B为疏水聚合物链段;所述氟化端基如式(I-1)所示:
所述氟化端基的来源包括七氟丁酸酐、七氟丁酸、七氟丁酰氯、五氟丙酸酐、五氟丙酸、五氟丙酰氯、九氟戊酸酐、九氟戊酸、九氟戊酰氯中至少一种;X为连接含氟基团到疏水链端基的功能基团,包括酯基,酰胺基,碳酸酯基,醚基,硫醚基中任一种。
2.根据权利要求1所述的氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,其特征在于,所述亲水聚合物链段选自mPEG、PVP、PVA或PAA中的一种或多种的组合,其分子量为2000-20000;所述疏水聚合物链段选自PLA、PLGA、PCL、PGA或PBLG中的一种或者多种的组合,其分子量为2000-20000。
3.根据权利要求1或2所述的氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,其特征在于,所述氟化端基两亲性聚合物的制备方法包括:在催化剂作用下,将两亲性聚合物与氟化物反应得到如式(I)所示的聚合物。
4.根据权利要求3所述的氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,其特征在于,所述氟化物包括七氟丁酸酐、七氟丁酸、七氟丁酰氯、五氟丙酸酐、五氟丙酸、五氟丙酰氯、九氟戊酸酐、九氟戊酸、九氟戊酰氯、中至少一种;所述催化剂包括4-二甲氨基吡啶、三乙胺、二异丙基乙胺、N-甲基吗啉中至少一种。
5.根据权利要求3所述的氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,其特征在于,反应在有机溶剂中进行,所述有机溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、二氧六环、二甲基亚砜、四氢呋喃中任一种或多种的组合。
6.根据权利要求3所述的氟化端基两亲性聚合物在制备抗肿瘤药物中的应用,其特征在于,所述两亲性聚合物与催化剂的摩尔比为1:0.1-2;两亲性聚合物与氟化物的摩尔比为1:2-10;反应时间为12-24h,反应温度为室温。
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