CN115844822B - 一种口服载药胶束组合物及其制备方法 - Google Patents
一种口服载药胶束组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种口服载药胶束组合物及其制备方法,该载药胶束组合物包含:由甘氨胆酸修饰的PLGA‑PEG高聚物,记为PLGA‑PEG‑GCA,及,疏水性小分子药物;其中,GCA‑PLGA‑PEG的疏水端PLGA聚集,包裹所述疏水性小分子药物,GCA‑PLGA‑PEG的亲水端向远离疏水端PLGA的方向伸展,形成球形载药胶束。本发明采用GCA修饰的PLGA‑PEG高聚物包裹疏水性小分子药物,得到胶束类纳米药物。实验证明,本发明的载药胶束组合物提高了疏水性小分子药物的口服生物利用度,在减少给药剂量的同时,能够实现更优的抗肿瘤治疗效果。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种口服载药胶束组合物及其制备方法。
背景技术
自20世纪40年代发现氮芥可用于治疗恶性肿瘤后,近几十年来化疗药物已经有了长足发展。其中,抗代谢药在癌症等肿瘤化学治疗领域中起着重要作用,越来越多被FDA批准上市。
抗代谢药物的化学结构与代谢物很相似,可与代谢必须的酶竞争性结合,抑制嘌呤、嘧啶及嘧啶核苷等的代谢途径;或作为伪代谢物与DNA形成假的无功能生物大分子,即导致所谓的致死性合成,从而使肿瘤细胞丧失功能而死亡。
吉西他滨(Gemcitabine)结构式如下:
其CAS号:95058-81-4,作为胞嘧啶衍生物类的抗代谢药物,自1996年被FDA批准上市至今,由于其廉价易得特性被广泛应用于包括癌症在内的多种癌症治疗中。该药物能够在细胞内转化为活性的三磷酸核苷类似物,抑制DNA多聚酶而阻断DNA合成,进而抑制肿瘤细胞的生长。但是,在实际使用过程中,该药物效果会受到多种因素影响而大打折扣,其中一个典型缺陷就是无法口服。吉西他滨及其类似物由于胞嘧啶片段中4号位氨基的存在,极易在肝脏中经胞嘧啶脱氨酶脱氨发生首过代谢,转化为无活性的尿嘧啶吉西他滨,使得吉西他滨口服效果差。因此,吉西他滨通常采用静脉连续滴注给药。然而,这一给药方式极大影响便捷性与临床应用。
为了克服上述问题,研究者对其结构进行了大量研究和改造以尝试实现口服给药,其中大多数都集中在前药策略上。然而,吉西他滨的直接化学结构修饰往往需要花费更复杂的合成路线;并且由于对小分子活性位点的结构改变,可能会导致意外的副作用。2009年礼来公司将胞嘧啶氨基改造为丙戊酰胺制得前药LY2334737,提高了吉西他滨的口服生物利用度,相对稳定的酰胺键能够在体内羧酸酯酶的作用下缓慢水解而发挥药效。这一结构改造有效减弱了肝脏脱氨酶对吉西他滨类药物的首过代谢影响。但是该候选化合物因在临床试验中出现较为严重的毒副作用,礼来公司于2013年终止了研发工作。时至今日,吉西他滨类药物口服给药的临床问题依然未被有效解决。
发明内容
本发明的目的是解决吉西他滨类药物难以口服给药的问题,提供一种载药胶束组合物,其给药载体经甘氨胆酸(GCA)修饰,利用肠道胆汁酸转运体提高药物的口服利用度,实现口服给药。
为了达到上述目的,本发明提供了一种口服载药胶束组合物,其包含:
由甘氨胆酸(GCA)修饰的PLGA-PEG高聚物,记为PLGA-PEG-GCA,及,
疏水性小分子药物;
其中,GCA-PLGA-PEG的疏水端PLGA聚集,包裹所述疏水性小分子药物,GCA-PLGA-PEG的亲水端向远离疏水端PLGA的方向伸展,形成球形载药胶束。
可选地,PLGA-PEG-GCA中,PLGA片段的分子量为8000Da-12000Da;PLGA-PEG-GCA中,PEG片段的分子量为3000Da-7000Da。
可选地,所述球形载药胶束粒径为20-200nm。
可选地,所述疏水性小分子药物包含:吉西他滨、阿霉素、柔霉素、表阿霉素、去甲阿霉素、缬霉素、蒽环类药物、放线菌素-D、博莱霉素、丝裂霉素-C、环磷酰胺、甲氯沙明、乌拉莫司汀、美法兰、氯霉素、异环磷酰胺、苯达莫司汀、卡马斯汀、洛莫司汀、链霉素、布沙凡、达卡巴嗪、替莫唑胺、硫代帕、阿曲他明、顺铂、卡铂、奈达铂、奥沙利铂、沙他铂、四硝酸三铂、5-氟尿嘧啶、6-巯基嘌呤、卡培他滨、克拉比滨、氯法拉滨、胱氨酸滨、氟尿嘧啶、氟达拉滨、羟脲、甲氨蝶呤、培美曲塞、戊他汀、硫鸟嘌呤;喜树碱、拓泊替康、伊立替康、依托泊苷、替尼泊苷、米托蒽醌、紫杉醇、多西他赛、依扎比酮、长春碱、长春新碱、长春地辛、长春瑞滨、***及其衍生物的一种或多种。
可选地,所述口服载药胶束中,疏水性小分子药物的载药率为11%-20%,以质量比计。
可选地,所述口服载药胶束中,疏水性小分子药物的包封率为70%-90%,以质量比计。
本发明还提供了一种上述的口服载药胶束组合物的制备方法,其包含:
步骤1,采用甘氨胆酸(GCA)修饰PLGA-PEG-COOH制备PLGA-PEG-GCA;
步骤2,将疏水性小分子药物、PLGA-PEG-GCA以1:5~1:10的质量比例加入到有机溶剂中溶解,在超声作用下,滴加到蒸馏水中,乳化形成包裹所述疏水性小分子药物的胶束,纯化、过滤,得到口服载药胶束。
可选地,所述步骤1包含:
步骤1.1,以甘氨胆酸(GCA)、乙二胺(EDA)为原料,在缩合剂作用下,常温反应制备GCA-EDA;
步骤1.2,氮气保护下,将PLGA-PEG-COOH的羧基活化,加入GCA-EDA,常温反应6h-12h,纯化处理,得到PLGA-PEG-GCA。
可选地,所述纯化步骤包含:通过蒸馏水进行透析,分子量12k Da-16kDa,纯化24h-72h,以除去游离在胶束外的疏水性小分子药物。
可选地,步骤2中,还加入PLGA。
本发明通过GCA修饰的PLGA-PEG高聚物包裹疏水性小分子药物(如,吉西他滨),得到的胶束类纳米药物。通过大鼠体内药动学等实验,证明能够提高吉西他滨口服生物利用度,通过体外细胞毒测试和小鼠体内药效学等实验,证明在减少给药剂量的同时,能够实现化疗药物吉西他滨的口服给药并发挥胰腺癌治疗效果。
附图说明
图1为本发明的一种口服载药胶束组合物的结构示意图。
图2为本发明的PLGA10K-PEG5k-GCA(PPG)聚合物的1H NMR图谱。
图3为本发明的实施例1-2、对比例1制备的3种吉西他滨胶束的TEM电镜图。其中,A代表Gem-PPG60,B代表Gem-PPG100,C代表Gem-PP100。
图4为本发明的实施例1-2、对比例1制备的3种吉西他滨胶束的体外释放测试图。
图5为BxPC-3荷瘤小鼠33天内肿瘤大小的进展情况示意图。
图6为BxPC-3荷瘤小鼠33天内体重变化情况示意图。
具体实施方式
胆汁酸的肠肝循环由两个主要过程组成:肝脏分泌和肠道吸收。胆汁酸分泌到十二指肠,并乳化不溶于水的营养物质,以促进肠道吸收。在远端小肠,胆汁酸通过被动扩散和主动转运吸收。被动扩散发生在小肠和结肠的近端区域,而主动转运仅限于回肠。在人类和其他脊椎动物中,回肠上皮已经发展出有效的转运机制,以回收胆汁酸。
为解决吉西他滨口服效果差的问题,本发明基于肠道胆汁酸转运机制开发口服药物制剂,开发了胆汁酸衍生物甘氨胆酸修饰的载药纳米粒子,其与小肠上皮膜的胆汁酸转运蛋白ASBT相互作用发生主动转运,从而促进所负载的小分子药物的摄取、转运和吸收。
甘氨胆酸(GCA)作为胆汁酸的重要衍生物,是人体胆汁中最丰富的成分,其logP值相对较低,能够更多地暴露于水相,因此会更加有效的被小肠膜的胆汁酸转运蛋白ASBT摄取和转运。因此,本发明使用GCA修饰的纳米粒子负载吉西他滨,能够极大促进负载小分子药物吉西他滨的胶束在小肠内被主动转运吸收,从而显著提高吉西他滨的口服生物利用度。
为了提高药物分子的缓释作用,需要GCA修饰的载药纳米粒子可选用生物可降解的医用高分子聚合物作为给药载体。本发明以PLGA-PEG高聚物作为药物分子载体示例说明。
如图1所示,为本发明的口服吉西他滨PPG胶束的结构示意图。甘氨胆酸(GCA)表面修饰的PLGA-PEG高聚物单体PLGA-PEG-GCA(简称,PPG)包含亲水端GCA、疏水端PLGA。基于相似相溶原理,疏水端由于疏水-疏水相互作用聚集成胶束,而亲水端GCA由于亲水性及位阻较大,向着远离疏水端PLGA的方向伸展。同样的原理,具有疏水性的小分子吉西他滨容易聚集到PLGA疏水端,即,被负载到PPG内,形成球形载药胶束组合物。
可以理解到,除吉西他滨外,其它疏水性小分子药物,比如吉西他滨、阿霉素、柔霉素、表阿霉素、去甲阿霉素、缬霉素、蒽环类药物、放线菌素-D、博莱霉素、丝裂霉素-C、环磷酰胺、甲氯沙明、乌拉莫司汀、美法兰、氯霉素、异环磷酰胺、苯达莫司汀、卡马斯汀、洛莫司汀、链霉素、布沙凡、达卡巴嗪、替莫唑胺、硫代帕、阿曲他明、顺铂、卡铂、奈达铂、奥沙利铂、沙他铂、四硝酸三铂、5-氟尿嘧啶、6-巯基嘌呤、卡培他滨、克拉比滨、氯法拉滨、胱氨酸滨、氟尿嘧啶、氟达拉滨、羟脲、甲氨蝶呤、培美曲塞、戊他汀、硫鸟嘌呤;喜树碱、拓泊替康、伊立替康、依托泊苷、替尼泊苷、米托蒽醌、紫杉醇、多西他赛、依扎比酮、长春碱、长春新碱、长春地辛、长春瑞滨、***及其衍生物等,也能够通过上述疏水-疏水相互作用,形成口服载药PPG胶束。该载药PPG胶束基于甘氨胆酸(GCA)的表面修饰,也能较大地促进负载的小分子药物在小肠内被主动转运吸收,从而显著提高该药物的口服生物利用度。
为了控制胶束粒径主要分布在20-200nm范围内,PLGA-PEG-GCA中,PLGA片段的分子量可以为8000Da-12000Da,本例中为10000Da,记做PLGA10k;PEG片段的分子量为3000Da-7000Da,本例中为5000Da,记做PEG5k。所述口服载药胶束中,疏水性小分子药物的载药率为11%-20%,以质量比计;疏水性小分子药物的包封率为70%-90%,以质量比计。
本发明还提供了上述口服载药胶束组合物的制备方法,包含:
步骤1,通过甘氨胆酸(GCA)修饰PLGA-PEG-COOH制备PLGA-PEG-GCA(PPG)。可以采用常规的方法,以形成酰胺的方式将GCA修饰到PLGA-PEG-COOH上。本例中,通过添加缩合剂,促进酰胺的形成,具体来说,步骤1包含:
步骤1.1,以甘氨胆酸(GCA)、乙二胺(EDA)为原料,在缩合剂作用下,常温反应制备GCA-EDA。本例中,缩合剂选择二环己基碳化二亚胺(DCC),可以理解到,其他常规的缩合剂也可以实现,本发明的实施例只是举例并非限制。该步骤中,可以EDA过量,如,可以是GCA:EDA=1:5~1:50,以质量比计。
步骤1.2,氮气保护下,将PLGA-PEG-COOH的羧基活化,加入GCA-EDA,常温反应6-12h,纯化处理,得到PLGA-PEG-GCA。所述羧基活化可以采用常规的活化方法。本例中,采用1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)作为活化剂,将PLGA-PEG-COOH的羧基活化,再与GCA-EDA常温反应,形成表面修饰的PLGA-PEG-GCA。
步骤2,将疏水性小分子药物、PLGA-PEG-GCA以1:5~1:10的质量比例加入到有机溶剂中溶解,在超声作用下,滴加到蒸馏水(该蒸馏水用量影响不大,只要能达到乳化的目的即可,本例中,疏水性小分子药物与蒸馏水的质量比为1:10000)中,乳化形成包裹所述疏水性小分子药物的胶束,纯化、过滤,除去游离在胶束外的疏水性小分子药物和/或PLGA-PEG-GCA的大分子聚集体,得到口服载药胶束。
所述纯化步骤包含:通过蒸馏水进行透析,分子量12k-16k Da,纯化24h-72h,以除去游离在胶束外的疏水性小分子药物。
为了控制胶束的粒径,步骤2中,还加入PLGA,其分子量可根据粒径大小需要选择,如为8000Da-12000Da,本例中,其分子量为10000Da。PLGA具有疏水性,基于疏水-疏水相互作用,当向疏水性小分子药物、PLGA-PEG-GCA的混合溶液中,加入PLGA后,进一步增强高聚物和小分子药物的疏水-疏水相互作用,使两者结合更加紧密,从而减小形成的胶束的空隙,降低胶束粒径。胶束粒径越小,与细胞的吸附作用越强,胶束内吞几率越大,使得胶束具有更好的口服生物利用度和药动学性质。
下面将结合附图对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
一、胶束及其高分子聚合单元的制备方法
1.材料来源
甘氨胆酸(GCA)、二环己基碳化二亚胺(DCC)、乙二胺(EDA)、N-羟基琥珀酰亚胺(NHS)、乙酸乙酯、二甲基甲酰胺(DMF)和甲醇均购自(中国上海)。1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)、二甲基亚砜(DMSO)和DMSO-d6均购自/>(中国上海)。PLGA10k,PLGA10K-PEG5k-COOH购自Tanch />(中国广州),吉西他滨购自Selleck Chemicals(中国上海),盐酸吉西他滨溶液购自CTTQ Pharma(中国南京)。
2.甘氨胆酸(GCA)修饰的PLGA-PEG聚合物(PPG)的两步合成方法
PPG的合成路线如下:
步骤1,将GCA(5500mg,1..00当量)、DCC(160mg,1.3当量)和EDA(3.2g,50当量)溶解在10mL干DMF中,在35℃下搅拌反应24小时。对反应溶液进行过滤,并在真空中去除未反应的EDA。然后,滤液在乙酸乙酯中沉淀,过滤,收集颗粒物,再用EA洗涤收集的颗粒物,并在真空中干燥24小时,得到干燥的GCA-EDA粉末。
步骤2,在氮气保护下,将PLGA10K-PEG5k-COOH(600mg,1.0当量)、EDC(15.3mg,2.0当量)和NHS(9.2mg,2.0等效)添加到10mL二甲基亚砜中。在30℃下将混合物搅拌4小时以激活羧基部分,然后添加步骤1制备的GCA-EDA(60.8mg,3.0当量)以及10μL蒸馏EDA,并将反应混合物再搅拌10小时。通过甲醇透析(分子量截止1000Da)纯化反应溶液,在真空中干燥,在10mL蒸馏水中再溶解,冻干,-20℃保存,得到GCA修饰的PLGA-PEG聚合物PPG。
3.三种负载吉西他滨的PLGA-PEG胶束(Gem-PPG60,Gem-PPG100和Gem-PP100)的制备
采用超声法分别制备Gem-PPG60,Gem-PPG100和Gem-PP100胶束。
实施例1:60nm粒径负载吉西他滨的PPG胶束(Gem-PPG60)的制备
将吉西他滨(6mg)、PLGA10k(6mg)和合成的PPG(30mg)溶解在1mL二甲基亚砜中。在超声波作用下,在5分钟内将混合物逐滴添加到20mL蒸馏水中,乳化形成包裹吉西他滨的胶束Gem-PPG。然后,将获得的Gem-PPG胶束与蒸馏水进行透析(分子量14k Da),纯化24小时,以去除游离在胶束外的吉西他滨。纯化后的Gem-PPG胶束溶液通过450nm过滤器(英国Whatman Nucleopore)过滤,收集滤液。该滤液以1500r/min的速度超滤(Millipore,美国),以去除未形成胶束的PPG,去除滤液。将去除滤液的超滤后的混合物通过220nm过滤器再次过滤,去除胶束聚集物,滤液为纯化的Gem-PPG60胶束。
将纯化的Gem-PPG60胶束在4℃保存。
实施例2:100nm粒径负载吉西他滨的PPG胶束(Gem-PPG100)的制备
将吉西他滨(3mg)和合成的PPG(30mg)溶解在1mL DMSO中。在超声波作用下,在5分钟内将混合物逐滴添加到20mL蒸馏水中,乳化形成包裹吉西他滨的Gem-PPG胶束。然后,将获得的Gem-PPG胶束与蒸馏水进行透析(分子量14k Da),纯化24小时,以去除游离的吉西他滨。纯化后的Gem-PPG胶束溶液通过450nm过滤器(英国Whatman Nucleopore)过滤,收集滤液。该滤液以1500r/min的速度超滤(Millipore,美国),以去除未形成胶束的PPG,去除滤液。将去除滤液的超滤后的混合物通过220nm过滤器再次过滤,去除胶束聚集物,滤液为纯化的Gem-PPG100胶束。
将纯化的Gem-PPG100胶束在4℃保存。
对比例1:100nm粒径负载吉西他滨的PP胶束(Gem-PP100)的制备
将吉西他滨(3mg)和PLGA10k-PEG5k-COOH(30mg)溶解在1mL DMSO中。在超声波作用下,在5分钟内将混合物逐滴添加到20mL蒸馏水中,乳化形成包裹吉西他滨的Gem-PP胶束。然后,将获得的Gem-PP胶束与蒸馏水进行透析(分子量截止14k Da膜),纯化24小时,以去除游离的吉西他滨。纯化后的粗胶束溶液通过450nm过滤器(英国Whatman Nucleopore)过滤,收集滤液。该滤液以1500r/min的速度超滤(Millipore,美国),以去除未形成胶束的PPG,去除滤液。将去除滤液的超滤后的混合物通过220nm过滤器再次过滤,去除胶束聚集物,滤液为纯化的Gem-PP100胶束。
将纯化的Gem-PP100胶束在4℃保存。
以下分别对实施例1制备的Gem-PPG60胶束、实施例2制备的Gem-PPG100胶束及对比例1制备的Gem-PP100胶束进行物理表征及药效测试。
二、胶束的物理性质表征
1.GCA修饰的PLGA-PEG聚合物(PPG)单元的接枝率测定
取10mg GCA-PEG5k-PLGA10K溶于0.45mL氘代DMSO-d6中,在Varian Unity 400MHz核磁共振波谱仪测定。如图2所示,PPG高聚物三个特征峰a(GCA),b(PEG),c(PLGA)分别为δ0.584(a,CH3,2H),1.468(c,CH3,210H),3.508(b,CH2,456H)。根据已知的PEG(5k Da)和PLGA(10k Da)的分子量,以1H NMR积分为依据计算GCA接枝率为2.0/(210/70)=66.7%。
2.胶束的形貌表征
对实施例1-2、对比例1制备的胶束的形貌采用透射电镜进行观测,激发电压为120kV。样品的制备方法如下:取浓度约为1mg/mL的胶束样品10μL滴在TEM铜网上,置于干燥器中静置8h自然风干后,用1%醋酸铀染色1min,用滤纸吸干染色剂。干燥后(60℃过夜)置于透射电镜下观测。从图3中可以清晰的看出,Gem-PPG60胶束(图3中的A)相对Gem-PPG100(图3中的B)和Gem-PP100(图3中的C)粒径较小,纳米胶束形态良好,均呈现出较为均匀的球形结构。
3.胶束粒径及表面电位测试
对实施例1-2、对比例1制备的负载吉西他滨的胶束样品的粒径分布以及表面电位使用BI-200SM动态光散射***(Brookhaven Instruments)在25℃下进行测量。散射光以90°检测并在自动加速器上收集。对于每组样品,取3次测量的平均值,如表1所示。较小的PDI值说明胶束大小较为均匀。胶束表面带有羧基而呈负电性。对于Gem-PPG60和Gem-PPG100胶束,由于GCA的修饰,羧基减少,负电性降低,较低的负电性更有利于胶束吸附于小肠细胞膜表面,促进小肠对胶束的吸收,从而提高胶束的口服生物利用度。
表1三种吉西他滨胶束的粒径及表面电位
样品 | 粒径(nm) | PDI | zeta-potential(mV) |
Gem-PPG60 | 66.32±4.16 | 0.062 | -23.2±0.7 |
Gem-PPG100 | 120.79±9.17 | 0.086 | -21.3±0.5 |
Gem-PP100 | 114.42±6.31 | 0.11 | -48.7±2..1 |
由上表可知,Gem-PPG60的粒径最小,且胶束大小较为均匀,其表面电位负电性最低,更加有利于小肠吸收,进而口服生物利用度较高。
4.胶束的包封率及载药量的测定
采用高效液相色谱法(HPLC)测定实施例1-2、对比例1制备的胶束中吉西他滨的药含量。采用移液枪取0.2mL胶束样品,在冻干机上冻干得到固体质量。将已称重的冻干后的胶束固体复溶,使用Phenomenex色谱柱,采用5-溴尿嘧啶作为内标,采用比例为3∶97的乙腈-0.1%三氟乙酸溶液为流动相,设置流速为1.0mL/min,在268nm波长处进行检测。检测结果如表2所示。
表2三种吉西他滨胶束的包封率及载药量
样品 | 包封率(%) | 载药量(%) |
Gem-PPG60 | 71.2 | 11.7 |
Gem-PPG100 | 72.1 | 11.2 |
Gem-PP100 | 64.9 | 9.6 |
由上表可知,Gem-PPG60和Gem-PPG100胶束相对于未修饰GCA的胶束Gem-PP100包封率和载药量均有所提升。
5.胶束体外释放测试
用透析法测定实施例1-2、对比例1制备的三种吉西他滨胶束Gem-PPG60,Gem-PPG100和Gem-PP100体外释放效果。胶束分散在蒸馏水中,将悬浮液放入透析膜袋中(分子量截止值14kDa)。将袋子密封,然后浸入PBS(20mL,2%吐温80,pH 7.4)。使用37℃的空气浴摇床从胶束中释放吉西他滨。以预定的时间间隔(0~120h)对外溶液进行取样,每次取样3mL,并用新鲜缓冲液替换取样的外溶液。通过HPLC测定每个样品(n=3)中吉西他滨的浓度,结果如图4所示。在120小时内,Gem-PPG60,Gem-PPG100和Gem-PP100释放率分别为42.7±2.1%,57.2±3.1%和62.5±3.2%,该体外实验说明60nm粒径GCA修饰的Gem-PPG60胶束释放更慢,其对于吉西他滨的缓释效果更佳。
三、胶束的大鼠体内药物代谢动力学实验
雄性Sprague-Dawley(SD)大鼠体重200±20g,购自广东医学实验动物中心(中国广东),饲养温度为25±1℃,湿度为50±10%,可自由获取食物和水。12只动物平均分为4组(n=3)。第一组通过静脉注射Gem-PPG100胶束(实施例2制备),第二组和第三组通过口服灌胃Gem-PPG100胶束(实施例2制备)和Gem-PPG60胶束(实施例1制备)。最后一组口服未经修饰的Gem-PP100胶束(对比例1制备)。所有组均接受10mg/kg的吉西他滨剂量。按照预定的时间间隔采集血样,每个样本0.2mL用于肝素钠抗凝,保存在-80℃直到分析。在添加1mL有机溶剂(甲醇:乙腈=1:9)后提取血浆中的吉西他滨,涡旋2min并以6000r/min的速度离心5min。将上清液冻干,用200μL醋酸铵缓冲液(pH 5.5)再溶解,涡旋2min并以6000r/min的速率离心5min,收集50μL上清液并用HPLC测定。使用Origin8.5(美国OriginLab)测定药代动力学参数。三种吉西他滨胶束的药物代谢动力学表征数据如表3所示。最大血浆浓度(Cmax)、达到Cmax的时间(Tmax),半衰期(T1/2),曲线下总面积(AUC),生物利用度(F%)等参数直接从药代动力学图中计算。
表3三种吉西他滨胶束的药物代谢动力学表征数据
由上表可知,未修饰GCA的Gem-PP100胶束口服生物利用度(F%)为19.3%,而修饰GCA的Gem-PPG60和Gem-PPG100胶束分别为80.7%和68.7%,证明口服Gem-PPG胶束大幅提高了吉西他滨的生物利用度,且Gem-PPG60的效果好于Gem-PPG100。
四、胶束的体外细胞毒性测试
人类胰腺癌细胞系BxPC-3和Mia-paca-2均购自美国模式培养物研究所(ATCC,Rockville,MD)。根据官方指南,所有细胞系在37℃、5% CO2的空气环境中进行常规传代培养,,在指数生长阶段生长的细胞将被收集并计数以备用。用CTG法分析抗肿瘤疗效。细胞台盼蓝染色后采用血球仪计数,。调整至合适的细胞密度,然后将135μL细胞悬液平板倒入分析平板,之后向空白孔中添加135μL分析介质。培养板在37℃、5% CO2、95%空气和100%相对湿度下过夜。稀释供试品(工作浓度的10倍浓度),然后向微孔中加入15μL稀释溶液,将分析板放回培养箱中,培养5天。为了检测细胞活力值,在第1天和第5天,在每个孔中添加75μLCellTiter Glo试剂(Promega,美国),在室温下轻轻摇动平板10分钟,然后在2104EnVision酶标仪(EnVision,美国)上记录发光情况。结果如表4所示:
表4Gem-PPG60胶束(实施例1制备),Gem-PP100胶束(对比例1制备)和商品化吉西他滨注射剂对BxPC-3和Mia Paca-2的体外细胞毒性
表中,GI50代表半数生长抑制值。
由上表可知,Gem-PPG60、Gem-PP100和吉西他滨注射剂在120小时内均表现出一定的剂量依赖性毒性:在BxPC-3细胞系的GI50分别为5.3nM,5.8nM和4.0nM,在Mia-Paca-2细胞系的GI50则分别为11.0nM,11.9nM和7.3nM。GCA修饰的Gem-PPG60胶束的GI50值相对未修饰GCA的Gem-PP100胶束较低,表明甘胆酸修饰对胶束的有效性。另外,由于吉西他滨被封装在胶束中,导致Gem-PPG60胶束的GI50值略高于商品化吉西他滨溶液,但未出现显著差异,证明于商品化吉西他滨溶液相比,Gem-PPG60胶束同样具备良好的体外细胞毒活性。
五、胶束的小鼠体内药效学实验
将含BxPC-3肿瘤细胞的200μL RPMI 1640培养基(美国Gibco),以1×107细胞/0.2mL的浓度注入小鼠右颈背部皮下,维持到实体瘤形成。为了评估治疗效果,Balb/c裸鼠被随机分为三组(每组5只)。在进食前1小时分别给予生理盐水(Saline,阴性对照组),腹腔注射商品化吉西他滨盐酸盐溶液(Gemcitabine hydrochloride injection,阳性对照组,60mg/kg,BIW)和口服Gem-PPG60胶束(实验组,30mg/kg,BIW),每周测量两次肿瘤大小(如图5所示)和体重(如图6所示)。实验在第33天终止,对小鼠实施安乐死,并获取肿瘤体积。如图5所示,口服Gem-PPG60胶束组肿瘤的体积进展最为缓慢。吉西他滨溶液组和Gem-PPG60胶束组肿瘤生长抑制率(TGI)分别为49.1%和68.1%,其计算公式为TGI(%)=[1-(T33-T0)/(V33-V0)]×100%,其中,T33代表实验组第33天的平均肿瘤体积,T0代表实验组开始前的平均肿瘤体积,V33代表对照组第33的平均肿瘤体积,V0代表对照组开始前的平均肿瘤体积。表明即使在剂量减半(30mg/kg)的情况下,口服Gem-PPG60胶束相对商品化盐酸吉西他滨注射给药在BxPC-3小鼠模型中更有效的抑制了肿瘤生长。此外,图6显示三组小鼠的体重未出现持续显著性差异,说明口服Gem-PPG60胶束的具有一定的安全性。
综上所述,本发明通过超声乳化法实现GCA修饰的PLGA-PEG高聚物包裹疏水性小分子药物(如,吉西他滨),得到载药胶束组合物。该载药胶束利用PPG高聚物的两亲性(PLGA疏水,GCA亲水),自乳化包裹疏水小分子,包封率超过70%,载药率超过11%,且缓释效果良好,口服生物利用度大幅提高。而且,通过体外细胞毒测试和小鼠体内药效学等实验,证明在减少给药剂量的同时,能够实现化疗药物吉西他滨的口服给药并发挥胰腺癌治疗效果。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (8)
1.一种口服载药胶束组合物,其特征在于,其包含:
由甘氨胆酸(GCA)修饰的PLGA-PEG高聚物,记为PLGA-PEG-GCA,及,
疏水性小分子药物;
其中,所述疏水性小分子药物与PLGA-PEG-GCA的质量比为1:5~1:10;所述疏水性小分子药物包含吉西他滨、卡培他滨及氟达拉滨中的至少一种;PLGA-PEG-GCA的疏水端PLGA聚集,包裹所述疏水性小分子药物,PLGA-PEG-GCA的亲水端向远离疏水端PLGA的方向伸展,形成球形载药胶束;PLGA-PEG-GCA中,PLGA片段的分子量为8000 Da -12000 Da;PEG片段的分子量为3000 Da -7000 Da。
2.如权利要求1所述的口服载药胶束组合物,其特征在于,PLGA-PEG-GCA中,所述球形载药胶束粒径为20-200 nm。
3.如权利要求1所述的口服载药胶束组合物,其特征在于,所述口服载药胶束中,疏水性小分子药物的载药率为11%-20%,以质量比计。
4.如权利要求1所述的口服载药胶束组合物,其特征在于,所述口服载药胶束中,疏水性小分子药物的包封率为70%-90%,以质量比计。
5.一种如权利要求1-4中任意一项所述的口服载药胶束组合物的制备方法,其特征在于,该方法包含:
步骤1,采用甘氨胆酸(GCA)修饰PLGA-PEG-COOH制备PLGA-PEG-GCA;
步骤2,将疏水性小分子药物、PLGA-PEG-GCA以1:5~1:10的质量比例加入到有机溶剂中溶解,在超声作用下,滴加到蒸馏水中,乳化形成包裹所述疏水性小分子药物的胶束,纯化、过滤,得到口服载药胶束。
6.如权利要求5所述的口服载药胶束组合物的制备方法,其特征在于,所述步骤1包含:
步骤1.1,以甘氨胆酸(GCA)、乙二胺(EDA)为原料,在缩合剂作用下,常温反应制备GCA-EDA;
步骤1.2,氮气保护下,将PLGA-PEG-COOH的羧基活化,加入GCA-EDA,常温反应6h-12h,纯化处理,得到PLGA-PEG-GCA。
7.如权利要求5所述的口服载药胶束组合物的制备方法,其特征在于,所述纯化步骤包含:通过蒸馏水进行透析,分子量12k Da -16k Da,纯化24h-72h,以除去游离在胶束外的疏水性小分子药物。
8.如权利要求6所述的口服载药胶束组合物的制备方法,其特征在于,步骤2中,还加入PLGA。
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