CN114025743A - 含有混合聚合物胶束的药物组合物 - Google Patents
含有混合聚合物胶束的药物组合物 Download PDFInfo
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- CN114025743A CN114025743A CN201980097585.4A CN201980097585A CN114025743A CN 114025743 A CN114025743 A CN 114025743A CN 201980097585 A CN201980097585 A CN 201980097585A CN 114025743 A CN114025743 A CN 114025743A
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Abstract
一种药物组合物,其包含混合聚合物胶束和包裹在胶束中的药物,其中所述混合聚合物胶束的粒径为1~1000nm,包括一个两亲嵌段共聚物和一个脂质聚合物。还公开了所述药物组合物的制备及其用于治疗癌症的用途。
Description
技术领域
本发明属于药物制剂技术领域,具体地涉及一种含有混合胶束的药物组合物。
背景技术
混合聚合物胶束作为低水溶性药物的有效载体已被广泛研究。通过位点特异性给药,可以改善药物的生物药剂学和药代动力学特性,从而提高药物疗效。
虽然传统的微粒或纳米颗粒是通过复杂的乳化过程形成的,需要使用表面活性剂来稳定,但粒径小于1微米的混合聚合物胶束,通常是通过简化的自组装过程制备的,不需要表面活性剂或其他药剂来实现稳定性。
目前,混合聚合物胶束由各种类型的聚合物形成,包括共聚物和脂质聚合物。例如Lee et al.,Journal ofControlledRelease,2003,91,103-113(Lee等人,2003年发表在Journal ofControlled Release第91卷,第103-113页的文章)和,Vakil et al.,Langmuir,2006,22,9723-9729(Vakil等人在2006年发表在Langmuir第22卷,第9723-9729页的文章)。含有这些聚合物胶束的组合物在稳定性、载药量和包封率方面仍需改进。
有必要开发具有改进性能的包含混合聚合物胶束的组合物。
发明内容
本发明的一个方面提供一种制备具有非显而易见的高稳定性、高载药量和高包封率的药物组合物的方法。
该方法包括:(1)准备起始原料,所述起始原料包括两亲嵌段共聚物、脂质聚合物和药物;(2)用溶剂将(1)中的原料混合;(3)除去溶剂,得到干膜或干饼;(4)加水溶解(3)中的干膜或干饼,形成含有混合聚合物胶束的溶液;(5)将溶液过滤,滤液即为药物组合物。
在该方法的一个实施方案中,所述脂质聚合物与配体缀合,并且起始原料还包括额外的未与配体缀合的脂质聚合物。
在本发明的范围内有三种相关的药物组合物,每一种都含有混合聚合物胶束和包裹在胶束中的药物。
所述第一药物组合物由上述方法制备。
所述第二药物组合物包含粒径为1~1000nm的混合聚合物胶束和包裹在胶束中的药物。所述混合聚合物胶束包括两亲嵌段共聚物和与配体缀合的脂质聚合物。所述两亲嵌段共聚物具有亲水链段和疏水链段,所述脂质聚合物具有亲水聚合物链和与其共价连接的疏水部分,所述配体是与亲水聚合物链共轭的靶向部分。可选地,所述混合聚合物胶束还包括额外的未与配体缀合的脂质聚合物。
所述第三药物组合物包含粒径为1~1000nm的混合聚合物胶束和包裹在胶束中的药物。所述混合聚合物胶束包括两亲嵌段共聚物和脂质聚合物,其载药量为10%~45%。
本发明进一步涵盖了一种通过向有需要的受试者施用有效量的上述三种药物组合物中的一种来进行治疗的方法。
本发明的细节在以下附图和描述中阐述。本发明的其他特征、目的和优点可以从以下几个实施例的详细描述以及所附权利要求中获得。
附图说明
以下说明针对随附的图片,其中:
图1为人口腔表皮样癌细胞KB在含有本发明4种不同药物组合物的培养基中孵育4小时和24小时后的存活率的条形图。
图2是在用本发明的药物组合物或Jevtana给药后的22天期间,荷瘤小鼠的肿瘤体积图。
图3是采用共载有Cy5.5的本发明的药物组合物处理后,小鼠肿瘤的相对荧光随日期的变化图。
具体实施方式
这部分详细介绍发明内容部分所述的第一、第二和第三种药物组合物。
为了便于讨论,首先描述第二种药物组合物。它包含混合聚合物胶束和包裹在胶束中的药物,其中所述混合聚合物胶束包括两亲嵌段共聚物和与配体缀合的脂质聚合物。所述混合聚合物胶束的粒径为1~1000纳米(例如30~500纳米)。
所述两亲嵌段共聚物具有亲水链段和疏水链段。所述亲水链段包括但不限于聚乙二醇(PEG)、甲氧基聚乙二醇(mPEG)、透明质酸和聚-γ-谷氨酸。所述疏水链段包括但不限于聚己内酯(PCL)、聚乳酸、聚乙交酯、聚乳酸-羟基乙酸共聚物、聚戊内酯、聚丁内酯、聚丙内酯、聚羧酸酯和聚二恶烷酮。一种示例性的两亲嵌段共聚物的亲水链段为mPEG,疏水链段为PCL。
所述脂质聚合物包括亲水聚合物链及与其共价连接的疏水部分。疏水部分的高疏水性可以大大提高混合聚合物胶束的稳定性、载药量和包封率。所述脂质聚合物包括但不限于PEG-胆固醇、PEG-磷脂和PEG-甘油二酯。一个示例性的PEG-磷脂是1,2-二硬脂酰-sn-丙三氧基-3-磷酸乙醇胺-N-甲氧基聚乙二醇(PEG-DSPE)。
所述配体是与脂质聚合物亲水聚合物链缀合的靶向部分。通常配体是大分子或分子量低于2000道尔顿的小分子。所述小分子配体,如蛙皮素和缓激肽,可以识别有功能的细胞表面纤溶酶原激活物。一个示例性的小分子配体是叶酸、N-乙酰组氨酸,或肽(如精氨酸-甘氨酸-天冬氨酸肽和由10-15个氨基酸组成的肽)。所述大分子配体包括但不限于抗体、抗体片段、核酸适配体、前列腺特异性膜抗原配体和生长因子(例如,表皮生长因子、血小板源性生长因子和血管内皮生长因子等)。
所述药物组合物中包含的药物可以作为治疗剂治疗癌症。所述药物包括但不限于卡巴他赛、紫杉醇、多西他赛、拉洛他赛、阿霉素、盐酸阿霉素、表阿霉素、吉西他滨、来曲唑、姜黄素、替西罗莫司、伏立康唑、泊沙康唑、西罗莫司、依维莫司、伊沙匹隆、喜树碱、喜树碱衍生物和光敏剂。特别的,卡巴他赛是迄今为止唯一已知的一种对多西他赛耐药癌症有效的紫杉醇。它通常与严重的剂量限制性毒性(如中性粒细胞减少症)有关。一种含有包封有卡巴他赛的混合聚合物胶束的组合物大大增强了卡巴他赛的生物物理性质(如水溶性)和生物利用度。注意,喜树碱衍生物是指从喜树碱衍生而来并在结构上接近喜树碱的化合物,其具有改善的药物特性,例如,溶解性、代谢稳定性和生物效价。例如Zunino等人,CurrentPharmaceuticalDesign,2002,8(27),2505-2520。
通常,上述混合聚合物胶束的多分散指数为0.08~1.0,优选地,<0.33,更优选地,<0.2。它具有大于80%,优选>90%,更优选>95%的药物包封率。
在一个实施例中,所述混合聚合物胶束还包括一个额外的没有与配体结合的脂质聚合物。所述脂质聚合物可以是PEG-胆固醇、PEG-磷脂、PEG-维生素E和PEG-二酰甘油等。例如,所述PEG-磷脂为PEG-DSPE。
在另一个实施例中,所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE,所述配体为叶酸或N-乙酰组氨酸,所述药物为卡巴他赛。所述组合物中的混合聚合物胶束粒径为30~500nm,多分散指数低于0.33,药物包封率大于90%。
在另一个实施例中,所述混合聚合物胶束包括两亲嵌段共聚物mPEG-PCL;配体结合的脂质聚合物配体-PEG-DSPE,所述配体是叶酸或N-乙酰组氨酸;脂质聚合物PEG-DSPE;和叫卡巴他赛的药物。所述组合物中的混合聚合物胶束粒径为30~500nm,多分散指数低于0.33,药物包封率大于90%。
在另一个实施例中,所述混合聚合物胶束包括与配体缀合的脂质聚合物。所述脂质聚合物占混合聚合物胶束重量的4~25%(例如,5~15%)。对于既含有与配体缀合的脂质聚合物,又含有无配体的脂质聚合物的混合聚合物胶束,两种脂质聚合物共占混合聚合物胶束重量的4~25%(例如,5~15%)。
转到第三种药物组合物,它包含粒径为1~1000nm的混合聚合物胶束(例如,30~500nm)和包裹在胶束中的药物,所述混合聚合物胶束包括两亲嵌段共聚物和可选择性地与配体缀合的脂质聚合物。所述混合聚合物胶束具有10~45%的高载药量(例如,15%~40%)。举例来说,所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE,所述药物为卡巴他赛,所述配体为叶酸或N-乙酰组氨酸。值得注意的是,当所述脂质聚合物与配体缀合时,所述混合聚合物胶束还可以包括额外的未与配体缀合的脂质聚合物。
最后,所述第一种药物组合物是按照上面发明内容部分所述的方法制备的,并在下面进行更详细的描述。
需要重申的是,所述方法包括提供起始原料,所述起始原料包括两亲嵌段共聚物、脂质聚合物、药物;将起始原料在溶剂中混合;去除溶剂,得到干膜或干饼;加水溶解干膜或干饼,形成包封有药物的混合聚合物胶束;可选地超声处理含有混合聚合物胶束的溶液;将溶液过滤,滤液即为药物组合物。
在一个示例方法中,所述脂质聚合物包括亲水聚合物链和共价连接在其上的疏水部分。所述脂质聚合物还包括与所述亲水性聚合物链缀合的配体。值得注意的是,起始材料可以进一步包括另一个脂质聚合物。例如,起始材料包括DSPE-PEG(除mPEG-PCL以外)、配体-PEG-DSPE(所述配体为叶酸或N-乙酰组氨酸)和卡巴他赛。
在另一个示例方法中,所述脂质聚合物不与配体缀合。优选地,所述脂质聚合物为PEG-DSPE,所述两亲嵌段共聚物为mPEG-PCL,所述药物为卡巴他赛。
仍在本发明范围内的是使用上述三种药物组合物之一治疗癌症的方法。该方法包括向有需要的受试者施用有效量的本发明的三种药物组合物中的一种。
在该方法的某些实施方案中,所述抗癌药物为卡巴他赛,所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE或叶酸-PEG-DSPE,其中混合聚合物胶束的粒径为30~500nm,多分散指数小于0.33,药物包封率大于90%。在另一个实施方案中,所述混合聚合物胶束包含PEG-DSPE和叶酸-PEG-DSPE。
癌症可以是叶酸受体过表达的实体瘤。所述实体瘤包括但不限于肺癌、卵巢肿瘤、乳腺癌(例如,转移性乳腺癌和三阴性乳腺癌)、子宫内膜癌、宫颈癌、肾癌、脑癌、头颈部癌、激素难治性转移性前列腺癌、膀胱癌、胃癌(例如,转移性胃癌)、移行细胞癌和脂肪肉瘤。
本文所述术语“治疗”是指对有上述疾病,例如癌症,上述疾病的症状或倾向于患上述疾病的人,施用上述药物组合物,以达到治疗或预防的效果。术语“有效量”是指是指实现这种作用所需的活性药物的量。本领域技术人员公知,有效剂量会因治疗疾病的种类、给药途径、辅料的使用情况以及与其他治疗方法联合使用的情况而变化。
本发明的药物组合物可以通过多种途径给药,例如肠胃外给药,具体如皮下、皮内、静脉内、腹膜内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射。
无菌可注射的药物组合物可以是在一种无毒的、肠胃外可接受的稀释剂或溶剂中的溶液或悬浮液,例如在1,3-丁二醇中的溶液。可以使用的载体和溶剂为甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,不挥发油(fixedoil)通常用作溶剂或悬浮介质(例如,合成的甘油单酯或甘油二酯)。脂肪酸,例如油酸及其甘油酯衍生物;天然药学上可接受的油,例如橄榄油和蓖麻油,尤其是它们的聚氧乙烯化形式,可用于制备注射剂。这些油溶液或悬浮液还可包含长链醇稀释剂或分散剂、羧甲基纤维素或类似的分散剂。其他通常用于制备药学上可接受的固体、液体或其他剂型的表面活性剂,如吐温和司盘或其他类似的乳化剂或生物利用度增强剂,也可用来制剂。
在不做进一步阐述的情况下,相信本领域技术人员可以在上述描述的基础上,最大限度地利用本发明。因此,下面的具体实施例将被解释为仅仅是说明性的,而不以任何方式限制披露的内容。所引用的所有出版物均通过引用并入本申请中。
实施例1:叶酸缀合脂质聚合物的制备
叶酸缀合脂质聚合物按照文献Cho等人,Journal ofNanomaterials,2015,16(1),Article No.36.中记载的方法制备。
更具体地,为制备叶酸缀合的脂质聚合物,将25mg叶酸溶于1mL二甲基亚砜(DMSO)中,100mg氨基取代的1,2-二硬脂酰-sn-丙三氧基-3-磷乙醇胺-N-甲氧基聚乙二醇(DSPE-PEG5k-NH2)溶于0.5mL含32.5mg N,N′-二环己基碳二亚胺(DCC)的吡啶中。将两溶液混合,室温静置4小时。随后旋转真空蒸发除去吡啶。加入3mL水,36000g离心15min,除去不溶物。所得上清液在Spectra/Por CE中用生理盐水透析24小时,再用水透析24小时。透析产物即冻干的叶酸-PEG5k-DSPE,使用前在-20℃的温度下保存。注意下标“5k”表示聚合物的分子量,即平均Mn为5000。
将得到的叶酸缀合的脂质聚合物用于制备含有卡巴他赛和mPEG5k-b-PCL2k的混合聚合物胶束。
实施例2:叶酸缀合的负载卡巴他赛的混合聚合物胶束的制备与表征
按照Cho等人,Journal ofNanomaterial,2015,16(1),Article No.36和Vakil等人,Langmuir,2006,22,9723-9729中所述的方法,制备了三种药物组合物,每种组合物含有不同的叶酸缀合的卡巴他赛混合聚合物胶束(CBZ-mPM)。
首先,在60℃下,将嵌段共聚物mPEG5k-b-PCL2k 10mg、叶酸-PEG5k-DSPE(0.46、0.97或2.20mg)和卡巴他赛5mg溶于1mL四氢呋喃(THF)中,制备混合物。随后,旋转蒸发除去THF,得到干膜或干饼。然后加入水在室温下对干膜或干饼进行溶解,在溶解过程中自发形成叶酸缀合的CBZ-mPM。进一步,将溶液在室温下超声5min,使生成的胶束粒径减小,粒径分布变窄。最后,采用0.22μm聚偏氟乙烯(PVDF)滤膜过滤去除未包封的卡巴他赛,得到药物组合物。
表1显示了三种示例性的叶酸缀合CBZ-mPM,即DFB001、DFB002和DFB003以及两种不含叶酸的CBZ-mPM,即DMB001和DMB002的表征数据。值得注意的是,DMB001和DMB002是按照上述方法制备的,其中将叶酸-PEG5k-DSPE用不与叶酸缀合的脂质聚合物(即,PEG5k-DSPE)替代。,表1还包括载有卡巴他赛的非混合聚合物胶束(CBZ-PM),即DB003,作为对比。
用粒径、多分散指数、卡巴他塞浓度、载药量和包封率5个参数对5种CBZ-mPM和1种CBZ-PM进行了表征。用激光粒度分析仪(BeckmanDelsaTM Nano S)测定粒径和多分散指数(PDI)。采用HPLC法测定每个CBZ-mPM中被包封的卡巴他赛的量。按下列公式计算药物相对聚合物的量百分比(D/P重量%)、载药量(DL)、包封率(EE):
D/P重量%=药物质量/总聚合物质量(mPEG-PCL+脂质聚合物)×100%
DL(%)=胶束中药物质量/(总聚合物质量+胶束中药物质量)×100%
EE(%)=过滤后药物质量/过滤前药物质量×100%
参照表1,“A”表示mPEG5k-b-PCL2k,“B”表示PEG5k-DSPE,“C”表示叶酸-PEG5k-DSPE,“粒径”表示粒径。“CBZ”、“PDI”分别指卡巴他赛和多分散指数。进一步扩展,将含有PEG5k-DSPE的两个CBZ-mPM,如DMB001和DMB002记为“AB”,而含有叶酸的CBZ-mPM,即DFB001、DFB002和DFB003记为“AC”。
表1.CBZ-mPM的表征
如表1所示,五种CBZ-mPM均表现出约50%的载药量和大于90%的包封率。另一方面,CBZ-PM即DB003的载药量为50%,包封率仅为72.5%。换句话说,五种CBZ-mPM均表现出比CBZ-PM更高的包封率,而所述六种胶束的载药量均相当。
这些结果表明本发明的CBZ-mPM出人意料地具有很高的包封率。
实施例3:CBZ-mPM体外抗肿瘤活性研究
本研究对实施例2所述的5种CBZ-mPM中DMB001、DFB001、DFB002这3种进行体外抗肿瘤活性评价。
进行MTT检测(MTT是指3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑)。方法参照Chan等人,Biomaterials,2009,30,1627-1634和Kumar等人,Biomaterials,2012,33,1180-1189。
具体地,人口腔表皮样癌细胞KB在37℃,5%CO2条件下,在添加了10%胎牛血清(FBS)、100U/mL青霉素、100mg/mL链霉素的RPMI-1640培养基中生长。将KB细胞以1.5万个/孔的密度接种于96孔板中,每孔200mL培养基中培养24h。然后用200mL含4种不同浓度(即,1.5625、3.125、6.25和12.5ng/ml)的DMB001、DFB001或DFB002的培养基进行替换,在37℃、5%CO2孵育4h和24h后进行检测。然后去除含有CBZ-mPM的培养基以避免对实验的干扰。加入含有0.5mg/mL的MTT溶液的培养基,继续孵育4小时。移除含有MTT的培养基,并用磷酸盐缓冲液冲洗细胞三次。然后加入200mLDMSO裂解细胞,所得混合物在室温下孵育30分钟。
在酶联免疫检测仪上测定每孔570nm的吸光度。未经处理的对照细胞的存活率按100%计算。根据以下公式(“OD”表示光密度)计算细胞存活率(%):
细胞存活率(%)=[(570nm下样本的OD值-空白样本的OD值)/对照组570nm的OD值]×100%
如图1所示,3个受试CBZ-mPM在4个受试剂量处理24h后均表现出较强的体外抗肿瘤活性。
出乎意料的是,与AB CBZ-mPM,即DMB001相比,两种AC CBZ-mPM,即DFB001和DFB002,在4小时和24小时的处理中对叶酸受体过表达的KB肿瘤细胞均表现出更高的抗肿瘤活性。更具体来说,在4h处理中,用4个不同浓度(即1.5625、3.125、6.25和12.5ng/ml)的DMB001处理的KB细胞,其细胞存活率约为90%,而DFB001或DFB002所显示的细胞存活率约为70%;在24小时处理中,浓度相同时,DMB001处理下KB细胞存活率为35-45%,而DFB001或DFB002处理时KB细胞存活率约为20%。显然,抗肿瘤活性增强的原因是DFB001和DFB002中使用了叶酸作为配体,而DMB001中不存在叶酸。
这些结果表明,本发明的CBZ-mPM在低剂量下对肿瘤具有很好的治疗效果。
实施例4:含PEG5k-DSPE、叶酸-PEG5k-DSPE或两者都有的CBZ-mPM的制备与表征
用实施例2中的方法制备8个示例性的CBZ-mPM,所述CBZ-mPM包含PEG5k-DSPE、叶酸-PEG5k-DSPE或PEG5k-DSPE和叶酸-PEG5k-DSPE。
更具体地,将mPEG5k-b-PCL2k 20mg、叶酸-PEG5k-DSPE 0~2mg、PEG5k-DSPE 0~3mg和卡巴他赛4mg溶于1mL 60℃的氯仿/甲醇(9:1v/v)中。随后通过旋转蒸发除去溶剂获得干膜或干饼。然后在室温下加入水溶解干膜或干饼,从而在溶解过程中自发形成CBZ-mPM。此外,在室温下进行超声处理5分钟以减小所得胶束的粒径并缩窄其粒径分布。最后,使用0.22μm的PVDF膜过滤器过滤去除未封装的卡巴他赛,获得药物组合物。
表2所示为8种示例性的CBZ-mPM和1种作为参考的CBZ-PM,即DB005的表征数据。在8个示例性的CBZ-mPM中,DMB022、DMB023、DMB025这三种含有PEG5k-DSPE;DFB008和DFB012这两种含有叶酸-PEG5k-DSPE;其中DFB009、DFB010、DFB014这三个同时含有PEG5k-DSPE和叶酸PEG5k-DSPE。
8种示例性的CBZ-mPM和CBZ-PM均采用粒径、多分散指数、卡巴他赛浓度、载药量和包封率5个参数表征。用激光粒度分析仪(Beckman DelsaTM Nano S)测定了粒径和PDI(多分散指数)。采用HPLC法测定各胶束中包封的卡巴他赛的量。用实施例2提供的公式计算包封率和载药量。
在表2中,同时含有PEG5k-DSPE和叶酸-PEG5k-DSPE的三个CBZ-mPM,即DFB009、DFB010和DFB014,记为“ABC”。有关“A”、“B”、“C”、“CBZ”、“粒径”、“PDI”、“DL”、“EE”、“AB”和“AC”的定义,请参见实施例2。
表2.CBZ-mPMAB,AC,andABC的表征
如表2所示,除了DFB012粒径为56.5nm外,CBZ-mPM和CBZ-PM粒径相近(全部在41~46nm范围内)。此外,9种胶束的多分散指数均小于0.3,包封率均约等于或大于90%。
这些结果表明,本发明的CBZ-mPM出乎意料地具有高包封率和窄粒径分布。
实施例5:CBZ-mPM的存储稳定性
实施例4中描述的8种CBZ-mPM和CBZ-PM在25℃的水中储存6天(144小时)。用激光粒度分析仪(Beckman DelsaTM Nano S)测量粒径,以监测存储稳定性。由此得到的稳定性数据如表3所示。
表3.CBZ-mPM在25℃的水中储存的稳定性
*p=析出
如表3所示,CBZ-PM即DB005在25℃的水中稳定时间短于24小时。相比之下,8种示例性CBZ-mPM在相同的储存条件下均稳定超过96小时。特别是DFB012、DFB010和DFB014,均含有15重量%的脂质聚合物(见表2第6列)最为稳定。
这些结果表明,本发明的CBZ-mPM的存储稳定性出人意料的高。他们还表明,增加胶束中所含脂质聚合物的量可以增强CBZ-mPM的存储稳定性。
进一步地,测定96h内浊度的变化以评价8种示例性CBZ-mPM以及参考样品DB005的血清稳定性。浊度的增加表示与血清蛋白(Z.-X.Zhao et al.,Biomaterials,2012,33,6793-6807)的非特异性相互作用引起的颗粒聚集。
具体来说,将8种CBZ-mPM水溶液和DB005水溶液100μl分别与等体积的FBS(100μl)在离心管中混合。随后将形成的混合溶液在37℃孵育。
以磷酸盐缓冲液(PBS)为空白溶液,通过630nm波长处测定不同时间点(即0小时、24小时和96小时)的吸光度值所反映的浊度来衡量血清诱导的聚集。由此得到的结果见下表4。
表4.CBZ-mPM的血清在37℃下的稳定性
*p=析出
如表4所示,含有CBZ-PM,即含有DB005的溶液的浊度,在37℃孵育24h后显著升高,CBZ-PM在24~96h间析出。另一方面,含有CBZ-mPM的溶液在孵育24小时后浊度没有像DB005一样增加。此外,在测试的8种CBZ-mPM中,DMB023、DMB025、DFB008、DFB009、DFB010、DFB014等6种明显比CBZ-mPM更稳定。它们在孵育96小时后没有析出。意外的是,同时含有PEG5k-DSPE和叶酸PEG5k-DSPE的CBZ-mPM相对于仅含有叶酸PEG5k-DSPE的CBZ-mPM具有更高的血清稳定性。
这些结果表明本发明的CBZ-mPM出乎意料地提高了贮存稳定性和血清稳定性。
实施例6:DFB014的体内抗肿瘤活性
用雌性裸鼠(nu/nu,体重20~25克)研究DFB014的体内抗肿瘤活性。对小鼠皮下植入人类表皮癌异种移植细胞系,KB细胞(每只动物2x107个细胞),它过度表达叶酸受体。植入后,肿瘤生长28天达到350mm3的体积,然后小鼠尾静脉给予单次量的Jevtana(卡巴他赛的商品名)或DFB014(等效剂量卡巴他赛=10毫克/千克)PBS悬浮液,记为第0天。在预定的时间点,使用卡尺测量肿瘤的长轴和短轴。然后利用公式(3/4)πa2b计算肿瘤体积,其中a和b分别为肿瘤短轴和长轴的长度。
然后,根据公式用肿瘤体积计算Jevtana和DFB014肿瘤生长抑制率%(TGI):
TGI=(VTm-VT0)*100%/VT0,
其中VTm为预定时间点的肿瘤体积,VT0为第0天即Jevtana/DFB014给药当天的肿瘤体积。
图2显示了Jevtana和DFB014处理22天肿瘤体积的变化。对于用Jevtana处理的肿瘤,从第0天到第11天肿瘤体积基本保持一致,但从第12天开始肿瘤体积明显增大。Jevtana处理的TGI在第15日为52%,第18日为131%,第22日为228%。
相比之下,DFB014治疗的肿瘤在第0天至第9天体积保持一致,第10天至第15天体积缩小,之后体积扩大。DFB014处理的TGI在第15天(负值表示肿瘤缩小)为-40%,第18天为-26%,第22天为13%,显著低于Jevtana在同一时间点的TGI。结果表明,DFB014的抗肿瘤活性明显高于Jevtana。
实施例7:CBZ-mPM的体内肿瘤靶向性
利用荧光成像研究CBZ-mPM的体内肿瘤靶向性。将近红外染料Cy5.5共载入DMB025(其中不包含叶酸)和DFB014(含叶酸)两种示例性的CBZ-mPM中,制备了两种含Cy5.5的CBZ-mPM,即CyDMB025和CyDFB014。具体来说,两种含Cy5.5的CBZ-mPM是在起始原料中加入了Cy5.5,按照实施例4所述的方法制备的。
下面的表5是两种含Cy5.5的CBZ-mPM的表征数据。两种CBZ-mPM均用粒径、多分散指数、Cy5.5浓度和卡巴他赛浓度四个参数进行表征。用激光粒度分析仪(Beckman DelsaTMNano S)测定了粒径和多分散指数。HPLC法测定各CBZ-mPM中包封Cy5.5和包封卡巴他赛的量。关于“A”、“B”、“C”、“CBZ”、“粒径”和“PDI”的定义,见实施例2。
表5.共载Cy5.5的CBZ-mPM的表征
在雌性胸腺裸鼠(nu/nu,体重20~25克)中研究了两种含Cy5.5的CBZ-mPM的肿瘤靶向性。小鼠皮下植入人表皮癌异种移植细胞系KB细胞(每只动物2×107个细胞)。植入后肿瘤生长28天,达到350mm3的体积。小鼠经尾静脉注射CyDMB025或CyDFB014,共注射2nmol的Cy5.5。随后,在各时间点荧光成像前用2%异氟醚麻醉小鼠。采用IVIS三维成像系统进行活体荧光成像。
图3为CyDMB025和CyDFB014处理小鼠的KB肿瘤的相对荧光随时间的变化图。如图所示,两种含Cy5.5的CBZ-mPM在4小时内逐渐进入KB肿瘤累积。重要的是,注射CyDFB014的小鼠相对肿瘤荧光始终高于注射CyDMB025的小鼠,说明CyDFB014更有效地在KB肿瘤中积累。这一优势是归因于CyDFB14中的叶酸配体,使得CBZ-mPM能够靶向叶酸受体过表达的肿瘤。
这些研究结果表明CyDFB14可以增强肿瘤靶向性。
实施例8:N-乙酰组氨酸缀合脂质聚合物的制备
一种N-乙酰组氨酸缀合脂质聚合物是按照在实施例1中所描述的步骤制备的。
更具体地,DSPE-PEG5k-NH225mg,N-乙酰组氨酸(NAcHis)4.93mg,DCC 5.2mg,N-羟基琥珀酰亚胺(NHS)2.9mg,4-二甲氨基吡啶(DMAP)3.1mg溶于0.4mL无水DMSO中。混合物在室温下搅拌48小时。随后,向混合液中加入2.5mL DMSO,反复过滤除去副产物二环己基碳二脲。然后将滤液用DMSO透析(截留分子量为3500)3天,以去除残留的NAcHis、NHS和DMAP。通过冷冻干燥得到最终产物NAcHis-PEG5k-DSPE。
实施例9:N-乙酰组氨酸缀合的CBZ-mPM的制备与表征
采用实施例4所述方法制备的含有PEG5k-DSPE和NAcHis-PEG5k-DSPE的CBZ-mPM,DHB001。
更具体地,首先将mPEG5k-b-PCL2k 20mg、NAc His-PEG5k-DSPE 2mg、PEG5k-DSPE1mg、卡巴他赛4mg溶于1mL 60℃的氯仿/甲醇(9:1v/v)中,旋转蒸发除去溶剂,得到干膜或干饼。然后加入水在室温下对干膜或干饼进行溶解,在溶解过程中自发形成DHB001。最后,采用0.22μm的PVDF膜过滤去除未包封的卡巴他赛,得到药物组合物。
下方表6显示了DHB001的表征数据。通过粒径(size)、多分散指数(PDI)、卡巴他赛(CBZ)浓度、载药量(DL)和包封率(EE)等5个参数对其进行表征。用激光粒度分析仪(Beckman DelsaTM Nano S)测定了粒径和多分散指数。采用HPLC法测定DHB001中包封的卡巴他赛的量。包封率和载药量用实施例2中的公式计算。
表6中,“C”代表NAcHis-PEG5k-DSPE,“粒径”、“PDI”、“CBZ”、“DL”和“EE”如前文所定义。关于“A”和“B”的定义,请参见实施例2。
表6.N-乙酰组氨酸缀合的CBZ-mPM的表征
如表6所示,DHB001与本发明的其他CBZ-mPM一样,出乎意料地表现出了较高的包封率和较窄的粒径分布。
其他实施例
本说明书中公开的所有特征都可以以任何形式组合。本说明书公开的每个特征都可以被具有相同、等同或相似目的的替代特征所取代。因此,除非另有明文规定,否则公开的每个特征都只是一系列等同或相似特征的一个示例。
此外,从以上描述,本领域技术人员可以很容易地确定本发明的本质特征,在不背离本发明的实质和范围的情况下,可以对本发明进行各种变化和修改,使之适应各种用途和条件。因此,其他实施例也落在本申请的权利要求中。
Claims (27)
1.一种药物组合物,所述药物组合物包含粒径为1~1000nm的混合聚合物胶束和包裹在所述胶束中的药物;
所述混合聚合物胶束含有两亲嵌段共聚物和与配体缀合的第一脂质聚合物;
所述两亲嵌段共聚物包括亲水链段和疏水链段;
所述第一脂质聚合物包括亲水聚合物链和与其共价连接的疏水部分;
所述配体是与亲水聚合物链共轭的靶向部分。
2.权利要求1所述的药物组合物,其中,所述亲水链段为聚乙二醇(PEG)、甲氧基聚乙二醇(mPEG)、透明质酸或聚-γ-谷氨酸;
所述疏水链段为聚己内酯(PCL)、聚乳酸、聚乙交酯、聚乳酸-羟基乙酸共聚物、聚戊内酯、聚丁内酯、聚丙内酯、聚羧酸酯或聚二恶烷酮。
3.根据权利要求1所述的药物组合物,其中,所述第一脂质聚合物是PEG-胆固醇、PEG-磷脂、PEG-维生素E或PEG-二酰基甘油。
4.根据权利要求1所述的药物组合物,其中,所述配体是叶酸、N-乙酰组氨酸、肽、抗体、抗体片段、核酸适配体、前列腺特异性膜抗原配体,或生长因子;所述生长因子选自表皮生长因子、血小板源性生长因子和血管内皮生长因子。
5.根据权利要求1所述的药物组合物,其中,所述药物为卡巴他赛、紫杉醇、多西他赛、拉罗他赛、阿霉素、盐酸阿霉素、表阿霉素、吉西他滨、来曲唑、姜黄素、替西罗莫司、伏立康唑、泊沙康唑、西罗莫司、依维莫司、伊沙匹隆、喜树碱、喜树碱衍生物或光敏剂。
6.根据权利要求2所述的药物组合物,其中,所述亲水链段为mPEG;所述疏水链段为PCL。
7.根据权利要求3所述的药物组合物,其中,所述PEG-磷脂为1,2-二硬脂酰-sn-丙三基-3-磷酸乙醇胺-N-甲氧基聚乙二醇(PEG-DSPE)。
8.根据权利要求4所述的药物组合物,其中,所述配体是叶酸或N-乙酰组氨酸。
9.根据权利要求5所述的药物组合物,其中所述药物为卡巴他赛。
10.根据权利要求1所述的药物组合物,其中所述两亲嵌段共聚物为mPEG-PCL,所述第一脂质聚合物为PEG-DSPE,所述配体为叶酸或N-乙酰组氨酸,所述药物为卡巴他赛。
11.根据权利要求1所述的药物组合物,其中所述第一脂质聚合物占所述混合聚合物胶束重量的4~25%。
12.根据权利要求1所述的药物组合物,其中,所述混合聚合物胶束还包含第二脂质聚合物;所述第二脂质聚合物不与配体缀合。
13.根据权利要求12所述的药物组合物,其中,所述第一脂质聚合物和第二脂质聚合物均分别为PEG-胆固醇、PEG-磷脂、PEG-维生素E或PEG-二酰基甘油。
14.根据权利要求13所述的药物组合物,其中,所述两亲嵌段共聚物为mPEG-PCL,所述第一脂质聚合物和所述第二脂质聚合物均为PEG-DSPE,所述配体为叶酸或N-乙酰组氨酸,所述药物为卡巴他赛。
15.根据权利要求12所述的药物组合物,其中所述第一脂质聚合物和所述第二脂质聚合物共占所述混合聚合物胶束重量的4~25%。
16.一种制备包含混合聚合物胶束和药物的药物组合物的方法,所述混合聚合物胶束的粒径为1~1000nm,所述药物被包裹在所述胶束中;该方法包括:
(1)准备起始原料,所述起始原料包括两亲嵌段共聚物、脂质聚合物和药物;
(2)用溶剂将(1)中原料混合;
(3)除去溶剂,得到干膜或干饼;
(4)加水溶解(3)中干膜或干饼,形成含有混合聚合物胶束的溶液;
(5)将溶液过滤,滤液即为药物组合物。
17.根据权利要求16所述的方法,其中所述脂质聚合物不与配体缀合。
18.根据权利要求17所述的方法,其中所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE,所述药物为卡巴他赛。
19.一种根据权利要求16所述的方法制备的药物组合物。
20.根据权利要求19所述的药物组合物,其中所述脂质聚合物未与配体缀合。
21.根据权利要求20所述的药物组合物,其中所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE,所述药物为卡巴他赛。
22.一种药物组合物,所述药物组合物包含粒径为1~1000nm的混合聚合物胶束和包裹在所述胶束中的药物;
所述混合聚合物胶束包含两亲嵌段共聚物和脂质聚合物,其载药量为10~45%。
23.根据权利要求22所述的药物组合物,其中所述脂质聚合物未与配体缀合。
24.根据权利要求23所述的药物组合物,其中所述两亲嵌段共聚物为mPEG-PCL,所述脂质聚合物为PEG-DSPE,所述药物为卡巴他赛。
25.一种治疗癌症的方法,该方法包括给需要的人施用有效量的权利要求1所述的药物组合物。
26.一种治疗癌症的方法,该方法包括给需要的人施用有效量的、采用权利要求16所述方法制备的药物组合物。
27.一种治疗癌症的方法,该方法包括给需要的人施用有效量的权利要求22所述的药物组合物。
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