CN116942850B - 一种用于易损斑块的纳米药物递送系统 - Google Patents
一种用于易损斑块的纳米药物递送系统 Download PDFInfo
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Abstract
本发明涉及一种用于易损斑块的纳米药物递送系统,为多层核壳结构,包括负载药物活性成分的脂质体,在脂质体表面的金属多酚网络涂层,以及修饰在金属多酚网络涂层表面的靶向配体。本发明提供的纳米药物递送系统兼具对易损斑块的治疗和诊断效果。靶向纳米载药治疗不仅明显遏制了斑块的进展,更出现了斑块体积不同程度的显著逆转和消退,显示出了极其显著主动脉富集功能,这种富集效应在靶向纳米制剂作用下更为明显;同时对易损斑块的示踪效果有了非常显著的提高。
Description
技术领域
本发明涉及易损斑块治疗和/或诊断技术领域,以及靶向给药技术领域;特别涉及一种用于易损斑块的纳米药物递送系统。
背景技术
心脑血管疾病(CVD)是高致残率、高病死率、高医疗风险及高医疗费用的第一大慢性疾病,是全球第一位的死亡原因。在关键技术层面探索发展攻克CVD的高质量筛查手段和治疗药物,是遏制 CVD 发病率和死亡率增长的趋势的根本手段,具有巨大的临床需求和市场前景。
动脉粥样硬化(AS)是一种典型的由于脂质沉积引起的慢性炎症性血管病变,是ASCVD和脑卒中的主要诱因。AS的形成主要是血管内皮损伤,慢性炎症和胆固醇沉积的过程。“易损斑块”(vulnerable plaque,VP),又称不稳定斑块,是指具有血栓形成倾向或极有可能快速进展成为"罪犯斑块"的动脉粥样硬化斑块,主要包括破裂斑块、侵蚀性斑块和部分钙化结节性病变。易损斑块的组织学表现包括活动性炎症、薄的纤维帽和大的脂质核心、内皮剥脱伴表面血小板聚集、斑块有裂隙或损伤以及严重的狭窄,以及表面钙化斑、黄色有光泽的斑块、斑块内出血和正性重构。大量研究证实,AS的易损斑块是导致患者发生急性不良心脑血管事件的主要原因,给家庭和社会带来沉重的医疗负担。
脂质体为常用的靶向给药系统。脂质体具有提高药效、降低药物毒副作用、提升药物的生物利用度、生物安全性强等明显优势。ZL201980001843.4公开了一项通过被动包封法制备靶向CD44的脂质体纳米药物, 可利用易损斑块内主要存在的巨噬细胞、单核细胞、内皮细胞、淋巴细胞和平滑肌细胞的表面上的CD44的表达状态及其与透明质酸(HA)的亲和能力,构建靶向斑块或与易损斑块相关的疾病的能够实现药物的脂质体药物递送体系用于诊断或治疗易损斑块并持续释放的靶向给药系统,但是目前手段仅限于被动载药方法。ZL201980001833.0公开了通过薄膜水化、探头超声两步法,将一系列具有亲水或疏水的治疗药物和造影剂包被在亲水内腔或者疏水脂质层中,进一步与靶向配体偶联。这种策略属于被动包封,虽然普适性强,但包封率往往不够高,治疗效果也有进一步提升空间。
在治疗方面,目前针对AS以全身药物治疗、介入治疗和外科搭桥手术治疗为主要手段。药物治疗是AS治疗的基石,目前对于诊断为AS性疾病的患者均采用抗血小板+调脂药物治疗,通过全身、终身用药,以减慢斑块进展的速度,然而,该方法对已经形成的斑块治疗效果有限。
对于AS易损斑块,目前尚无特效的治疗方法。同时在诊断方面,目前临床常用AS诊断手段包括动脉CTA、动脉造影,此外在介入手术中可以采用腔内影像学检测手段-光学相干断层扫描(OCT)和血管内超声(IVUS)。其中,CTA、动脉造影只能显示血管狭窄程度,不能分析斑块性质,无法对易于发生斑块破裂的易损斑块高危患者进行预警;OCT和IVUS可判断斑块性质,但需要在手术中使用,有创且价格昂贵,不适用于大规模筛查使用。
得益于纳米生物医学技术的飞速发展,纳米尺寸的医用材料在药物递送、生物成像等领域展现出强大的应用潜力,如脂质体、配位聚合物等。其中,能够同时满足将药物靶向递送至病灶部位和在病灶部位辅助成像需求的诊疗一体化纳米药物递送系统引起了人们广泛的关注。脂质体由于其良好的生物相容性及优异的药物负载能力,已有被成功开发的商业化纳米药物制剂Doxil。通过主动载药法,药物活性成分分子可以以极高的包封率被负载进脂质体内部的空腔里。CD44是一类黏附分子,广泛分布于淋巴细胞、单核细胞、内皮细胞等的表面。CD44分子的主要配体是透明质酸(hyaluronic acid,缩写为“HA”)。基于表达细胞的活化状态,可以将CD44分为相对静止状态(不能结合HA)、诱导活化状态(激活后可结合HA)和结构活跃状态(无需激活即可与HA结合),而大多数正常细胞表面的CD44处于相对静止状态,从而不能与HA相结合。与正常细胞相比,易损斑块中的细胞诸如内皮细胞、巨噬细胞和平滑肌细胞等的表面的CD44会被易损斑块的微环境(诸如在炎症因子的影响下)所诱导活化,导致与HA的结合能力会骤然增强数十倍。这一发现提示,易损斑块处的细胞表面存在的大量活化的CD44分子为以HA为靶向配体的靶向给药系统提供了理想的靶位。申请人已有的研究成果表明(专利号: WO2023030524A1),通过主动载药法能够以高包封率制备出负载活性药物成分的长循环脂质体,并且在脂质体表面靶向配体的作用下,该脂质体能够在炎症斑块处主动富集并起到良好的治疗效果。然而该专利本身不能实现易损斑块的诊断,如果要实现易损斑块的诊断,需要另外进行示踪剂的给药,比如CT示踪剂或者MRI示踪剂。这样的多次分别进行药物和示踪剂的给药不能实时监测纳米药物分布及治疗过程,从而不能实时反馈纳米药物对个体的治疗效果。
金属多酚网络(MPN)由于其金属离子组分可调、配位方式温和等特点,被广泛应用于纳米载体表面功能涂层的构筑(专利号:CN113030064 A)。通过将金属离子组分调控为Fe(III)或Gd(III)等离子,所得的功能涂层修饰的纳米载体可以被应用于特定部位的磁共振成像(MRI),进行辅助诊断。因此在已有治疗炎症斑块的长循环脂质体的研究基础上,发明人构筑了可以同时实现药物靶向递送和MRI成像的诊疗一体化纳米药物递送系统,通过表面构建功能纳米涂层,加固载药纳米载体的外部结构,提高纳米药物循环稳定性,涂层含金属离子,赋予纳米载体核磁成像功能和抗炎作用,纳米载体偶联 HA 对局部高表达CD44 炎性斑块靶向识别。针对易损斑块处的高炎症和微弱酸性的特症,纳米涂层包裹的载药脂质体,可以改善纳米递送系统在体内的药代动力学和组织分布,并进一步增强其在易损斑块局部富集和酸性微环境下的可控释放,实现先进纳米载体介导药物体内行为的时空调控。这对于具有炎症的易损斑块的诊治具有重要的科研价值和现实意义。
发明内容
为了解决现有技术中对于易损斑块治疗/诊断中, 难以兼顾药物递送和MRI成像的诊疗,纳米药物递送平台不能实现诊疗一体化。本发明在脂质体表面生成金属多酚网络涂层后再进行靶向配体的螯合,而非将靶向配体直接引入于脂质体的磷脂双分子层中。具体而言,本发明制备出负载药物活性成分的脂质体,在脂质体表面构筑了金属多酚网络涂层,通过配位作用及分子间弱作用力,在金属多酚网络涂层表面引入靶向配体,所得纳米药物可以在靶向配体的作用下于炎症斑块处富集,在递送药物活性成分分子进行斑块逆转治疗的同时,起到辅助MRI成像的功能。体外实验结果表明,本发明所得诊疗一体化纳米药物可以在表面靶向配体的作用下,在CD44高表达的细胞中富集,并与单纯负载药物的脂质体相比,呈现出不同的药物释放特征,并且能起到对比明显的辅助MRI成像效果。体内实验结果也表明,意外的发现,MPN中的多酚本身的抗氧化性,可用于和递送药物协同发挥治疗斑块的作用,效果更为显著,所得纳米药物安全性良好,可以在炎症斑块中富集,在靶向释放药物进行治疗的同时起到MRI成像进行辅助诊断的功能。本发明为构筑应用于AS的诊疗一体化纳米药物递送系统提供了新思路。
本发明通过以下技术方案实现上述目的:
一种用于易损斑块的纳米药物递送系统,为多层核壳结构,包括负载药物活性成分的脂质体,在脂质体表面的金属多酚网络涂层,以及修饰在金属多酚网络涂层表面的靶向配体。
进一步地,所述药物活性成分为对易损斑块有治疗作用的物质,具体选自他汀类药物、贝特类药物、抗凝药物、血管紧张素转换酶抑制剂、钙离子拮抗剂、β受体阻滞剂中的至少一种。更进一步地,药物活性成分的负载量为0.01~100 mg/mL,优选为1-30 mg/mL。
更优选地,所述药物活性成分选自以下一种或多种:洛伐他汀、阿托伐他汀、瑞舒伐他汀、辛伐他汀、匹伐他汀、普伐他汀、苯扎贝特、环丙贝特、吉非贝齐、阿司匹林、阿西美辛、奥扎格雷钠、替罗非班以及它们的药效片段或药学上可接受的盐。在本发明一个具体实施方式中,所述药物活性成分选自瑞舒伐他汀、阿托伐他汀、辛伐他汀、匹伐他汀、普伐他汀中的至少一种,优选地,所述药物活性成分选自瑞舒伐他汀钙、阿托伐他汀钙、辛伐他汀钙、匹伐他汀钙、普伐他汀钙中的至少一种。
进一步地,所述脂质体为磷脂和胆固醇按照质量比3-6:1的复配,比如磷脂和胆固醇质量比为4:1;其中磷脂选自非离子磷脂或阳离子磷脂中的至少一种,所述非离子磷脂选自磷脂酰胆碱类(二硬脂酰基磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二油酰基卵磷脂、氢化大豆磷脂酰胆碱)、磷脂酰乙醇胺类(二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺、培化磷脂酰乙醇胺)、磷脂酰甘油类(二油酰磷脂酰甘油、二硬脂酰磷脂酰甘油)、磷脂酸类(叠氮磷酸二苯酯、二硬脂酰磷脂酸、二油酰磷脂酸)、磷脂酰丝氨酸类(二棕榈酰基磷脂酰丝氨酸、二硬脂酰基磷脂酰丝氨酸、二肉豆蔻酰基磷脂酰丝氨酸)、磷脂肌醇类(二棕榈酰磷脂酰肌醇、二硬脂酰磷脂酰肌醇、二油酰基磷脂酰肌醇)中的至少一种;所述阳离子磷脂选自(2,3-二油酰基-丙基)-三甲基铵-氯盐、3β-[N-(N',N'-二甲基胺乙基)氨基甲酰基]胆固醇盐酸盐、1,2-二油醇-3-二甲基氨基-丙烷、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯、1,2-双十八烯氧基-3-甲基铵丙烷等阳离子脂质中的至少一种。
在本发明一个优选实施方式中,所述脂质体为二硬脂酰基磷脂酰胆碱、培化磷脂酰乙醇胺、胆固醇按照质量比3-4:1-2:1的复配。
所述靶向配体是能够与易损斑块CD44分子特异性结合的配体,具体选自透明质酸(HA)、胶原蛋白、选择蛋白、骨桥蛋白、以及单克隆抗体HI44a、HI313、A3D8、H90、IM7中的任意一种或者两种以上的组合。优选地,所述靶向配体为透明质酸。
在本发明一个优选实施方式中,所述纳米药物递送系统的靶向配体为透明质酸,所述多价金属离子为Fe(III),所述多酚类化合物为单宁酸和邻苯三酚按照质量比为3-5:1的复配,所述药物活性成分为瑞舒伐他汀或其药学上可接受的盐。优选地,所述多酚类化合物为单宁酸和邻苯三酚按照质量比为4:1的复配。
所述金属多酚网络是多价金属离子和多酚类化合物构成的三维网络,所述多价金属离子选自Fe(III)、Mn(III)、Gd(III)、Al(III)、Co(II)、Ni(II)、Cu(II)、Zn(II)、Zr(IV)、Ti(IV)中的至少一种,所述多酚类化合物选自单宁酸、没食子酸、邻苯三酚、吡咯烷醇、表儿茶素没食子酸酯、木质素、儿茶酚、表儿茶素、表没食子儿茶素、鞣花酸、咖啡酸、原儿茶醛、懈皮素中的至少一种。
更进一步地,所述多酚类化合物为单宁酸和邻苯三酚按照质量比3-5:1的复配。发明人预料不到发现,单一的单宁酸或者单一的邻苯三酚作为多酚类化合物,倾向于得到交联糊状的产物,同时,以上述复配所得修饰在脂质体表面的金属多酚网络可以有效地提升后续的靶向配体的修饰效率,从而提升靶向递送和治疗的效果。
本发明中,药物活性成分通过与金属阳离子之间的配位作用负载于脂质体内部,之后通过多价金属离子和多酚类化合物的配位作用,在负载药物活性成分的脂质体表面包覆金属多酚网络,最后通过配位作用和/或分子间作用力,在金属多酚网络表层修饰靶向配体。
发明人还发现,金属多酚网络不仅赋予了本发明药物递送系统易损斑块的诊断作用,而且还加强了对易损斑块的治疗作用,可能是由于多酚本身的抗氧化性能对于炎症斑块的治疗也有一定的促进作用。
本发明第二个目的是提供所述用于易损斑块的纳米药物递送系统的制备方法,包括以下步骤:
(S1)注入法制备负载药物活性成分的脂质体(Drug@Liposome):将脂质体载体材料溶于良溶剂乙醇形成脂质体溶液;向脂质体溶液中加入盐溶液,使脂质体内外溶液形成酸度梯度,进行水化,分散成粗脂液;粗脂液经过聚碳酸酯膜挤出,得到粒径200nm以下的精制脂质体溶液,超滤纯化,加入待包被物质药物活性成分,孵育,使药物活性成分进入脂质体内部得到负载药物活性成分的脂质体溶液;
进一步地,步骤(S1)中,脂质体溶液中脂质体浓度为100-200 mg/mL,比如120 mg/mL;盐溶液浓度为30-40 mg/mL,比如35 mg/mL;盐溶液的加入量是脂质体溶液质量的8-10倍;水化温度为45~65℃;聚碳酸酯膜的孔径 100-200 nm;超滤是以纯化水作为交换介质,经切向流超滤膜包,将体系中未形成脂质体的游离组分进行分离和除去,超滤膜规格为100-300 kD;药物活性成分加入量使得最终负载药物活性成分的脂质体API含量为0.5-3.0mg/mL,比如1.5 mg/mL。
进一步地,步骤(S1)中,所述盐为弱酸强碱盐;优选地,所述盐的阴离子部分选自以下一种或多种:醋酸根、依地酸根、碳酸氢根、枸橼酸根、苯甲酸根和葡萄糖酸根;和/或所述盐的阳离子部分选自下一种或多种:钙离子、铜离子、镍离子、钡离子、镁离子和锌离子;更优选地,所述盐选自以下一种或多种:醋酸钙、碳酸氢钙、枸橼酸镁和葡萄糖酸铜。
(S2)金属多酚网络的包覆(Drug@Liposome@MPN):将步骤(S1)所得负载药物活性成分的脂质体溶液分散在缓冲溶液中,加入多酚和多价金属离子,在负载药物活性成分的脂质体表面形成金属多酚网络包覆层,透析,超滤,得到金属多酚网络包覆的负载药物活性成分的脂质体溶液;
进一步地,步骤(S2)中,所述缓冲溶液为pH为 7-8的Tris-HCl缓冲溶液,负载药物活性成分的脂质体溶液和缓冲溶液体积比为1:6-10,比如1:8,1:9;负载药物活性成分的脂质体溶液、多酚、多价金属离子的加入量为20-30 mL:160-200 mg:0.12-0.15 mmol;金属多酚网络包覆的负载药物活性成分的脂质体溶液中API含量为0.8-1.0 mg/mL;所述透析是以水为透析介质,所述超滤是经切向流超滤膜包除去未反应的原料,超滤膜规格为100-300kD。
优选地,步骤(S2)中,加入多酚和多价金属离子时,多酚是加入到缓冲溶液中,多价金属离子的盐是加入到水中,向负载药物活性成分的脂质体溶液中先加入含有多酚的缓冲溶液,充分搅拌10-30min后,在搅拌条件下缓慢加入多价金属离子的盐水溶液,10-30min内加入完毕,继续搅拌5-15min。
(S3)靶向配体的修饰(Drug@Liposome@MPN@HA):向步骤(S2)所得金属多酚网络包覆的负载药物活性成分的脂质体溶液中加入靶向配体的溶液,充分反应后,透析,超滤,冷冻干燥,得到所述纳米药物递送系统。
进一步地,步骤(S3)中,靶向配体的溶液浓度为1-5 mg/mL,靶向配体的溶液和步骤(S2)所得金属多酚网络包覆的负载药物活性成分的脂质体溶液体积比为1-3:1-3。透析,超滤步骤和步骤(S2)相同,透析是以水为透析介质,所述超滤是经切向流超滤膜包除去未反应的原料,超滤膜规格为100-300 kD。
本发明还提供了所述纳米药物递送系统在制备治疗/诊断易损斑块试剂中的用途。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是实施例1步骤(S1)所得负载瑞舒伐他汀的脂质体溶液(RST@Liposome)的cryo-TEM图;
图2是实施例1所得诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA10kD)的TEM图;
图3是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的XPS图;
图4是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的XRD图;
图5是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的红外图谱;
图6A是根据实施例1制得不同Fe含量浓度的RST@Liposome@MPN@HA在T1和T2成像模式下的MRI图像;
图6B是根据实施例1制得不同Fe含量浓度的RST@Liposome@MPN@HA信号拟合图;
图7是实施例3制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA3)的TEM图;
图8是实施例4制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA4)的TEM图;
图9是实施例5制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA5)的TEM图;
图10是实施例6制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA6)的TEM图;
图11是基于表面等离子共振技术表征HA的靶蛋白CD44与主动靶向MPN包被脂质体亲和力测试图;
图12为载体递送系统对动脉粥样硬化的体内治疗效果;
图13是服用不同药物对小鼠斑块逆转体积影响;
图14是实施例1制得的RST@Liposome@MPN@HA10kD小鼠动脉粥样硬化易损斑块模型显影前和显影后的MRI图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅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。
实施例1
(S1)称量二硬脂酰基磷脂酰胆碱(72 g)、培化磷脂酰乙醇胺(24g)、胆固醇(24g)投入反应瓶中,使用称量好的无水乙醇(600.0 g)涮洗漏斗并加入到反应瓶中。放入搅拌子后,密封,开始搅拌,温度60℃,搅拌30分钟至完全溶解,形成有机相溶液,即脂质体溶液。之后称量水(6570g)和醋酸钙(214.64g)于10L不锈钢桶中,搅拌5分钟至完全溶解,形成水相盐溶液。将有机相溶液和过滤后的水相盐溶液经过T型管进行混合水化,保持温度60℃。混合后的溶液继续搅拌10分钟。在挤出器中安装好孔径200nm的聚碳酸脂膜后,使用挤出泵将水化后溶液通过挤出器进行挤出操作。重复挤出操作3次后, 停止挤出。使用切向流超滤膜(300K)对挤出后的溶液进行超滤。超滤过程需要持续进行搅拌,透出30L液体后停止超滤。称取瑞舒伐他汀钙(21.05 g),溶于3000.0g水,搅拌溶解,过无菌滤膜处理。将过滤后液体与超滤后脂液于60℃下混合,并持续搅拌30min。搅拌完成后冷却至室温,过无菌滤膜并封装,得负载瑞舒伐他汀的脂质体溶液(RST@Liposome)(API含量:1.5 mg/mL)。
(S2)取步骤(S1)所得负载瑞舒伐他汀的脂质体溶液(20 mL)分散于Tris-HCl缓冲溶液(pH 7.4, 180 mL)中,称取160 mg 多酚(单宁酸和邻苯三酚按照质量比3:1的混合多酚)溶于Tris-HCl缓冲溶液(pH 7.4, 160 mL)中,称取0.15 mmol 六水合氯化铁溶于40 mL水中。向脂质体溶液中先滴加多酚溶液,充分搅拌0.5 h后,在搅拌条件下缓慢滴加氯化铁溶液,完全混合后继续反应5 min,之后用纯水作为透析介质,经切向流超滤膜包(300K)除去未反应原料,透出4L液体后停止超滤,得金属多酚网络涂层修饰的纳米药物(RST@Liposome@MPN)(API含量:0.85 mg/mL)。
(S3)取步骤(S2)所得得金属多酚网络涂层修饰的纳米药物(100 mL),向体系中加入透明质酸钠溶液(100 mL,1 mg/mL,Mw:10kD),充分搅拌2h后,用纯水作为透析介质,经切向流超滤膜包(300K)除去未反应原料,超滤过程需要持续进行搅拌,透出2L液体后停止超滤并浓缩,将所得样品冻干,即得具有靶向作用的诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA10kD) (API含量:0.97 mg/mL)。
图1是实施例1步骤(S1)所得负载瑞舒伐他汀的脂质体溶液(RST@Liposome)的cryo-TEM图。可以看出活性药物分子被成功地负载进包含磷脂双分子层的脂质体内部。
使用Malvern粒度仪测得所得载药脂质体RST@Liposome的DLS粒径为145.2 nm,PDI:0.14。冷冻电镜(Cryo-TEM)测试结果表明,瑞舒伐他汀药物被成功地负载于脂质体内部,载药后的脂质体粒径为131nm,这与DLS测试所得的水合粒径为 145.2 nm相符合。将脂质体溶液使用Triton溶液破乳后使用色谱法测定料液中总药量,随后使用色谱法测定经超滤离所分离出的未包封的游离药。以如下所示的计算公式计算得出包封率为98%,载药量为2.0 mg/mL。
图2是实施例1所得诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA10kD)的TEM图。可以看出,所得纳米药物递送系统成球形,分散性良好,表现出球形形貌,粒径在150nm左右。与单纯负载药物脂质体的冷冻电镜结果相比,纳米药物表现出颜色更深的厚度约为10 nm的涂层,表明多酚中和Fe在脂质体表面成功经配位组装形成金属多酚网络(MPN)涂层。动态光散射(DLS)的测试结果表明,金属多酚网络涂层修饰后所得RST@Liposome@MPN的水合粒径在164.9 nm, 与单纯负载药物的脂质体相比,粒径增长了19.7 nm,这表明脂质体表面成功生成了金属多酚网络涂层;进一步的,靶向配体修饰后所得RST@Liposome@MPN@HA的水合粒径为176.4nm,与未修饰靶向配体的RST@Liposome@MPN相比,增长了11.5 nm,这表明靶向配体HA的成功修饰。并且RST@Liposome@MPN@HA10kD的水合粒径为176.4 nm的结果与透射电镜图片展示的结果相符合。
实施例1中,RST @Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD三者的Zeta电位分别为-17.5 eV、-27.8 eV和-37.2 eV;不同样品的Zeta 电位测试结果表明,金属多酚网络涂层的修饰使得药物表面电负性增加,由涂层修饰前的-17.5 eV增长为-27.8eV, 这可以归因于多酚的成功引入。进一步的靶向配体HA的修饰使得纳米药物表面电负性进一步增加至-37.2 eV,这可以归因于HA的成功配位。
图3是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的XPS图,可以看出,在金属多酚网络涂层修饰后(RST@Liposome@MPN)及靶向配体HA修饰后(RST@Liposome@MPN@HA10kD),样品中均出现了Fe的特征峰,这可以归因于金属多酚网络涂层的成功修饰并且靶向配体的引入方法并不会使得金属多酚网络解体。进一步的对Fe的峰进行分析,结果表明,所得纳米药物中的Fe基本上呈现出归属于三价铁Fe2p3/2 的710.34eV的特征峰,这表明在制备过程中,铁离子的价态未产生明显的变化。
图4是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的XRD图。可以看出,在金属多酚网络修饰前,脂质体(RST@Liposome)呈现出一定的结晶态,而在金属多酚网络修饰后RST@Liposome@MPN和靶向配体修饰后(RST@Liposome@MPN@HA10kD),二者均呈现出无定形的鼓包峰,这可以归因于金属多酚网络涂层为无定形态。
图5是实施例1所得RST@Liposome、RST@Liposome@MPN、RST@Liposome@MPN@HA10kD的红外图谱。可以看出,与单纯载药脂质体(RST@Liposome)相比,金属多酚网络涂层修饰后的RST@Liposome@MPN在1605 cm-1和1190 cm-1展现出新的吸收峰,表明成功基于多酚中的TA和Fe(III)之间的配体作用在脂质体表面构筑了金属多酚网络涂层。进一步的,靶向配体修饰后的RST@Liposome@MPN@HA10kD在1645 cm-1所展示的特征峰可以归因于HA的成功引入。综合以上测试的表征结果与分析,本实施例成功的基于配位作用在脂质体表面构筑了金属多酚网络涂层并进一步引入了靶向配体透明质酸(HA),从而最终制备出RST@Liposome@MPN@HA10kD。
图6A是根据实施例1制得不同Fe含量的浓度的RST@Liposome@MPN@HA10kD在T1和T2成像模式下的MRI图像,图6B是根据实施例1制得不同Fe含量浓度的RST@Liposome@MPN@HA10kD的信号拟合图,拟合图线性好代表性质好,MRI图分别为纯化水和不同倍数稀释的RST@Liposome@MPN@HA10kD样品图像。本发明中基于Fe(III)和多酚中的TA的配位作用在脂质体表面构筑了金属多酚网络涂层,Fe(III)离子的引入使得纳米药物本身有应用于MRI辅助成像的潜力。MRI测试结果表明,所得诊疗一体化纳米药物RST@Liposome@MPN@HA10kD在T1成像中有着优异的辅助成像功能,与纯水相比,RST@Liposome@MPN@HA10kD在高浓度下呈现出更亮更显著的信号特征,这样的亮信号可以有助于对病灶部位的诊断。随着浓度的降低,T1成像中的信号值也随之降低,逐渐衰弱变暗。同时,T1值的倒数和浓度之间线性关系良好,这再次强有力的表明了RST@Liposome@MPN@HA10kD有着作为T1对比剂的潜力。而在T2成像中,并未显示明显的变暗,这是由于纳米药物本身T1信号太强,从而对T2的信号值产生干扰。
实施例2 (不同分子量HA修饰的RST@Liposome@MPN@HA80kD)
称取二硬脂酰基磷脂酰胆碱、培化磷脂酰乙醇胺、胆固醇(质量比为3:1:1),乙醇溶解。加醋酸钙水溶液(250 mM)在 65℃的恒温水浴锅中使脂材溶液充分水化,形成粗制脂质体悬浮液。使用挤出仪分别经过200 nm、100 nm的聚碳酸酯膜挤出控制粒径最终为140nm。使用超滤膜包分离未包封的醋酸钙,收集内液,取20 mL与40 mL瑞舒伐他汀钙(2.5 mg/mL)混匀后,于60℃条件下孵育10 min,得到药物脂质体(RST@Liposome)。
取上述所得所得RST@Liposome(20 mL)分散于Tris-HCl缓冲溶液(pH 7.4, 180mL),向脂质体溶液中滴加多酚溶液(160 mg),在搅拌条件下缓慢滴加氯化铁溶液(40 mg),完全混合后, 超滤除去未反应原料,得金属多酚网络涂层修饰的纳米药物(RST@Liposome@MPN)。
取上述所得RST@Liposome@MPN(100 mL),向体系中加入透明质酸钠溶液(100 mL,1 mg/mL,Mw:80kD),充分搅拌后,超滤除去未反应原料,即得不同分子量HA修饰的具有靶向作用的诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA80kD)。
实施例3
其他条件和实施例1相同,区别仅在于脂质体为二硬脂酰基磷脂酰胆碱、培化磷脂酰乙醇胺、胆固醇按照质量比4:2:1的混合物,脂质体总量不变,仍为720g。图7是实施例3制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA3)的TEM图。
实施例4
其他条件和实施例1相同,区别仅在于步骤(S2)中,160 mg 多酚(单宁酸和邻苯三酚按照质量比3:1的混合多酚)替换为200 mg 多酚(单宁酸和邻苯三酚按照质量比5:1的混合多酚)。图8是实施例4制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA4)的TEM图。
实施例5
其他条件和实施例1相同,区别仅在于步骤(S2)中,160 mg 多酚为单一的单宁酸。图9是实施例5制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA5)的TEM图。
实施例6
其他条件和实施例1相同,区别仅在于步骤(S2)中,160 mg 多酚为单一的邻苯三酚。图10是实施例6制备得到诊疗一体化纳米药物递送系统(RST@Liposome@MPN@HA6)的TEM图。
通过图2(实施例1)、图7(实施例3)、图8(实施例4)、图9(实施例5)、图10(实施例6)的比较,可以看出,当采用单宁酸和邻苯三酚复配的多酚,不会出现药物团聚导致的糊化现象。
试验例1.基于表面等离子共振技术表征HA的靶蛋白CD44与主动靶向MPN包被脂质体亲和力大小
BIAcore T200是新兴的实时定量检测生物大分子之间相互作用的仪器,其核心原理是表面等离子共振(Surface plasmon resonance, SPR)技术,即利用光在玻璃与金属薄膜界面处发生全内反射时渗透到金属薄膜内产生的消逝波,引发金属中的自由电子产生表面等离子体,在入射角或波长为某一适当值的条件下,表面等离子与消逝波发生共振。该仪器可用于分析弱相互作用的平衡常数、热力学常数及速率常数等,简单且快速。
采用捕获法,将CD44蛋白捕获在Fc2,Fc1通道作为参比通道,将配制好的一系列浓度的脂质体样品流经芯片表面,进行相互作用测定。互作缓冲液为:1.0×PBS(pH7.4)。
本实验采用Proten A芯片捕获法,将CD44蛋白捕获于Fc2通道。CD44蛋白捕获条件为:用PBS缓冲液稀释至约4.5μg/mL,流速设置为20μL/min,持续捕获15s,使捕获量达到约150RU水平。
样品分析条件:流速为30μL/min,结合时间为120s,解离时间为1200s。
再生条件:以Glycine缓冲液(pH1.5)作为再生缓冲液,流速为30μL/min,再生30s,再生完成后,稳定芯片60s再分析下一个样品。
分析温度:样品仓温度为15℃,芯片仓温度为25℃。实验采用多循环运行,响应信号以分析时间为横坐标,响应值为纵坐标。所得数据通过BIAcore T200分析软件进行拟合,所采用的拟合模型为1:1 Langmuir结合模型,确定其结合速率常数、解离速率常数及结合解离常数等动力学常数。
供试品与CD44s蛋白的结合测定采用多循环动力学分析法(Kinetic analysis)对数据进行分析。图11是基于表面等离子共振技术表征HA的靶蛋白CD44与主动靶向MPN包被脂质体亲和力测试图,其中各循环的CD44s蛋白捕获水平见图11的A,各轮循环捕获CD44 的量反映芯片捕获蛋白的重复性和分析体系的稳定性,结果表明分析体系稳定性良好,重复性良好。CD44s蛋白与各组纳米药物的多循环动力学测试曲线见图11的B(RST@liposome@MPN)、图11的C(RST@liposome@MPN@HA10kD)、图11的D(RST@liposome@MPN@HA80kD),其结合解离动力学参数计算为:RST@Liposome@MPN不亲和,RST@Liposome@MPN@HA10kD亲和力数值KD=2.024×10-8M,RST@Liposome@MPN@HA80kD亲和力数值KD=8.137×10-8M。结果表明,表面连接HA的分子量的加大,亲和力增加。上述结果质量系统自评估指标均合格,且质控指标Chi<10% Rmax、U-value<25,均达到参数拟合可靠性指标,结果可信。
按照同样条件和方法测试实施例4-6所得RST@Liposome@MPN@HA4、RST@Liposome@MPN@HA5、RST@Liposome@MPN@HA6对CD44的亲和力。实施例4为KD=2.427×10-8M,实施例5为KD=1.322×10-8M,实施例6为KD=9.475×10-7M。说明多酚为单宁酸和邻苯三酚的复配,有利于亲和力的增加。如果为单一的单宁酸或者单一的邻苯三酚,并不能达到增加亲和力的效果。
试验例2纳米药物递送系统对动脉粥样硬化的影响的体内实验
本试验例的目的是验证RST@Liposome(没有金属多酚网络和靶向配体),RST@Liposome@HA10kD(没有金属多酚网络),RST@Liposome@MPN(没有靶向配体),以及实施例1所得具有靶向作用的诊疗一体化纳米药物递送系统RST@Liposome@MPN@HA10kD对动脉斑块的体内治疗作用,明确MPN涂层对增加稳定性的影响。制备RST@Liposome@HA10kD:取S1所得RST@Liposome(100 mL),向体系中加入透明质酸钠(HA)溶液(100 mL,1 mg/mL,Mw:10kD),充分搅拌后,超滤除去未反应原料,即得RST@Liposome@HA10kD。
(1)配制游离瑞舒伐他汀(Drug)的生理盐水溶液(2mg/mL),RST@Liposome,RST@Liposome@HA10kD,RST@Liposome@MPN,RST@Liposome@MPN@HA10kD,种含有的瑞舒伐他汀(Drug)浓度均为2.0 mg/mL。
(2)ApoE-/-小鼠动脉粥样硬化模型的建立:取SPF级ApoE-/-小鼠(5-6周龄,体重20±1g)作为实验动物。给予小鼠适应性高脂饮食(脂肪10%(w/w),胆固醇2%(w/w),胆酸钠0.5%(w/w),其余部分为小鼠普通饲料)喂养24周后造模成功。
(3) 实验动物分组及治疗:
将实验动物随机分为以下各组,每组5只:
动脉粥样硬化模型对照组(A):该组动物不进行任何治疗性处理;
纳米制剂给药组:(B) RST@Liposome,(C) RST@Liposome@HA10kD,(D) RST@Liposome@MPN,(E) RST@Liposome@MPN@HA10kD组:以0.5 mg 瑞舒伐他汀/kg体重的剂量进行静脉注射给药处理.
除动脉粥样硬化模型对照组外,治疗组的治疗每隔2天进行1次,共计给药4周。给药结束后处死动物,油红染色计算斑块面积。
图12为不同载体递送系统对动脉粥样硬化的体内治疗效果。如图所示,静脉注射游离他汀仅能延缓斑块进展,而不能使已有斑块消退,靶向纳米载药治疗则不仅明显遏制了斑块的进展,更出现了斑块体积不同程度的显著逆转和消退。相比较于注射他汀药物,纳米递送体系显示出了其显著主动脉富集功能,相比较于不包被MPN递送体系,这种富集效应在靶向纳米制剂(RST@Liposome@MPN@HA10kD)作用下更为明显。
综上所述,对于小鼠体内动脉粥样硬化而言,口服及静脉给予游离的瑞舒伐他汀都未能呈现出逆转斑块的效果。当将他汀药物负载在本发明所述的纳米递送系统中时,其对于动脉粥样硬化的治疗效果发生了显著的提升,并起到了缩小斑块的治疗效果,带有靶向配体修饰的纳米系统效果更佳。
试验例3不同HA分子量修饰的脂质体体内药代动力学对比
6周龄ApoE-/-小鼠高脂饮食饲养24周,主动脉斑块生成造成AS动物模型。将造模成功的动物按血脂和体重随机分为斑块模型对照组A1,口服他汀组B1,静脉他汀组C1,非靶向纳米他汀制剂组D1(RST@Liposome@MPN, 5 mg/kg),靶向纳米他汀制剂-1(E1 RST@Liposome@MPN@HA10kD,剂量5 mg/kg),靶向纳米他汀制剂-2(F1,RST@Liposome@MPN@HA80kD,剂量5 mg/kg,iv),每组5只。治疗每2天一次,共治疗27天,疗程3周。疗程结束后行主动脉斑块病理学(en-face),靶向制剂短时间可实现AS模型小鼠主动脉斑块逆转,且在(E1)RST@Liposome@MPN@HA10kD制剂组呈现约显著的斑块逆转。图13是服用不同药物对小鼠斑块逆转体积的影响。可以看出,开发配体偶联的主动靶向纳米递送体系需要关注配体在纳米载体表面的偶联多糖的分子量,作为具有特殊生理功能的配体分子,多糖分子量显著影响靶向效果,实施例2的RST@Liposome@MPN@HA80kD显示体外高亲和力,但在体内不利于靶部位富集,实施例1表现出更优的靶部位富集效应。
试验例4递送系统对动脉易损斑块的体内示踪实验(MRI示踪)效果
HA是CD44的抗体,能够起到靶向易损斑块的作用,MPN含有 Fe离子,可用于MRI造影的T1或T2成像。本实验例的目的是验证本发明实施例制备的 RST@Liposome@MPN,RST @Liposome@MPN@HA10kD对动脉易损斑块的体内示踪效果。
(1)采用上述实施例所述的方法制备负载MRI示踪剂靶向递送系统。
(2)构建小鼠动脉粥样硬化易损斑块模型:取SPF级ApoE-/-小鼠(10周龄,体重20±1g)作为实验动物,给予小鼠适应性高脂饮食(脂肪10%(w/w),胆固醇2%(w/w),胆酸钠0.5%(w/w)喂养40周后开始实验。
(3)实验动物易损斑块示踪:
将实验动物随机分为以下各组,每组6只:
RST@Liposome@MPN@HA10kD组:Fe给药剂量为0.1mg/kg体重;
实验组分别经尾静脉注入相应的示踪剂,并于给药前以及给药后2h进行MRI成像,观察各组动物的动脉粥样硬化易损斑块的识别情况。图14是实施例1制得的RST@Liposome@MPN@HA10kD小鼠动脉粥样硬化易损斑块模型显影前和显影后的MRI图。
在我们之前的研究中发现,与非靶向的RST@Liposome@MPN相比,靶向的RST@Liposome@MPN@HA10kD,其对于易损斑块的示踪效果有了非常显著的提高。实验结果发现,使用本发明所述的表面修饰有靶向配体的靶向递送系统给药有望显著提高MRI示踪剂对动脉易损斑块的识别作用,产生更好的示踪效果。
Claims (10)
1.一种用于易损斑块的纳米药物递送系统,其特征在于,为多层核壳结构,包括负载药物活性成分的脂质体,在脂质体表面的金属多酚网络涂层,以及修饰在金属多酚网络涂层表面的靶向配体;所述靶向配体是能够与易损斑块CD44分子特异性结合的配体;所述药物活性成分选自他汀类药物、贝特类药物、抗凝药物、血管紧张素转换酶抑制剂、钙离子拮抗剂、β受体阻滞剂中的至少一种;
所述金属多酚网络是多价金属离子和多酚类化合物构成的三维网络,所述多价金属离子选自Fe(III)、Mn(III)、Gd(III)、Co(II)、Ni(II)、Cu(II)、Ti(IV)中的至少一种;所述多酚类化合物为单宁酸和邻苯三酚按照质量比3-5:1的复配;
所述靶向配体选自透明质酸、胶原蛋白、选择蛋白、骨桥蛋白、以及单克隆抗体HI44a、HI313、A3D8、H90、IM7中的任意一种或者两种以上的组合。
2.根据权利要求1所述的用于易损斑块的纳米药物递送系统,其特征在于,所述药物活性成分的负载量为0.01~100 mg/mL。
3.根据权利要求1所述的用于易损斑块的纳米药物递送系统,其特征在于,所述药物活性成分的负载量为1-30 mg/mL。
4.根据权利要求1所述的用于易损斑块的纳米药物递送系统,其特征在于,所述药物活性成分选自以下一种或多种:洛伐他汀、阿托伐他汀、瑞舒伐他汀、辛伐他汀、匹伐他汀、普伐他汀、苯扎贝特、环丙贝特、吉非贝齐、阿司匹林、阿西美辛、奥扎格雷钠、替罗非班或药学上可接受的盐。
5.根据权利要求1所述的用于易损斑块的纳米药物递送系统,其特征在于,所述脂质体为磷脂和胆固醇按照质量比3-6:1的复配,其中磷脂选自非离子磷脂或阳离子磷脂中的至少一种。
6.根据权利要求5所述的用于易损斑块的纳米药物递送系统,其特征在于,所述非离子磷脂选自磷脂酰胆碱类、磷脂酰乙醇胺类、磷脂酰甘油类、磷脂酸类、磷脂酰丝氨酸类、磷脂酰肌醇类中的至少一种;所述阳离子磷脂选自(2,3-二油酰基-丙基)-三甲基铵-氯盐、3β-[N-(N',N'-二甲基胺乙基)氨基甲酰基]胆固醇盐酸盐、1,2-二油醇-3-二甲基氨基-丙烷、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯、1,2-双十八烯氧基-3-甲基铵丙烷阳离子脂质中的至少一种。
7.根据权利要求6所述的用于易损斑块的纳米药物递送系统,其特征在于,所述磷脂酰胆碱类选自二硬脂酰基磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二油酰基卵磷脂、氢化大豆磷脂酰胆碱中至少一种,所述磷脂酰乙醇胺类选自二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺、培化磷脂酰乙醇胺中的至少一种,所述磷脂酰甘油类选自二油酰磷脂酰甘油、二硬脂酰磷脂酰甘油中的至少一种,所述磷脂酸类选自叠氮磷酸二苯酯、二硬脂酰磷脂酸、二油酰磷脂酸中的至少一种,所述磷脂酰丝氨酸类选自二棕榈酰基磷脂酰丝氨酸、二硬脂酰基磷脂酰丝氨酸、二肉豆蔻酰基磷脂酰丝氨酸中的至少一种,所述磷脂酰肌醇类选自二棕榈酰磷脂酰肌醇、二硬脂酰磷脂酰肌醇、二油酰基磷脂酰肌醇中的至少一种。
8.根据权利要求5所述的用于易损斑块的纳米药物递送系统,其特征在于,所述脂质体为二硬脂酰基磷脂酰胆碱、培化磷脂酰乙醇胺、胆固醇按照质量比3-4:1-2:1的复配。
9.根据权利要求1-8任一项所述的用于易损斑块的纳米药物递送系统,其特征在于,所述靶向配体为透明质酸,所述多价金属离子为Fe(III),所述药物活性成分为瑞舒伐他汀或其药学上可接受的盐。
10.权利要求1-8任一项所述的纳米药物递送系统在制备治疗/诊断易损斑块试剂中的用途。
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