CN116807995A - 一种含昆布多糖的主动靶向纳米制剂及其制备方法和应用 - Google Patents

一种含昆布多糖的主动靶向纳米制剂及其制备方法和应用 Download PDF

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CN116807995A
CN116807995A CN202310664315.5A CN202310664315A CN116807995A CN 116807995 A CN116807995 A CN 116807995A CN 202310664315 A CN202310664315 A CN 202310664315A CN 116807995 A CN116807995 A CN 116807995A
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laminarin
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周兴
张成元
袁玉川
娄杰
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Chongqing Quansheng Pharmaceutical Technology Co ltd
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Abstract

本发明提供了一种含昆布多糖的主动靶向纳米制剂及其制备方法和应用，其中纳米制剂，包括核心和包覆所述核心的核壳，所述核心和核壳通过静电相互作用构建形成呈负电性或电中性的所述纳米制剂；所述核心由带负电性活性物质和带正电性活性物质构成；所述核壳为带负电性的昆布多糖或其衍生物；其制备方法，包括以下步骤：制备核心、核壳，然后利用核心、核壳制备靶向纳米制剂；本发明提供的上述含昆布多糖的主动靶向纳米制剂可应用于制备治疗癌症、炎症疾病的药物中；本发明制剂可依靠单核细胞自动募集于诸如乳腺癌肿瘤、脑内神经胶质瘤、结肠炎等炎症相关疾病病灶部位的病理特性，将不同的治疗活性物质递送至相应病灶部位，进而获得显著的治疗效果。

Description

一种含昆布多糖的主动靶向纳米制剂及其制备方法和应用
技术领域
本发明涉及生物医药技术领域，具体而言，涉及一种含昆布多糖的主动靶向纳米制剂及其制备方法和应用。
背景技术
目前临床上相对成熟的纳米制剂主要为抗肿瘤化疗药物的脂质体制剂，该类制剂主要依靠纳米制剂固有的被动靶向能力获得靶向部位优于其他制剂类型的药物分布与治疗效果。这一类制剂已成为当前临床肿瘤治疗当中的核心策略之一。尽管如此，单纯依靠纳米制剂的被动靶向能力所获得病灶部位药物浓度并未达到理想的水平，仍有巨大的提升空间。
在临床前研究阶段，研究者已开始利用病灶部位特有的生理环境设计出一系列的主动靶向纳米制剂。该类制剂目前主要通过化学合成或膜修饰的方式，赋予纳米制剂主动识别病灶部位的能力，进一步提高因被动靶向而提升的病灶部位药物浓度。然而上述制剂：一方面因其主动靶向功能主要依靠人工合成高分子材料或者提取的特定细胞膜，整体工艺技术复杂，制剂安全性风险较大。另一方面，目前的主动靶向策略大部分是站在被动靶向的基础之上，仅能提供对病灶部位的主动识别，而不能主动地迁移至目标位置，其靶向效率不高。以上两者为限制主动靶向纳米制剂进入实际转化过程的主要原因。
发明内容
发明人经研究发现：虽然静脉注射可以使活性物质直接进入体内，快速发挥全身调节作用，但依靠现有技术难以实现正电荷活性物质直接通过静脉注射进入体内，这是受到正电荷物质在血液循环过程中有导致包括溶血等系统性生物安全风险的限制。因此，发明人创新性地将纳米制剂制作呈负电性或电中性并利用静脉注射给药的方式，可以有效避免静脉注射后的系统性生物安全风险。本发明不仅仅是利用昆布多糖的单核细胞主动靶向性，更是利用昆布多糖的负电荷性质在血液循环过程中对纳米系统生物安全性质的提升，昆布多糖只有修饰在表面，并在血液循环的过程中才会体现出体内循环的安全性，因此可以实现安全的静脉注射治疗。
本发明的目的在于提供一种含昆布多糖的静脉注射主动靶向纳米制剂及其制备方法和应用，其制剂可依靠单核细胞自动募集于诸如乳腺癌肿瘤、脑内神经胶质瘤、结肠炎等炎症相关疾病病灶部位的病理特性，将不同的治疗活性物质递送至相应病灶部位，进而获得显著的治疗效果。
本发明的实施例通过以下技术方案实现：
一种含昆布多糖的主动靶向纳米制剂，包括核心和包覆所述核心的核壳，所述核心和核壳通过静电相互作用构建形成呈负电性或电中性的所述纳米制剂；所述核心由含羧基或磷酸基团的负电性活性物质和含氨基的正电性活性物质构成；所述核壳为带负电性的昆布多糖或其衍生物。
进一步地，所述核心和核壳的质量比为0.01-1000。
进一步地，所述核心包括含羧基的负电性免疫调控药(NegIr)/含氨基的正电性抗肿瘤药(PosAT)组合物、含氨基的正电性免疫调控药(PosIr)/含羧基的负电性抗肿瘤药(NegAT)组合物、含氨基的正电性聚合物(PosP)/含羧基的负电性抗肿瘤药(NegAT)组合物、含氨基的正电性聚合物(PosP)/含磷酸基团的免疫调控基因(MrGen)组合物中的一种。
进一步地，所述核心包括吲哚美辛/阿霉素无载体纳米粒、酮洛芬(KETO)/阿霉素无载体纳米粒、水杨酸(ASP)/阿霉素无载体纳米粒、聚赖氨酸(PLL)/伊立替康(Iri)无载体纳米粒、聚乙酰亚胺(PEI)/miRNA-155无载体纳米粒或PLL/水杨酸(ASP)无载体纳米粒中的一种。
进一步地，所述核心中负电性活性物质和带正电性活性物质的质量比为20:1-1:20。
一种含昆布多糖的主动靶向纳米制剂的制备方法，包括以下步骤：
S1.制备核心：将负电性活性物质和带正电性活性物质分别溶于纯水或有机溶剂中，然后将溶解后含负电性活性物质的溶液滴入含正电性活性物质的溶液中，搅拌混合后透析一段时间；
S2.制备核壳：将带负电性的昆布多糖或其衍生物充分溶解于纯水或有机溶剂中，备用；
S3.制备靶向纳米制剂：将S1中透析后的核心离心，取沉淀物，重新分散，然后加入S2制备的核壳溶液，超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散体系。
进一步地，所述有机溶剂包括DSMO、DMF、乙醇、甲醇或乙腈中的一种或多种。
具体地，所述纳米制剂可以是如下情况：
①昆布多糖(LA)/负电性免疫调控药(NegIr)/正电性抗肿瘤药(PosAT)纳米制剂
将NegIr与PosAT按照20:1-1:20的处方比例，准确称量后溶于0.01-100mL溶剂(水、DSMO、DMF、乙醇、甲醇、乙腈)中，在超纯水中透析0.1-100小时后，离心，取沉淀物，重新分散，加入质量比为0.01-1000的LA。超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散剂。
②昆布多糖(LA)/正电性聚合物(PosP)/负电性抗肿瘤药(NegAT)纳米制剂
将PosP与NegAT按照20:1-1:20的处方比例，准确称量后溶于0.01-100mL溶剂(水、DSMO、DMF、乙醇、甲醇、乙腈)中，在超纯水中透析0.1-100小时后，离心，取沉淀物，重新分散，加入质量比为0.01-1000的LA。超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散剂。
③昆布多糖/正电性聚合物(PosP)/巨噬细胞表性调控基因(MrGen)纳米制剂
将PosP与MrGen按照氮磷比(N/P)0.01-1000在纯水中混合后，加入质量比为0.01-1000的LA，离心，取沉淀，重新分散，获得基因纳米制剂。
本发明提供的上述含昆布多糖的主动靶向纳米制剂在用于制备静脉注射治疗癌症、炎症等疾病的药物中的应用。
进一步地，所述癌症、炎症疾病包括但不限于乳腺癌肿瘤、脑内神经胶质瘤、结肠炎、脂肪肝、糖尿病。
本发明实施例的技术方案至少具有如下优点和有益效果：
本发明针对目前主动靶向纳米制剂工艺复杂、安全风险未知等行业问题，基于天然生物大分子昆布多糖的单核细胞靶向能力与负电性，通过静电相互作用构建纳米制剂。该类制剂通过静脉注射进入体内，而后依靠其在血液循环中对单核细胞的主动靶向行为而跟随单核细胞自动募集于诸如乳腺癌肿瘤、脑内神经胶质瘤、结肠炎等炎症相关疾病病灶部位，进而实现将不同的治疗活性物质通过静脉注射的给药途径递送至相应病灶部位，进而获得显著的治疗效果。
另外，本发明可以实现对负电性活性基因药物的体内靶向给药，有效避免基因药物的血液循环降解过程。
同时，本发明中所用组分均为生物安全性已知的市售药用辅料、小分子药物、食品级天然大分子，纳米制剂的生物安全性风险极小且无复杂的化学合成步骤，转化前景巨大。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，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相关的附图。
图1为本发明实验例1提供的DOX/IDM、LA(DOX/IDM)透射电镜图；
图2为本发明实验例2提供的活体成像观察不同药物在肿瘤部位的浓度图；
图3为本发明实验例2提供的肿瘤组织中药物和单核巨噬细胞共定位图像；
图4为本发明实验例3提供的治疗期间小鼠肿瘤体积增长图；
图5为本发明实验例3提供的不同治疗组荷瘤小鼠存活率图；
图6为本发明实验例4提供的静脉注射治疗神经胶质瘤体内治疗效果图；
图7为本发明实验例5提供的静脉注射治疗结肠炎体内治疗效果图；
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，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。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
一、以下提供三种无载体纳米粒(即核心)的制备方法，分别是：吲哚美辛/阿霉素无载体纳米粒、酮洛芬(KETO)/阿霉素无载体纳米粒及水杨酸(ASP)/阿霉素无载体纳米粒：
(1)吲哚美辛/阿霉素无载体纳米粒的制备
实施例1-IDM/DOX(1:4)
将10mg/mL浓度的IDM/DMSO溶液滴入40mg/ml浓度的DOX 10mL DMSO中，搅拌15分钟后透析2小时。
实施例2-IDM/DOX(1:2)
将0.1mg/mL浓度的IDM/DMSO溶液滴入0.2mg/mL浓度的DOX 5mL DMSO中，搅拌20分钟后透析10小时。
实施例3-IDM/DOX(1:1)
将5mg/mL浓度的IDM/DMSO溶液滴入5mg/mL的DOX 2mL DMSO中，搅拌30分钟后透析24小时。
实施例4-IDM/DOX(2:1)
将2mg/mL浓度的IDM/DMSO溶液滴入1mg/ml的DOX 1mL DMSO中，搅拌20分钟后透析0.5小时。
实施例5-IDM/DOX(4:1)
将8mg/mL浓度的IDM/DMSO溶液滴入2mg/mL的DOX 20mL DMSO中，搅拌20分钟后透析36小时。
(2)酮洛芬(KETO)/阿霉素无载体纳米粒的制备
实施例6-KETO/DOX(1:4)
将10mg/mL浓度的KETO/DMSO溶液滴入40mg/ml浓度的DOX 10mL DMSO中，搅拌15分钟后透析2小时。
实施例7-KETO/DOX(1:2)
将0.1mg/mL浓度的KETO/DMSO溶液滴入0.2mg/mL浓度的DOX 5mL DMSO中，搅拌20分钟后透析10小时。
实施例8-KETO/DOX(1:1)
将5mg/mL浓度的KETO/DMSO溶液滴入5mg/mL的DOX 2mL DMSO中，搅拌30分钟后透析24小时。
实施例9-KETO/DOX(2:1)
将2mg/mL浓度的KETO/DMSO溶液滴入1mg/ml的DOX 1mL DMSO中，搅拌20分钟后透析0.5小时。
实施例10-KETO/DOX(4:1)
将8mg/mL浓度的KETO/DMSO溶液滴入2mg/mL的DOX 20mL DMSO中，搅拌20分钟后透析36小时。
(3)水杨酸(ASP)/阿霉素无载体纳米粒的制备
实施例11-ASP/DOX(1:4)
将10mg/mL浓度的ASP/DMSO溶液滴入40mg/ml浓度的DOX 10mL DMSO中，搅拌15分钟后透析2小时
实施例12-ASP/DOX(1:2)
将0.1mg/mL浓度的ASP/DMSO溶液滴入0.2mg/mL浓度的DOX 5mL DMSO中，搅拌20分钟后透析10小时。
实施例13-ASP/DOX(1:1)
将5mg/mL浓度的ASP/DMSO溶液滴入5mg/mL的DOX 2mL DMSO中，搅拌30分钟后透析24小时。
实施例14-ASP/DOX(2:1)
将2mg/mL浓度的ASP/DMSO溶液滴入1mg/ml的DOX 1mL DMSO中，搅拌20分钟后透析0.5小时。
实施例15-ASP/DOX(4:1)
将8mg/mL浓度的ASP/DMSO溶液滴入2mg/mL的DOX 20mL DMSO中，搅拌20分钟后透析36小时。
二、以下提供几种纳米制剂的制备方法，分别是：昆布多糖/吲哚美辛/阿霉素(LA/ IDM/DOX)纳米制剂、昆布多糖(LA)/聚赖氨酸(PLL)/伊立替康(Iri)纳米制剂、昆布多糖/聚 乙酰亚胺(PEI)/miRNA-155纳米制剂。
实施例16：昆布多糖/吲哚美辛/阿霉素(LA/IDM/DOX)纳米制剂
精密称取1mg昆布多糖溶于1mL纯水中，制成1mg/mL的溶液，精密称取实施例1中冻干后的纳米粒1mg溶于纯水中，将二者混合，超声10min，使制剂分散均一。
实施例17：昆布多糖/吲哚美辛/阿霉素(LA/IDM/DOX)纳米制剂
精密称取10mg昆布多糖溶于1mL DMSO中，制成10mg/mL的溶液，精密称取1mg IDM/DOX纳米制剂溶于纯水中，将二者混合，超声3min，使制剂分散均一。
实施例18：昆布多糖(LA)/聚赖氨酸(PLL)/伊立替康(Iri)纳米制剂的制备
将10mg/mL浓度的PLL纯水溶液滴入1mg/ml浓度的Iri 1mL DMSO中，搅拌25分钟后透析24小时。加入11质量当量的LA，超声分散后，离心，取沉淀物得纳米制剂。
实施例19：昆布多糖(LA)/聚赖氨酸(PLL)/伊立替康(Iri)纳米制剂的制备
将1mg/mL浓度的PLL DMSO溶液滴入1mg/ml浓度的Iri 1mL DMSO中，搅拌25分钟后透析48小时。加入20质量当量的LA，超声分散后，离心，取沉淀物得纳米制剂。
实施例20：昆布多糖/聚乙酰亚胺(PEI)/miRNA-155纳米制剂
将PEI与miRNA-155按照N/P＝1:1，准确称量后溶于0.5mL水中，在超纯水中透析18小时后，离心，取沉淀物，重新分散，加入质量比为10倍质量当量的LA。超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散剂。
实施例21：昆布多糖/聚乙酰亚胺(PEI)/miRNA-155纳米制剂
将PEI与miRNA-155按照N/P＝5:1，准确称量后溶于2mL水中，在超纯水中透析18小时后，离心，取沉淀物，重新分散，加入质量比为5倍质量当量的LA。超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散剂。
实验例
需要说明的是，以下所述的DOX+IDM组为吲哚美辛和阿霉素的混合物(即不形成纳米粒结构)，iDOX指的是：吲哚美辛/阿霉素无载体纳米粒(IDM/DOX)。
以实施例1的IDM/DOX、实施例16的LA(IDM/DOX)、实施例18的昆布多糖(LA)/聚赖氨酸(PLL)/伊立替康(Iri)纳米制剂、实施例20的昆布多糖/聚乙酰亚胺(PEI)/miRNA-155纳米制剂为例进行说明。
实验例1、实施例1的IDM/DOX及实施例16的LA(IDM/DOX)透射电镜观察其形貌结构
将实施例1的IDM/DOX及实施例16的LA(IDM/DOX)透析纯化后的溶液分别滴到铜网膜上，静置数分钟后，用滤纸吸取多余的液体，滴加磷钨酸负染1-2min，用滤纸吸去多余负染液，待干后置于低压透射电镜下观察，结果见图1；由图1可知纳米粒及纳米制剂均基本呈现形貌均一的圆形球状颗粒。
实验例2、LA/IDM/DOX纳米颗粒对肿瘤细胞的靶向能力
建立小鼠乳腺癌肿瘤模型，将4T1肿瘤细胞(约2×106个细胞/mL)皮下注射到雌性BALB/c小鼠的右后腿位置，当肿瘤体积达到60-90mm3，可以进行后期的动物实验。
随后将小鼠随机分成5组:Saline组、DOX组、DOX+IDM组、iDOX组、LA/iDOX组。通过尾静脉将药物注射到每只小鼠中，24小时后处死小鼠，切除主要脏器及肿瘤组织，利用小动物活体成像系统观察药物在小鼠主要脏器、肿瘤部位的分布，研究其肿瘤靶向性以及与通过单核细胞靶向到达肿瘤部位的能力，结果见图2-3。
实验例3、LA/IDM/DOX纳米颗粒在体内的抗肿瘤实验
种植异位肿瘤6天后，肿瘤的大小约55-95mm3。随后将小鼠随机分成5组，分别为Saline组、DOX组、DOX+IDM组、iDOX组、LA/iDOX组。测量和记录每只小鼠的肿瘤尺寸与生存情况，治疗21天，绘制肿瘤体积增长曲线与生存曲线，结果见图4-5。
实验例4、LA/PLL/Iri纳米制剂体内神经胶质瘤治疗
在C57小鼠上建立神经胶质瘤模型，10天后，随机分为5组：Saline组，Iri组，LA组,PLL组,LA/PLL/Iri组。每隔三天静脉给药一次，共干预三次。通过活体成像观察脑内肿瘤生长状况并绘制肿瘤生长曲线，结果见图6。
实验例5、昆布多糖/聚乙酰亚胺(PEI)/miRNA-155纳米制剂治疗结肠炎
在Balb/C小鼠上建立结肠炎模型，然后将小鼠随机分为四组：Saline组，LA组，LA+PEI组,LA/PEI/miRNA-155组，同时以正常小鼠作为对照。静脉注射给药10天后处死小鼠，取整个结肠，测量结肠的长度以评价治疗效果，结果见图7。
综上所述，本发明昆布多糖可通过正电荷吸附于带负电荷的纳米粒表面，经单核巨噬细胞表面表达的dectin-1受体与之结合被单核巨噬细胞摄取，利用炎症细胞在相关疾病部位募集，将药物主动靶向递送至病灶部位。本发明所得的纳米制剂具有优异地主动靶向功能以及联合治疗潜力。
以上仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (9)

1.一种含昆布多糖的主动靶向纳米制剂，其特征在于：包括核心和包覆所述核心的核壳，所述核心和核壳通过静电相互作用构建形成呈负电性或电中性的所述纳米制剂；
所述核心由含羧基或磷酸基团的负电性活性物质和含氨基的正电性活性物质构成；所述核壳为带负电性的昆布多糖或其衍生物。
2.根据权利要求1所述的含昆布多糖的主动靶向纳米制剂，其特征在于，所述核心和核壳的质量比为0.01-1000。
3.根据权利要求1所述的含昆布多糖的主动靶向纳米制剂，其特征在于，所述核心包括负电性免疫调控药/正电性抗肿瘤药组合物或正电性免疫调控药/负电性抗肿瘤药或正电性聚合物/负电性抗肿瘤药物或正电性聚合物/免疫调控性基因药物组合物中的一种。
4.根据权利要求3所述的含昆布多糖的主动靶向纳米制剂，其特征在于，所述核心包括吲哚美辛/阿霉素无载体纳米粒、酮洛芬/阿霉素无载体纳米粒、水杨酸/阿霉素无载体纳米粒或聚乙酰亚胺/miRNA-155纳米粒或聚赖氨酸/伊立替康纳米粒中的一种。
5.根据权利要求1所述的含昆布多糖的主动靶向纳米制剂，其特征在于，所述核心中负电性活性物质和带正电性活性物质的质量比为20:1-1:20。
6.一种根据权利要求1-5任一项所述的含昆布多糖的主动靶向纳米制剂的制备方法，其特征在于，包括以下步骤：
S1.制备核心：将负电性活性物质和带正电性活性物质分别溶于纯水或有机溶剂中，然后将溶解后含负电性活性物质的溶液滴入含正电性活性物质的溶液中，搅拌混合后透析一段时间；
S2.制备核壳：将带负电性的昆布多糖或其衍生物充分溶解于纯水或有机溶剂中，备用；
S3.制备靶向纳米制剂：将S1中透析后的核心离心，取沉淀物，重新分散，然后加入S2制备的核壳溶液，超声分散后，离心，取沉淀物，重新分散后得到纳米制剂分散体系。
7.根据权利要求6所述的含昆布多糖的主动靶向纳米制剂的制备方法，其特征在于，所述有机溶剂包括DSMO、DMF、乙醇、甲醇或乙腈中的一种或多种。
8.一种含昆布多糖的主动靶向纳米制剂在用于制备治疗癌症、炎症疾病的药物中的应用。
9.根据权利要求8所述的含昆布多糖的主动靶向纳米制剂的应用，其特征在于，所述癌症、炎症疾病包括肿瘤、结肠炎、脂肪肝、糖尿病。
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