CN115531345A - 一种乏氧响应仿生纳米递送系统及其制备方法 - Google Patents
一种乏氧响应仿生纳米递送系统及其制备方法 Download PDFInfo
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Abstract
本发明属于医药技术领域，涉及一种乏氧响应仿生纳米递送系统及其制备方法和用途。本发明所述递送系统通过聚乙二醇‑聚赖氨酸乏氧响应共聚物作为纳米核心，通过薄膜挤出技术在纳米核心外层包裹细胞膜，该乏氧响应仿生递送系统可包裹疏水性药物，其粒径均一稳定，包封率良好，还具有良好的乏氧响应特性，细胞实验显示该乏氧响应仿生递送系统更容易被4T1细胞摄取，经动物实验结果显示，该递送系统在三阴性乳腺癌肺转移模型中具有良好的靶向性，且可抑制三阴性乳腺癌模型中原位肿瘤的生长和肺转移。
Description
技术领域
本发明属于医药技术领域，具体涉及一种乏氧响应仿生纳米递送系统及其制备方法和用途。
背景技术
文献报道了乳腺癌是女性最常见的恶性肿瘤之一。在世界范围内，乳腺癌占所有癌症发病率的10％，女性恶性肿瘤发病率的25％-30％，女性肿瘤相关死亡率的15％。三阴性乳腺癌(Triple Negative Breast Cancer，TNBC)是指雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)均为阴性的乳腺癌，占全部乳腺癌的10％-20％。三阴性乳腺癌与其他亚型乳腺癌相比具有发病年纪轻、恶性程度高、易复发转移、生存率化等特点，加之缺乏内分泌治疗和靶向治疗的理想靶点，三阴性乳腺癌成为目前乳腺癌治疗领域的难题之一。
随着近年来诊断技术的发展、手术治疗水平的提高，原位癌本身已不是乳腺癌致死的主要原因，而癌症的远处转移成为TNBC患者死亡的首要原因。临床实践显示，当乳腺癌发生转移后，传统手术切除疗法已无法有效控制，放射疗法及化疗成为为数不多的抗肿瘤转移方式。放射治疗可以有效杀伤位于转移部位的肿瘤细胞，但其仅对局部转移灶效果显著，此外其对转移部位周围的正常组织也造成一定程度的伤害。尽管近年来放射治疗的辐射范围不断减小，经典的包含区域淋巴结的大视野辐照方式已被取代，靶向杀伤肿瘤能力得以提高，但其不良反应依然较大，患者易产生骨髓抑制、呕吐等症状。细胞毒性化疗药物作为经典的临床抗乳腺癌转移选择，可以对肿瘤细胞进行杀伤并抑制其扩散，但遗憾的是，由于化疗药物缺少靶向肿瘤组织及选择性杀伤肿瘤细胞的能力，导致其临床抑制转移效果欠佳且毒副作用严重；此外多次给予化疗药物易使肿瘤细胞产生多药耐药情况，上述问题极大限制了化疗药物的临床应用。据临床分析，肺部是乳腺癌产生转移概率最大的器官，乳腺癌转移中肺转移概率高达60％，因此如何有效抑制乳腺癌肺转移既是改善乳腺癌治疗效果的关键问题，同时也是亟待克服的难题。
为解决乳腺癌转移难题，纳米药物递送系统应运而生，其主要由人工合成或来源天然的纳米载体与治疗活性物质(药物)构成，粒径在1nm-1000nm之间，典型的纳米药物递送系统包括纳米粒、脂质体、胶束等。纳米药物递送系统中药物可以包载于纳米载体中或嵌合于纳米载体表面。在循环系统中，纳米递药系统较游离药物相比更加稳定，可以减少药物提前释放及清除。此外通过渗透与滞留增强(EPR)效应，递药系统可以将药物被动靶向递送至肿瘤组织以提高药物的抗肿瘤效果。基于上述优势，纳米药物递送系统为抗乳腺癌转移提供了新选择。但现有技术中的纳米制剂仍然存在对转移灶的靶向效率低，药物在转移灶浓集差的缺陷，这些因素限制了乳腺癌转移的治疗效果。
基于现有技术的现状，本申请的发明人拟提供一种乏氧响应仿生纳米递送系统及其制备方法和用途。
发明内容
本发明的目的在于，基于现有技术的现状及存在的缺陷，提供一种乏氧响应仿生纳米递送系统，该递送系统以具有转移灶微环境乏氧响应功能的聚合物为纳米核心，外层包覆具有转移灶靶向功能的中性粒细胞膜。
具体而言，本发明是通过如下技术实现的：
本发明提供了一种乏氧响应仿生纳米递送系统，所述递送系统由乏氧响应纳米核心和细胞膜外壳组成。
所述乏氧响应纳米核心由聚乙二醇-聚赖氨酸乏氧响应共聚物制备，所述共聚物中赖氨酸共价链接乏氧响应基团，所述乏氧响应基团为硝基咪唑基团，该纳米核心可包载疏水性药物。
所述聚乙二醇-聚赖氨酸乏氧响应共聚物具有如下结构式：
所述聚乙二醇-聚赖氨酸乏氧响应共聚物中亲水段为聚乙二醇(PEG),亲脂端为聚赖氨酸共价链接乏氧响应基团，
优选地，所述亲水端PEG分子量为5000Da。
所述疏水性药物为紫杉醇，索拉非尼、阿霉素、全反式维甲酸、阿霉素乏氧响应前药，全反式维甲酸乏氧响应前药、香豆素-6、长链亲脂性二烷基碳菁类染料Dir、长链亲脂性二烷基碳菁类染料Did、长链亲脂性二烷基碳菁类染料DiI中的一种或多种。
所述的乏氧响应仿生纳米递送系统中，所述疏水性药物为全反式维甲酸和阿霉素的组合或者阿霉素乏氧响应前药和全反式维甲酸乏氧响应前药的组合。
所述全反式维甲酸乏氧响应前药具有如下结构式：
所述细胞膜为中性粒细胞膜。
所述中性粒细胞膜为体外培养时加入TNF-α激活后的中性粒细胞膜。
本发明还提供了一种所述的乏氧响应仿生纳米递送系统的制备方法，所述制备方法为薄膜分散法，将聚乙二醇-聚赖氨酸乏氧响应共聚物和疏水性药物溶于有机溶剂，旋转蒸发去除有机溶剂，加入水相超声，制备纳米核心，加入细胞膜，采用薄膜挤出技术制备乏氧响应仿生递送系统。
所述共聚物和疏水性药物的质量比为1:0.01-0.2。
所述共聚物和细胞膜的质量比为1:0.01-2。
本发明进一步提供一种所述的乏氧响应仿生纳米递送系统的用途，所述乏氧响应递送系统可用于特异性靶向乳腺癌的转移病灶。
本发明与现有技术相比，具有如下优势：
1.本发明的药物递送系统可以实现乳腺癌转移灶的有效靶向；
2.本发明的药物递送系统可响应乏氧微环境，实现药物在转移灶的快速释放；
3.细胞膜包裹后生物安全性良好；
4.本发明的递送系统可在同时包裹分化药物和化疗药物后，可实现分化肿瘤干细胞，协同消除肿瘤细胞的效果。
附图说明
图1为聚乙二醇-聚赖氨酸乏氧响应共聚物的合成路径。
图2为化合物3核磁共振氢谱。
图3为化合物4核磁共振氢谱。
图4为化合物5核磁共振氢谱。
图5为化合物5的凝胶色谱分析法(GPC)测定的分子量图。
图6为透射电镜图，A图为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，B图为中性粒细胞膜囊泡，C图为乏氧响应仿生纳米递送系统。
图7为粒度仪检测的粒径图，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，Neutrophil membrane为中性粒细胞膜囊泡，NM-M-NI为乏氧响应仿生纳米递送系统。
图8为Zeta电势图，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，Neutrophil membrane为中性粒细胞膜囊泡，NM-M-NI为乏氧响应仿生纳米递送系统。
图9为模拟体外乏氧环境的紫外吸收光谱，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，M-NI+Na2S2O4为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心加入连二亚硫酸钠共孵育。
图10为模拟体外乏氧环境的粒径变化图，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，M-NI+Na2S2O4为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心加入连二亚硫酸钠共孵育。
图11为4T1细胞摄取图，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，NM-M-NI为乏氧响应仿生纳米递送系统。
图12为4T1肺转移模型中活体成像图，M-NI为聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心，NM-M-NI为乏氧响应仿生纳米递送系统。
图13为4T1原位肿瘤模型中肿瘤重量图，Saline为注射生理盐水组，M-NI为注射聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心组，NM-M-NI为注射乏氧响应仿生纳米递送系统组。
图14为4T1原位肿瘤模型中肿瘤体积变化图，Saline为注射生理盐水组，M-NI为注射聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心组，NM-M-NI为注射乏氧响应仿生纳米递送系统组。
图15为4T1原位肿瘤模型中肿瘤中乙醛脱氢酶(ALDH)表达情况，Saline为注射生理盐水组，M-NI为注射聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心组，NM-M-NI为注射乏氧响应仿生纳米递送系统组。
图16为4T1肺转移模型中肺结节数量，Saline为注射生理盐水组，M-NI为注射聚乙二醇-聚赖氨酸乏氧响应共聚物制备的纳米核心组，NM-M-NI为注射乏氧响应仿生纳米递送系统组。
具体实施方式
现通过以下实施例来进一步描述本发明的有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明所保护范围之内。
实施例1
化合物1-2采用文献(ACS Appl Mater Interfaces，2015,7(9):5444-5453)方法合成。
化合物3：将化合物2置于圆底烧瓶中，加入10ml三氟乙酸和0.5ml氢溴酸/乙酸的混合体系，室温搅拌3小时，将反应液转移至透析袋中(MW 3500)，置于2L纯水中透析24h，每8小时换一次水，冷冻干燥即得化合物。
1H NMR(400MHz,dmso)δ8.06(s,1H),4.23(s,2H),3.47(d,J＝27.9Hz,29H),3.24(s,1H),2.75(s,3H),2.57–2.42(m,5H),1.89(s,1H),1.62(s,1H),1.52(s,4H),1.31(s,2H),1.23(s,1H),0.04–-0.03(m,1H).。
实施例2
化合物4：称取2-羟甲基-1-甲基-5-硝基咪唑，对硝基苯基氯甲酸酯，二甲氨基吡啶，三乙胺，加入四氢呋喃溶解，室温反应8小时，通过硅胶柱柱层析(石油醚:乙酸乙酯＝4：1)纯化得到纯品。
1H NMR(400MHz,dmso)δ8.34(d,J＝8.8Hz,3H),8.13(s,1H),7.60(d,J＝8.8Hz,3H),5.47(s,3H),3.96(s,5H),3.36(s,23H),2.50(s,13H).。
实施例3
化合物5：称取化合物3，化合物4，二甲氨基吡啶，三乙胺，加入N’N-二甲基甲酰胺(DMF)溶解，室温反应8小时，将反应液转移至透析袋中(MW 3500)，置于1L DMF中透析24h，再置于2L纯水中透析24h，冷冻干燥即得化合物5。
1H NMR(400MHz,dmso)δ7.97(d,J＝56.1Hz,47H),7.38(s,1H),7.38(s,24H),5.13(s,46H),4.18(s,9H),3.89(s,68H),3.51(s,532H),3.35(s,655H),2.94(s,47H),2.51(s,153H),1.63(s,7H),1.54(d,J＝49.5Hz,36H),1.36(s,26H),1.24(s,18H).。
实施例4
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，加入1ml(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心。
实施例5
提取中性粒细胞膜，取小鼠胫骨和股骨，分离组织，剪断胫骨和股骨两端，用1ml注射器在胫骨和股骨中吹灌1640培养基至骨头泛白，3000rpm离心3min，弃去培养基，加入2ml重悬细胞悬液离心管加2ml 78％,65％,52％Percoll分离液，再加入细胞悬液，1500rpm，离心30min，吸取细胞层。加入RBC裂解液裂解红细胞，PBS洗3次，加入TNF-α激活中性粒细胞。裂解液裂解细胞后12000rpm，10min，取上清，超速离心100000xg，1h，下层为中性粒细胞膜沉淀。
实施例6
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，紫杉醇1mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测紫杉醇包封率为79.3％。加入提取的中性粒细胞膜1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例7
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，阿霉素0.1mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测阿霉素包封率为90.5％。加入提取的中性粒细胞膜5mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例8
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，香豆素-6 0.5mg，加入1mlN’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测香豆素-6包封率为62.1％。加入提取的中性粒细胞膜20mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例9
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，索拉非尼0.5mg，加入1mlN’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测索拉非尼包封率为42.8％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例10
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，全反式维甲酸0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测包封率为32.6％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例11
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，全反式维甲酸0.5mg，阿霉素0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测全反式维甲酸包封率为22.6％，阿霉素包封率为55.5％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例12
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，全反式维甲酸乏氧响应前药0.5mg，阿霉素乏氧响应前药0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测全反式维甲酸乏氧响应前药包封率为59.2％，阿霉素乏氧响应前药包封率为62.1％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例13
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，荧光探针DiD 0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测荧光探针DiD包封率为63.6％，阿霉素包封率为55.5％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例14
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，荧光探针DiR 0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜，即得乏氧响应纳米核心，检测荧光探针DiR为62.6％，阿霉素包封率为55.5％。加入提取的中性粒细胞膜0.1mg，薄膜挤出器反复挤压，即得乏氧响应仿生递送系统。
实施例15
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，DiR 0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜。
实施例16
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，阿霉素0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜。
实施例17
称取制备的聚乙二醇-聚赖氨酸乏氧响应共聚物10mg，全反式维甲酸0.5mg，阿霉素0.5mg，加入1ml N’N-二甲基甲酰胺(DMF)溶解，置于圆底烧瓶中，油泵旋蒸除去DMF，加入超纯水，超声2小时，过0.45微米滤膜。
验证实施例
验证实施例1
将聚乙二醇-聚赖氨酸乏氧响应共聚物(化合物5)通过凝胶色谱分析法检测分子量，结果如图5所示。
验证实施例2
通过磷钨酸复染样品，使用透射电子显微镜观察实施例4制备的纳米核心，实施例5提取的中性粒细胞膜囊泡，实施例11制备的乏氧响应仿生纳米递送系统。如图6可见制备的乏氧响应仿生纳米递送系统具有双层结构。
验证实施例3
通过纳米粒度仪检测实施例4制备的纳米核心，实施例5提取的中性粒细胞膜囊泡，实施例11制备的乏氧响应仿生纳米粒的粒径和Zeta电势。结果如图7-8所示乏氧响应仿生纳米递送系统粒径相比于纳米核心升高约20nm，Zeta电势接近中性粒细胞膜囊泡。
验证实施例4
通过连二亚硫酸钠模拟体外乏氧环境，与实施例11孵育后通过纳米粒度仪检测粒径变化。结果如图显示10所示，在加入连二亚硫酸钠后，纳米核心粒径快速变大，升高约500nm。
验证实施例5
通过连二亚硫酸钠模拟体外乏氧环境，与实施例4孵育后通过紫外分光光度计检测吸收波长变化。如图9所示，在加入连二亚硫酸钠后，聚乙二醇-聚赖氨酸乏氧共聚物的吸收波长发生红移。
验证实施例6
将4T1细胞铺于24孔板上，基础培养基稀释实施例7和实施例16所得制剂至相同浓度，孵育0.5h和2h，倒置荧光显微镜观察细胞摄取情况。结果如图11所示，乏氧响应仿生纳米递送系统具有更高的细胞摄取。
验证实施例7
将ERFP-4T1细胞通过尾静脉注射于BalB/C小鼠体内，一周后形成肺转移模型，分别注射相同Dir浓度的实施例14和实施例15通过活体成像观察体内分布情况，结果图12显示，乏氧响应仿生纳米递送系统在肺部具有更多的聚集。
验证实施例8
将4T1细胞注射于BalB/C小鼠右侧第二脂肪垫构建小鼠原位乳腺癌模型，14天后，分别间隔2天连续注射生理盐水，实施例11所得制剂，实施例17所得制剂，35d检测小鼠的肿瘤体积和体重，结果如图13-14所示，乏氧响应仿生纳米递送系统可有效抑制肿瘤生长。进一步通过ALDH试剂盒检测原位肿瘤中ALDH的表达情况，结果如图15所示，乏氧响应仿生纳米递送系统可降低ALDH的表达，由于ALDH为肿瘤干细胞标志物，这暗示该乏氧响应仿生纳米递送系统可降低肿瘤中肿瘤干细胞的数量。
验证实施例9
将4T1细胞通过尾静脉注射于BalB/C小鼠体内，一周后形成肺转移模型，分别间隔一天连续四次注射生理盐水，实施例11所得制剂，实施例17所得制剂，第15天检测肺转移的结节数量，结果如图16所示，乏氧响应仿生纳米递送系统可降低肺转移中结节的数量。
Claims (9)
1.一种乏氧响应仿生纳米递送系统，其特征在于，所述递送系统由乏氧响应纳米核心和细胞膜外壳组成；所述乏氧响应纳米核心由聚乙二醇-聚赖氨酸乏氧响应共聚物制备，所述共聚物中赖氨酸共价链接乏氧响应基团，所述乏氧响应基团为硝基咪唑基团，该纳米核心可包载疏水性药物；所述细胞膜为中性粒细胞膜。
2.根据权利要求1所述的乏氧响应仿生纳米递送系统，其特征在于，所述疏水性药物为紫杉醇，索拉非尼、阿霉素、全反式维甲酸、阿霉素乏氧响应前药，全反式维甲酸乏氧响应前药、香豆素-6、长链亲脂性二烷基碳菁类染料Dir、长链亲脂性二烷基碳菁类染料DiD、长链亲脂性二烷基碳菁类染料DiI中的一种或多种。
3.根据权利要求1所述的乏氧响应仿生纳米递送系统，其特征在于，所述疏水性药物为全反式维甲酸和阿霉素的组合或者阿霉素乏氧响应前药和全反式维甲酸乏氧响应前药的组合。
4.根据权利要求1所述的乏氧响应仿生纳米递送系统，其特征在于，所述聚乙二醇-聚赖氨酸乏氧响应共聚物具有如下结构式：
5.根据权利要求1或4所述的乏氧响应仿生纳米递送系统，其特征在于，所述的聚乙二醇-聚赖氨酸乏氧响应共聚物中亲水端为聚乙二醇(PEG),亲脂端为聚赖氨酸共价链接乏氧响应基团。
6.根据权利要求5所述的所述的乏氧响应仿生纳米递送系统，其特征在于，所述的亲水端PEG分子量为5000Da。
7.一种权利要求1-6所述的乏氧响应仿生纳米递送系统的制备方法，其特征在于，采用薄膜分散法，将聚乙二醇-聚赖氨酸乏氧响应共聚物和疏水性药物溶于有机溶剂，旋转蒸发去除有机溶剂，加入水相超声制备纳米核心，加入细胞膜，采用薄膜挤出技术制备乏氧响应仿生递送系统。
8.根据权利要求7所述的制备方法，其特征在于，所述的共聚物和疏水性药物的质量比为1:0.01-0.2。
9.权利要求1所述的乏氧响应仿生纳米递送系统在制备用于特异性靶向乳腺癌的转移病灶药物中的用途。
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