CN116602923A - 一种用于关节炎治疗的靶向仿生纳米治疗载体系统 - Google Patents
一种用于关节炎治疗的靶向仿生纳米治疗载体系统 Download PDFInfo
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Abstract
本发明的目的是提供一种靶向仿生纳米治疗载体系统，能够携带抗炎物质更准确地识别和调控炎症环境的巨噬细胞，从而实现精准协同抗炎治疗。所提供的靶向仿生纳米治疗载体系统，是由磷脂、活性氧响应性芳基硼酸酯修饰磷脂酰丝氨酸（BPS）、胆固醇和助剂构成的纳米脂质体；所述的抗炎物质，为疏水性抗炎物质或亲水性抗炎物质。本发明中制备靶向仿生纳米脂质体系统易于携带抗炎物质，避免正常生理环境中单核巨噬细胞系统清除，而在关节炎部位炎症环境中发生模拟细胞凋亡的转变，从而实现针对关节炎部位巨噬细胞的靶向协同抗炎治疗。
Description
技术领域
本发明属于纳米生物技术领域，具体涉及一种用于关节炎治疗的靶向仿生纳米治疗载体系统。
背景技术
炎症反应是先天免疫系统为移除有害刺激或病原体及促进修复的保护措施，但抑炎、致炎失衡则与关节炎、动脉粥样硬化、帕金森病、某些肿瘤，及病变受损组织再生不佳等密切相关，这些炎症相关疾病严重影响人类的身体健康和生活质量。抗炎被视为防治这些炎症相关疾病的重要策略，但如何提高抗炎效果，实现精准治疗仍是制约该策略成功的难点。
近年来，人们认识到巨噬细胞具有极强的可塑性和功能多样性，在炎症等病理过程中发挥重要作用，靶向调控其极性和相应功能正成为治疗关节炎等炎症相关疾病的重要策略。鉴于巨噬细胞可识别凋亡细胞表面的磷脂酰丝氨酸（PS）来激活吞噬及自身向抗炎M2亚型极化，利用凋亡细胞仿生信号PS可构建靶向巨噬细胞的协同抗炎治疗系统。然而，正常生理环境中单核巨噬细胞系统的存在限制了PS仿生治疗系统直接靶向炎症环境中的巨噬细胞，治疗作用受到限制。
发明内容
本发明的目的是提供一种靶向仿生纳米治疗载体系统，能够携带抗炎物质更准确地识别和调控炎症环境的巨噬细胞，从而实现精准协同抗炎治疗。
本发明首先提供一种靶向仿生纳米治疗载体系统，是由磷脂、活性氧响应性芳基硼酸酯修饰磷脂酰丝氨酸（BPS）、胆固醇和助剂构成的纳米脂质体；
其中芳基硼酸酯修饰磷脂酰丝氨酸（BPS），其结构式如下：
所述的芳基硼酸酯修饰磷脂酰丝氨酸（BPS）是4-硝基苯基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苄基酯（NBC）和磷脂酰丝氨酸反应获得的；
所述的磷脂为磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酸或磷脂酰甘油中的一种或几种；
所述的助剂为吐温、胆酸、脱氧胆酸盐和司盘中的一种或几种；作为优选，所述的助剂为胆酸或脱氧胆酸；
所述的载体系统中，其中胆固醇与磷脂的摩尔比为1:4~6；
所述的助剂与磷脂的摩尔比为1：1~40；
所述的BPS与磷脂的摩尔比为1：2~10；
本发明所提供的仿生纳米治疗载体系统可用于包载抗炎物质；
所述的抗炎物质，为疏水性抗炎物质或亲水性抗炎物质；
所述的抗炎物质，为疏水性姜黄素、疏水性雷公藤甲素、疏水性紫杉醇、亲水性双氯芬酸钠、亲水性地塞米松等；
本发明再一个方面还提供一种用上述的靶向仿生纳米治疗载体系统制备的炎症治疗制品，所述的制品为包载有抗炎物质的所述的纳米BPS脂质体载体系统；
所述的治疗制品，其中包载疏水性抗炎物质的制备方法如下：
1）将磷脂、BPS、胆固醇用有机溶剂溶解，并混匀，随后加入疏水性抗炎物质，再次溶解混匀；
2）在真空条件下蒸发有机溶液制得脂质体薄膜；
3）将得到的脂质体薄膜用溶解有助剂的生理盐水水化，得到脂质体悬浮液；
4）脂质体悬浮液通过超声处理后，通过挤出装置过膜后得到载疏水性药物的炎症治疗制品。
所述的治疗制品，其中包载亲水性抗炎物质的制备方法如下：
1）将磷脂、BPS、胆固醇用有机溶剂溶解，并混匀；
2）在真空条件下蒸发有机溶液制得脂质体薄膜；
3）将得到的脂质体薄膜用溶解有助剂、亲水性抗炎物质的生理盐水进行水化，得到脂质体悬浮液；
4）脂质体悬浮液通过超声处理后，通过挤出装置过膜后得到载亲水性药物的炎症治疗制品。
所述的有机溶剂为甲醇、氯仿或乙醇中的一种或几种；优选氯仿；
所述的蒸发优选为采用旋转蒸发仪。
所述的超声功率为100 W~1000 W，时间为1~10 min；
所述的超声优选为探头超声；
所述的挤出过膜的膜孔径为50 nm~500 nm；
所述的挤出过膜的次数为2~6次。
本发明中制备靶向仿生纳米脂质体系统易于携带抗炎物质，避免正常生理环境中单核巨噬细胞系统清除，而在关节炎部位炎症环境中发生模拟细胞凋亡的转变，从而实现针对关节炎部位巨噬细胞的靶向协同抗炎治疗。
附图说明
图1是实施例1-3得到靶向仿生纳米治疗载体系统的透射电镜照片；其中，a是实施例1的载姜黄素的纳米BPS脂质体，b是实施例2的载地塞米松的纳米BPS脂质体，c是实施例3的载姜黄素的纳米BPS脂质体。
图2 是实施例4中流式细胞仪检测表面含PS信号脂质体的百分率结果图。
图3 是实施例5中巨噬细胞摄取仿生纳米BPS脂质体系统的荧光显微镜照片图。
图4是实施例6关节炎模型小鼠治疗效果图。
图5是实施例1制备的载姜黄素的纳米BPS脂质体减轻DMM诱导的OA疼痛的效果数据图。
具体实施方式
本发明提供由磷脂、芳基硼酸酯修饰磷脂酰丝氨酸（BPS）、胆固醇及助剂构成的靶向仿生治疗纳米脂质体载体系统，可以装载亲水性或疏水性抗炎物质。
本发明所使用的芳基硼酸酯修饰磷脂酰丝氨酸（BPS）的结构式如下：
所述的芳基硼酸酯修饰磷脂酰丝氨酸（BPS）是4-硝基苯基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苄基酯（NBC）和磷脂酰丝氨酸反应获得的；其一种具体的制备方法如下：将1mmol的磷脂酰丝氨酸溶解于10mL的氯仿/甲醇（v:v=8:2）中，加入0.30mL的四甲基胍，搅拌均匀；室温下，缓慢滴加含1mmol的NBC的10mL四氢呋喃溶液，搅拌反应6小时，再加入1mL的1M盐酸，搅拌30min，收集有机相，硅胶柱层析分离，得到BPS。
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1载姜黄素的纳米BPS脂质体制备
将6.5μmol的磷脂酰胆碱、1.5μmol的BPS、2μmol的胆固醇和3.75μmol姜黄素先后溶解在5mL氯仿中，震荡混合均匀。经旋转蒸发仪蒸干氯仿，得到脂质薄膜。用5mL含有0.8 μmol的脱氧胆酸钠的生理盐水溶液将脂质薄膜水化，得到脂质体悬浮液。使用探头超声仪超声5min（300 W）后，采用Liposoeasy LE-800挤出仪，在氩气压力下通过100 nm聚碳酸酯膜三次，得到载姜黄素的纳米BPS脂质体悬浮液。所得载姜黄素的纳米BPS脂质体的透射电镜照片如图1中的a所示，平均粒径在100nm左右。
实施例2载地塞米松的纳米BPS脂质体制备
将6.5μmol的磷脂酰胆碱、1.5μmol的BPS、2μmol的胆固醇混合溶解在5mL氯仿中，震荡混合均匀。经旋转蒸发仪蒸干氯仿，得到脂质薄膜。用5mL含有0.5μmol的地塞米松和0.8 μmol的脱氧胆酸钠的生理盐水溶液将脂质薄膜水化，得到脂质体悬浮液。使用探头超声仪超声10 min（300 W），然后采用Liposoeasy LE-800挤出仪，在氮气压力下通过100nm聚碳酸酯膜三次，得到载地塞米松的纳米BPS脂质体悬浮液。所得载地塞米松的纳米BPS脂质体的透射电镜照片如图1中的b所示，平均粒径在140nm左右。
实施例3载姜黄素的纳米BPS脂质体制备
将6.5mmol的磷脂酰胆碱、1.5μmol的BPS、2μmol的胆固醇和3.75μmol姜黄素先后溶解在5mL氯仿中，震荡混合均匀。经旋转蒸发仪蒸干氯仿，得到脂质薄膜。用5mL含有0.8μmol的脱氧胆酸钠的生理盐水溶液将脂质薄膜水化，得到脂质体悬浮液。使用探头超声仪超声5min（100 W），然后采用Liposoeasy LE-800挤出仪，在氩气压力下通过500nm聚碳酸酯膜三次，得到载姜黄素的纳米BPS脂质体悬浮液。所得载姜黄素的纳米BPS脂质体的透射电镜照片如图1中的c所示，平均粒径约为500nm。
实施例4体外模拟炎症活性氧环境的仿生纳米治疗系统响应性转变
根据Annexin V与PS特异性结合的原理，使用含荧光素的Annexin V凋亡试剂盒检测纳米BPS脂质体发生响应性转变后表面出现的PS信号。
取100μL的实施例1所制备的载姜黄素的纳米BPS脂质体悬浮液倒入EP管中，加入5μL的5%H2O2模拟炎症活性氧环境，混匀反应1小时；加入凋亡试剂盒（凯基生物）中等体积的Annexin缓冲液，混匀；随后加入5μL的 Annexin V-FITC，混匀后室温避光孵育30min。孵育结束后加入500μL的PBS清洗，并使用100 kDa分子截止量的超滤离心管进行浓缩，除去多余的Annexin V-FITC溶液。收集离心管中100μL的样品并加入200μL的PBS溶液混匀，采用流式细胞仪（BD FACSCanto）检测表面结合Annexin V-FITC的脂质体的百分率。
同样，分别以未经H2O2处理的实施例1所制备的载姜黄素的纳米BPS脂质体，以及按实施例1方案，采用PS替代BPS制备的载姜黄素的纳米PS脂质体作为对照组，采用上述方法进行检测。如图2所示，结果表明实施例1制备的载药纳米BPS脂质体系统在活性氧环境中发生响应性转变，其表面暴露PS信号。
实施例5巨噬细胞对仿生纳米BPS脂质体系统的摄取行为
首先，按实施例1方案，采用荧光标记物DHPE代替姜黄素制备DHPE-BPS脂质体作为测试组1，其经5%的H2O2处理1h后所得样品作为测试组2，而进一步采用PS代替BPS制备的DHPE-PS脂质体则作为测试组3（阳性对照）；然后，使用荧光显微镜来观察巨噬细胞对上述测试组的摄取行为。
步骤如下：在共聚焦皿中铺板105个/孔的Raw264.7巨噬细胞，放置CO2培养箱过夜。在更换培养基后，分别加入500μM总脂质浓度的各组样品，再与巨噬细胞共孵育1h，吸出所有培养基，在避光条件下加入PBS清洗三次。对于细胞膜染色，加入10μM的细胞膜染色剂DIL在室温条件下作用20min，PBS清洗三次。随后采用荧光显微镜进行拍摄。如图3所示，Raw264.7巨噬细胞几乎没有摄取未经H2O2处理的纳米BPS脂质体系统，而经过H2O2处理的纳米BPS脂质体则由于PS的暴露，能够被巨噬细胞摄取，与阳性对照组表现出的现象一致。
实施例6关节炎模型小鼠的治疗
采用DMM法成功建立小鼠OA模型，并在尾静脉注射实施例1制备的载姜黄素的纳米BPS脂质体，每周1次，连续5次后。在治疗周期结束后，将膝关节脱钙并行石蜡切片，采用HE及S/O染色评估小鼠关节软骨破坏的情况，如图4所示，结果表明关节软骨氨糖的丢失显著减轻，延缓了关节退变。
与此同时，如图5所示，观察到尾静脉注射实施例1制备的载姜黄素的纳米BPS脂质体可以减轻DMM诱导的OA疼痛，在动物行为学上得到明显的改善。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种靶向仿生纳米治疗载体系统，其特征在于，所述的载体系统是由磷脂、活性氧响应性芳基硼酸酯修饰磷脂酰丝氨酸BPS、胆固醇和助剂构成的纳米脂质体，
其中BPS的结构式如下：
。
2.如权利要求1所述的载体系统，其特征在于，所述的芳基硼酸酯修饰磷脂酰丝氨酸是4-硝基苯基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苄基酯和磷脂酰丝氨酸反应获得的。
3.如权利要求1所述的载体系统，其特征在于，所述的磷脂为磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酸或磷脂酰甘油中的一种或几种。
4.如权利要求1所述的载体系统，其特征在于，所述的助剂为吐温、胆酸、脱氧胆酸盐或司盘中的一种或几种。
5.如权利要求1所述的载体系统，其特征在于，所述的载体系统中胆固醇与磷脂的摩尔比为1:4~6，助剂与磷脂的摩尔比为1：1~40；所述的BPS与磷脂的摩尔比为1：2~10。
6.权利要求1-5任一项所述载体系统作为载体在运载抗炎物质中的应用。
7.如权利要求6所述的应用，其特征在于，所述的抗炎物质为疏水性抗炎物质或亲水性抗炎物质。
8.一种炎症治疗制品，其特征在于，所述的制品中使用权利要求1-5任一项所述载体系统来运载抗炎物质。
9.如权利要求8所述的炎症治疗制品，其特征在于，所述的抗炎物质为疏水性抗炎物质，所述的制品的制备方法如下：
1）将磷脂、BPS、胆固醇用有机溶剂溶解，并混匀，随后加入疏水性抗炎物质，再次溶解混匀；
2）在真空条件下蒸发有机溶液制得脂质体薄膜；
3）将得到的脂质体薄膜用溶解有助剂的生理盐水水化，得到脂质体悬浮液；
4）脂质体悬浮液通过超声处理后，通过挤出装置过膜后得到负载疏水性药物的炎症治疗制品。
10.如权利要求8所述的炎症治疗制品，其特征在于，所述的抗炎物质为亲水性抗炎物质，所述的制品的制备方法如下：
1）将磷脂、BPS、胆固醇用有机溶剂溶解，并混匀；
2）在真空条件下蒸发有机溶液制得脂质体薄膜；
3）将得到的脂质体薄膜用溶解有助剂、亲水性抗炎物质的生理盐水进行水化，得到脂质体悬浮液；
4）脂质体悬浮液通过超声处理后，通过挤出装置过膜后得到载亲水性药物的炎症治疗制品。
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116753A1 (en) * | 2004-05-03 | 2007-05-24 | Hermes Biosciences, Inc. | Liposomes useful for drug delivery |
| US20110020242A1 (en) * | 2007-12-12 | 2011-01-27 | Gang Zheng | High-density lipoprotein-like peptide-phospholipid scaffold ("hpps") nanoparticles |
| CN102793668A (zh) * | 2012-08-30 | 2012-11-28 | 绍兴文理学院 | 一种ps-脂质体 |
| CN105999290A (zh) * | 2016-04-21 | 2016-10-12 | 中国人民解放军第四军医大学 | 一种磷脂酰丝氨酸修饰的姜黄素纳米粒 |
| CN106074390A (zh) * | 2016-07-22 | 2016-11-09 | 泰山医学院 | 一种沙利度胺脂质体纳米制剂及其制备方法和应用 |
| CN112138166A (zh) * | 2020-09-27 | 2020-12-29 | 中国人民解放军军事科学院军事医学研究院 | 一种纳米药物、其制备方法及用途 |
| CN113081965A (zh) * | 2021-04-16 | 2021-07-09 | 烟台大学 | 一种基于ros敏感及h2s响应的多功能脂质体及其制备方法和应用 |
| WO2022242762A1 (zh) * | 2021-05-21 | 2022-11-24 | 杭州高田生物医药有限公司 | 一种特定药脂比的药物组合物在抗肿瘤中的应用 |
Family Cites Families (2)
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Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116753A1 (en) * | 2004-05-03 | 2007-05-24 | Hermes Biosciences, Inc. | Liposomes useful for drug delivery |
| US20110020242A1 (en) * | 2007-12-12 | 2011-01-27 | Gang Zheng | High-density lipoprotein-like peptide-phospholipid scaffold ("hpps") nanoparticles |
| CN102793668A (zh) * | 2012-08-30 | 2012-11-28 | 绍兴文理学院 | 一种ps-脂质体 |
| CN105999290A (zh) * | 2016-04-21 | 2016-10-12 | 中国人民解放军第四军医大学 | 一种磷脂酰丝氨酸修饰的姜黄素纳米粒 |
| CN106074390A (zh) * | 2016-07-22 | 2016-11-09 | 泰山医学院 | 一种沙利度胺脂质体纳米制剂及其制备方法和应用 |
| CN112138166A (zh) * | 2020-09-27 | 2020-12-29 | 中国人民解放军军事科学院军事医学研究院 | 一种纳米药物、其制备方法及用途 |
| CN113081965A (zh) * | 2021-04-16 | 2021-07-09 | 烟台大学 | 一种基于ros敏感及h2s响应的多功能脂质体及其制备方法和应用 |
| WO2022242762A1 (zh) * | 2021-05-21 | 2022-11-24 | 杭州高田生物医药有限公司 | 一种特定药脂比的药物组合物在抗肿瘤中的应用 |
Non-Patent Citations (1)
| Title |
|---|
| TROY J. ATTARD，等: "The synthesis of phosphopeptides via the Bpoc-based approach", 《ORG. BIOMOL. CHEM.》, vol. 5, pages 664 - 470 * |
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