CN114404604A - 一种碘驱动靶向识别智能响应型磁性纳米递药系统及其制备方法和应用 - Google Patents
一种碘驱动靶向识别智能响应型磁性纳米递药系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种碘驱动靶向识别智能响应型磁性纳米递药系统及其制备方法和应用,以氨基功能化修饰的磁球为载体,壳聚糖为包覆层,戊二醛为交联剂,将紫杉醇包覆于壳聚糖层内,实现紫杉醇的负载并防止提前泄露;随后,利用壳聚糖表面丰富的功能基团成功修饰4‑甲酰苯硼酸,靶向驱动力分子碘与阿霉素分别通过配位作用与硼酸亲和成功修饰于载体表面,最终制得碘驱动靶向识别智能响应型磁性纳米递药系统。本发明所制备碘驱动靶向识别智能响应型磁性纳米递药系统通过硼酸基团实现碘负载,并利用碘驱动力特异性识别甲状腺癌细胞,实现在肿瘤部位的累积和富集,发展了新型甲状腺癌靶向识别策略。
Description
技术领域
本发明属于纳米医用材料制备技术领域,具体涉及一种碘驱动靶向识别智能响应型磁性纳米递药系统及其制备方法和应用。
背景技术
甲状腺癌是内分泌系统最常见的恶性肿瘤,占全世界每年诊断癌症的3.4%,且发病率在持续上升,在某些地区,甲状腺癌已经成为发病率增长最快的癌症。目前,甲状腺癌的标准治疗方法有手术治疗、放射性碘治疗、甲状腺激素治疗以及化疗,这些治疗方法虽然具有抗癌效果,但是均存在一定的局限性。由于纳米药物递送系统相对于传统治疗具有其独特的优势,近年来已有数篇通过纳米药物递送系统用于甲状腺癌治疗的相关文献被报道。等人通过叶酸靶向,将载有药物芬戈莫德的介孔二氧化硅纳米粒子递送至肿瘤部位,以有效抑制侵袭性甲状腺癌细胞增殖和侵袭;Wang等人将抗体贝伐珠单抗偶联到纳米粒子表面,用于血管内皮生长因子靶向和抗血管生成以实现甲状腺癌治疗。
但是,基于肽或抗体靶向的纳米递药系统存在靶组织中积累不足的缺点,这会抑制治疗效果并引发脱靶毒性。此外,基于叶酸的靶向策略同样面临应用限制,比如,其必须依靠自然生理运输过程将纳米货物复合物带到靶标附近才能发挥功效,但其有可能永远不会接近靶标。
因此,为了进一步拓宽靶点类型并提高纳米递药系统的主动靶向特性、降低脱靶率,需要新的策略来设计特定的“内在驱动”靶向给药系统,利用组织的生理特性实现在特定组织的靶向聚集。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供一种碘驱动靶向识别智能响应型磁性纳米递药系统及其制备方法和应用。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
1)以氨基功能化磁球为载体,戊二醛为交联剂,壳聚糖为包覆层,将紫杉醇包覆于壳聚糖层内,制得负载紫杉醇的磁性纳米载体;
2)通过席夫碱反应在紫杉醇负载的磁性纳米载体表面修饰4-甲酰苯硼酸,得到苯硼酸修饰的载药磁性纳米载体;
3)将苯硼酸修饰的载药磁性纳米载体、阿霉素和碘均通过配位键结合,通过外加磁场对生成的反应产物进行分离,经洗脱、干燥处理,制得碘驱动靶向识别智能响应型磁性纳米递药系统。
优选地,步骤1)中,具体操作如下:
通过溶剂热法制备氨基功能化磁球;
将壳聚糖与冰乙酸超声混合均匀,制得混合液;
向混合液中加入氨基功能化磁球和紫杉醇,超声混合均匀,再加入戊二醛,在室温下充分搅拌反应2~8h,将反应物分离、洗涤、干燥,制得紫杉醇负载的磁性纳米载体。
进一步优选地,将壳聚糖和冰乙酸按照(50~100)mg:(20~60)mL的用量比混合,超声处理10~50min;壳聚糖、氨基功能化磁球、紫杉醇和戊二醛的用量比为(50~100)mg:(50~200):(5~20)mg:(5~20)mL,向混合液中加入氨基功能化磁球和紫杉醇后超声处理10min,再加入戊二醛。
优选地,步骤2)中,具体操作为:
向紫杉醇负载的磁性纳米载体和4-甲酰苯硼酸中加入甲醇,超声混匀,得到混合液,向混合液中边搅拌边加入硼氢化钠,持续搅拌反应12~48h,通过外加磁场分离产物并洗涤、干燥,制得苯硼酸修饰的载药磁性纳米载体;
其中,4-甲酰苯硼酸、紫杉醇负载的磁性纳米载体、甲醇和硼氢化钠的用量比为(200~450)mg:(60~160)mg:(10~60)mL:(300~420)mg。
优选地,步骤3)中,具体操作为:
将苯硼酸修饰的载药磁性纳米载体、阿霉素和碘化钾溶液按照(6~18)mg:(3.6~7.2)mg:(0.8~2.8)mg的用量比,在PBS缓冲液中振荡反应1~4h,生成反应产物。
本发明还公开了采用上述的制备方法制得的碘驱动靶向识别智能响应型磁性纳米递药系统,该碘驱动靶向识别智能响应型磁性纳米递药系统的粒径为20~30nm。
本发明还公开了上述的碘驱动靶向识别智能响应型磁性纳米递药系统在制备治疗肿瘤的药物中的应用。
优选地,所述的肿瘤为甲状腺癌。
优选地,所述碘驱动靶向识别智能响应型磁性纳米递药系统能够实现双重pH值响应性药物释放。
与现有技术相比,本发明具有以下有益效果:
本发明公开了一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,首先,以氨基功能化磁球为载体,壳聚糖为包覆层,将紫杉醇包覆于壳聚糖层内,实现紫杉醇的负载;随后,在壳聚糖表面修饰4-甲酰苯硼酸;阿霉素与碘分别通过硼酸亲和与配位作用实现负载,最终制得碘驱动靶向识别智能响应型磁性纳米递药系统。所制备碘驱动靶向识别智能响应型磁性纳米递药系统通过碘靶向特异性识别甲状腺癌细胞,并实现在肿瘤部位的累积和富集;同时,在肿瘤微酸环境下,硼酯键的断裂及壳聚糖的溶解使化疗药物阿霉素和紫杉醇有效释放,两者协同发挥化疗作用,提高纳米药物递送系统的抗肿瘤能力。因此本发明的优势体现在:
(1)利用甲状腺癌细胞对碘的特异性识别摄取能力,成功制备新型甲状腺癌靶向治疗药物,为甲状腺癌靶向治疗提供新策略。
(2)利用碘驱动力实现甲状腺癌细胞的特异性识别摄取,增强纳米递药系统的药物递送能力并降低毒副作用。
(3)采用作用机制不同的两种药物联合化疗降低单一药物的使用剂量,同时增加克服肿瘤耐药性的可能。
(4)采用酸响应的壳聚糖包覆层和硼酯键进行药物负载,在肿瘤微酸环境下实现药物的酸响应性药物释放。
本发明公开了上述方法制备的碘驱动靶向识别智能响应型磁性纳米递药系统,该磁性纳米递药系统粒径均一、磁响应强、药物负载量高、生物安全性好,且对甲状腺癌细胞具有高的特异性识别作用。
本发明公开的上述碘驱动靶向识别智能响应型磁性纳米递药系统因其可实现特异性识别靶向甲状腺癌,并在肿瘤微酸环境下双重酸响应实现两种化疗药的有效递送,实现联合化疗,达到更加高效的肿瘤治疗效果。因此所制备纳米递药系统可作为甲状腺癌靶向治疗药物,为甲状腺癌治疗提供新思路。
附图说明
图1为本发明实施例1制得的碘驱动靶向识别智能响应型磁性纳米递药系统与细胞共培养后的细胞摄取情况;
图2为本发明实施例1制得的碘驱动靶向空载磁性纳米载体与细胞共培养48h后的细胞活性;
图3为本发明实施例1制得的碘驱动靶向识别智能响应型磁性纳米递药系统与细胞共培养48h后的细胞活性。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将结合本发明实施例中的附图,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的实施例,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,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面结合附图对本发明做进一步详细描述:
本发明利用甲状腺具有特异性吸收和浓集碘的性质,通过化学作用实现碘离子的负载,开发并制备出碘驱动靶向识别纳米递药系统用于甲状腺癌的靶向治疗。
阿霉素和紫杉醇是两种使用范围较广的抗癌药物,阿霉素是一种蒽醌类化合物,通过插入DNA链并抑制随后生物大分子的合成而表现出抗癌活性。紫杉醇是一种疏水性抗癌药物,通过诱导和促进微管蛋白聚集形成微管并抑制解聚而表现出抗癌活性。将作用机制不同的两种药物联合化疗可以降低单一药物的剂量,并达到相同的化疗效果,同时增加克服肿瘤耐药性的可能。因此,本发明以氨基功能化的磁性纳米球为载体,壳聚糖为包覆层,紫杉醇和阿霉素为联合药物,碘识别为靶向驱动力制备出一种具有良好生物相容性的碘驱动靶向识别智能响应型磁性纳米递药系统。
具体实施例如下:
实施例1
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。50mg壳聚糖和20mL冰乙酸充分超声混合10min后,该混合液被转移到装有50mg氨基功能化磁球和5mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入5mL戊二醛,在室温下搅拌反应2h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取60mg紫杉醇负载的磁性纳米载体和200mg 4-甲酰苯硼酸,加入10mL甲醇,超声得到混悬液,边搅拌边加入300mg硼氢化钠,并持续搅拌12h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取6mg苯硼酸修饰的载药磁性纳米载体与3.6mg阿霉素和0.8mg碘化钾溶液在20mL PBS缓冲液中振荡反应1h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
实施例2
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。60mg壳聚糖和20mL冰乙酸充分超声混合20min后,该混合液被转移到装有100mg氨基功能化磁球和8mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入8mL戊二醛,在室温下搅拌反应4h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取80mg紫杉醇负载的磁性纳米载体和250mg 4-甲酰苯硼酸,加入20mL甲醇,超声得到混悬液,边搅拌边加入340mg硼氢化钠,并持续搅拌24h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取8mg苯硼酸修饰的载药磁性纳米载体与4.0mg阿霉素和1.2mg碘化钾溶液在20mL PBS缓冲液中振荡反应1.5h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
实施例3
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。70mg壳聚糖和30mL冰乙酸充分超声混合30min后,该混合液被转移到装有100mg氨基功能化磁球和10mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入10mL戊二醛,在室温下搅拌反应4h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取100mg紫杉醇负载的磁性纳米载体和300mg 4-甲酰苯硼酸,加入30mL甲醇,超声得到混悬液,边搅拌边加入360mg硼氢化钠,并持续搅拌24h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取10mg苯硼酸修饰的载药磁性纳米载体与4.8mg阿霉素和1.6mg碘化钾溶液在20mL PBS缓冲液中振荡反应2h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
实施例4
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。80mg壳聚糖和40mL冰乙酸充分超声混合10min后,该混合液被转移到装有150mg氨基功能化磁球和15mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入15mL戊二醛,在室温下搅拌反应6h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取120mg紫杉醇负载的磁性纳米载体和350mg 4-甲酰苯硼酸,加入40mL甲醇,超声得到混悬液,边搅拌边加入380mg硼氢化钠,并持续搅拌36h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取12mg苯硼酸修饰的载药磁性纳米载体与5.6mg阿霉素和2.0mg碘化钾溶液在20mL PBS缓冲液中振荡反应2h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
实施例5
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。90mg壳聚糖和50mL冰乙酸充分超声混合10min后,该混合液被转移到装有150mg氨基功能化磁球和18mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入18mL戊二醛,在室温下搅拌反应6h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取140mg紫杉醇负载的磁性纳米载体和400mg 4-甲酰苯硼酸,加入50mL甲醇,超声得到混悬液,边搅拌边加入400mg硼氢化钠,并持续搅拌36h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取15mg苯硼酸修饰的载药磁性纳米载体与6.4mg阿霉素和2.4mg碘化钾溶液在20mL PBS缓冲液中振荡反应3h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
实施例6
一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,包括以下步骤:
步骤一、将1.0g氯化铁、3.6g无水乙酸钠、6.0g己二胺和25mL乙二醇置于反应釜中,在200℃下反应7h,反应结束后,将反应产物用超纯水洗至中性,在30℃、0.06MPa下真空干燥4h,制得氨基功能化磁球。100mg壳聚糖和60mL冰乙酸充分超声混合10min后,该混合液被转移到装有200mg氨基功能化磁球和20mg紫杉醇的三口烧瓶中,超声混匀搅拌反应10min后,加入20mL戊二醛,在室温下搅拌反应8h。将反应产物分离、洗涤、真空干燥,制得紫杉醇负载的磁性纳米载体;
步骤二、称取160mg紫杉醇负载的磁性纳米载体和450mg 4-甲酰苯硼酸,加入60mL甲醇,超声得到混悬液,边搅拌边加入420mg硼氢化钠,并持续搅拌48h。之后通过外加磁场分离产物并洗涤,干燥,得到苯硼酸修饰的载药磁性纳米载体。
步骤三、称取18mg苯硼酸修饰的载药磁性纳米载体与7.2mg阿霉素和2.8mg碘化钾溶液在20mL PBS缓冲液中振荡反应4h后经过分离、洗涤和干燥制得碘驱动靶向识别智能响应型磁性纳米递药系统。
此外,对实施例1制得的碘驱动靶向识别智能响应型磁性纳米递药系统的靶向性、载体生物安全性和药物毒性进行了研究,结果如下:
将甲状腺癌细胞接种于24孔板中,每孔细胞密度为1×105,然后在37℃,5%CO2培养箱中培养24h。之后将未接枝碘的智能响应性磁性纳米递药系统与碘驱动靶向识别智能响应型磁性纳米递药系统分别加入到预培养的24孔板中,与细胞共孵育2h后,采用细胞爬片技术处理细胞,之后在荧光共聚焦显微镜下观察细胞摄取情况。如图1所示,细胞摄取实验表明,与未经碘修饰的递药系统(图1A)相比,经过碘修饰后的递药系统(图1B)处理后的细胞内绿色和红色荧光信号明显更强,即进入甲状腺癌细胞内的纳米数目远大于未经碘修饰的,说明所制备的碘驱动靶向识别智能响应型磁性纳米递药系统具有强的细胞摄取能力和良好的甲状腺癌靶向识别能力。另外,图1中的B中绿色荧光与红色荧光的重合,说明递药系统在靶向进入并累积在甲状腺癌细胞前,所负载的DOX未提前泄露,可降低对正常组织的毒副作用。
随着碘驱动靶向空载磁性纳米载体浓度的增大,甲状腺癌细胞的存活率基本未发生变化,直至浓度为128μg/mL时,细胞的存活率依然在95%以上,说明载体具有良好的生物安全性(图2)。之后,对碘驱动靶向识别智能响应型磁性纳米递药系统的细胞毒性进行了评估,其中单载纳米递药系统(Fe3O4-PTX@I和Fe3O4@DOX/I)作为对照组用于验证两种药物联合化疗效果。如图3所示,三种纳米递药系统均表现出时间和浓度依赖的细胞毒性。不同浓度的纳米粒子与细胞培养48h后,随着浓度的增大,细胞存活率逐渐降低。且经Fe3O4-PTX@DOX/I处理后,细胞存活率下降速度远大于单载纳米递药系统组。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (9)
1.一种碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,其特征在于,包括以下步骤:
1)以氨基功能化磁球为载体,戊二醛为交联剂,壳聚糖为包覆层,将紫杉醇包覆于壳聚糖层内,制得负载紫杉醇的磁性纳米载体;
2)通过席夫碱反应在紫杉醇负载的磁性纳米载体表面修饰4-甲酰苯硼酸,得到苯硼酸修饰的载药磁性纳米载体;
3)将苯硼酸修饰的载药磁性纳米载体、阿霉素和碘均通过配位键结合,通过外加磁场对生成的反应产物进行分离,经洗脱、干燥处理,制得碘驱动靶向识别智能响应型磁性纳米递药系统。
2.根据权利要求1所述的碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,其特征在于,步骤1)中,具体操作如下:
通过溶剂热法制备氨基功能化磁球;
将壳聚糖与冰乙酸超声混合均匀,制得混合液;
向混合液中加入氨基功能化磁球和紫杉醇,超声混合均匀,再加入戊二醛,在室温下充分搅拌反应2~8h,将反应物分离、洗涤、干燥,制得紫杉醇负载的磁性纳米载体。
3.根据权利要求2所述的碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,其特征在于,将壳聚糖和冰乙酸按照(50~100)mg:(20~60)mL的用量比混合,超声处理10~50min;壳聚糖、氨基功能化磁球、紫杉醇和戊二醛的用量比为(50~100)mg:(50~200):(5~20)mg:(5~20)mL,向混合液中加入氨基功能化磁球和紫杉醇后超声处理10min,再加入戊二醛。
4.根据权利要求1所述的碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,其特征在于,步骤2)中,具体操作为:
向紫杉醇负载的磁性纳米载体和4-甲酰苯硼酸中加入甲醇,超声混匀,得到混合液,向混合液中边搅拌边加入硼氢化钠,持续搅拌反应12~48h,通过外加磁场分离产物并洗涤、干燥,制得苯硼酸修饰的载药磁性纳米载体;
其中,4-甲酰苯硼酸、紫杉醇负载的磁性纳米载体、甲醇和硼氢化钠的用量比为(200~450)mg:(60~160)mg:(10~60)mL:(300~420)mg。
5.根据权利要求1所述的碘驱动靶向识别智能响应型磁性纳米递药系统的制备方法,其特征在于,步骤3)中,具体操作为:
将苯硼酸修饰的载药磁性纳米载体、阿霉素和碘化钾溶液按照(6~18)mg:(3.6~7.2)mg:(0.8~2.8)mg的用量比,在PBS缓冲液中振荡反应1~4h,生成反应产物。
6.采用权利要求1~5中任意一项所述的制备方法制得的碘驱动靶向识别智能响应型磁性纳米递药系统,其特征在于,该碘驱动靶向识别智能响应型磁性纳米递药系统的粒径为20~30nm。
7.权利要求6所述的碘驱动靶向识别智能响应型磁性纳米递药系统在制备治疗肿瘤的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述的肿瘤为甲状腺癌。
9.如权利要求7所述的应用,其特征在于,所述碘驱动靶向识别智能响应型磁性纳米递药系统能够实现双重pH值响应性药物释放。
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