CN113041402B - 具有抗肿瘤和组织缺损修复作用的双功能支架和制备方法 - Google Patents
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Abstract
本发明提供一种具有抗肿瘤和组织缺损修复作用的双功能支架及其制备方法,涉及生物医学材料技术领域。本发明的双功能支架采用以下方法制备得到:制备纳米颗粒:将铁盐、镁盐、多巴胺和/或盐酸多巴胺混合均匀,得到聚多巴胺络合铁离子和镁离子的纳米颗粒;制备乳化糊:将聚乳酸羟基乙酸、有机溶剂、磷酸三钙、表面活性剂以及上述纳米颗粒混合均匀,得到复合乳化糊;打印成型:以上述复合乳化糊为打印墨水,打印形成支架,即得。本发明的支架,具有协同CDT/PTT杀伤肿瘤细胞和促进成骨细胞分化的作用,可以应用于对抗骨转移瘤术后复发以及组织缺损。
Description
技术领域
本发明涉及生物医学材料技术领域,特别是涉及一种具有抗肿瘤和组织缺损修复作用的双功能支架和制备方法。
背景技术
骨是许多晚期癌症最常见的转移部位,如肺癌、乳腺癌和前列腺癌。当癌细胞转移到骨组织后,在骨微环境中与破骨细胞、成骨细胞等相互作用,使骨吸收和骨形成失去平衡,最终造成病理性骨折、疼痛等骨相关事件,严重影响患者的生活质量。
目前,骨转移瘤的局部肿瘤消融主要是外科切除,但癌细胞难以完全切除,容易复发并且不可避免地会伴有骨缺损。除此之外,骨转移瘤患者的骨组织常被转移性肿瘤细胞侵蚀,成骨细胞分化障碍导致骨缺损部位难以自我再生,这是临床上尚未解决的一大难题。骨再生的临床治疗主要包括骨移植物和材料引导的组织再生,但通常存在二次手术并伴随着免疫炎症的风险。因此,研发对抗骨转移瘤术后复发以及骨组织缺损修复的双功能生物材料具有广泛的临床需求和巨大的经济价值。
发明内容
基于此,有必要针对上述问题,提供一种具有抗肿瘤和组织缺损修复作用的双功能支架,该支架具有协同CDT/PTT杀伤肿瘤细胞和促进成骨细胞分化的作用,可以用于对抗骨转移瘤术后复发以及组织缺损。
一种具有抗肿瘤和组织缺损修复作用的双功能支架的制备方法,包括以下步骤:
制备纳米颗粒:将铁盐、镁盐、多巴胺(DA)和/或盐酸多巴胺混合均匀,得到聚多巴胺络合铁离子和镁离子的纳米颗粒;
制备乳化糊:将聚乳酸羟基乙酸(PLAG)、有机溶剂、磷酸三钙(β-TCP)、表面活性剂以及上述纳米颗粒混合均匀,得到复合乳化糊;
打印成型:以上述复合乳化糊为打印墨水,打印形成支架,即得双功能支架。
上述制备方法,以络合铁盐和镁盐的聚多巴胺纳米颗粒为打印原料打印得到支架,金属络合物中的Fe3+发生芬顿反应产生活性氧的化学动力学治疗(chemokinetictherapy,CDT)和聚多巴胺良好的光热治疗(photothemal therapy,PTT)具有协同杀伤肿瘤细胞的作用,同时,金属络合物中的Mg2+具有高效的促成骨细胞分化作用,将该支架植入骨缺损部位可以进行骨再生。本发明制备得到的支架具有协同CDT/PTT杀伤肿瘤细胞和促进成骨细胞分化的作用,原位植入该支架可促进骨转移瘤的肿瘤消融以及缺损修复,为骨转移瘤治疗过程中避免二次手术和肿瘤复发提供了新的策略。
在其中一个实施例中,所述制备纳米颗粒步骤中,铁盐、镁盐和多巴胺的摩尔比为(0.020~0.025):(1.4~1.6):(0.20~0.25)。优选地,铁盐、镁盐和多巴胺的摩尔比为0.0229:1.5:0.2373。
在其中一个实施例中,铁盐为氯化铁,镁盐为氯化镁。
在其中一个实施例中,所述制备乳化糊步骤中,有机溶剂为二氯甲烷(DCM),表面活性剂为吐温20(Tween 20)。
在其中一个实施例中,所述打印成型步骤中,采用3D打印机进行打印。
在其中一个实施例中,所述制备纳米颗粒步骤具体为:将铁盐、镁盐、多巴胺和/或盐酸多巴胺、水混合均匀后,加入Tris溶液继续混合,离心,去除上清液,得到聚多巴胺络合铁离子和镁离子的纳米颗粒。
在其中一个实施例中,所述制备乳化糊步骤具体为:将聚乳酸羟基乙酸和有机溶剂混合均匀,加入磷酸三钙,冰浴超声处理25~35min,加入纳米颗粒、表面活性剂和水,超声混匀,得到复合乳化糊;其中,聚乳酸羟基乙酸、有机溶剂、磷酸三钙、纳米颗粒、表面活性剂和水的比例为(2~4)g:(8~12)mL:(2~4)g:(0.2~0.4)mg:(45~55)μL:(0.8~1.2)mL。
在其中一个实施例中,所述打印成型具体为:将复合乳化糊加入3D打印机的注射器中,调节环境温度为-32~-28℃,进行逐层打印,打印完成进行冷冻干燥,即得双功能支架。
本发明还提供一种采用上述制备方法制备得到的具有抗肿瘤和组织缺损修复作用的双功能支架。本发明双功能支架具有协同CDT/PTT杀伤肿瘤细胞和促进成骨细胞分化的作用。
在其中一个实施例中,所述双功能支架为具有多孔的三维框架结构,所述三维框架结构由6~10层单层结构堆叠而成,每层单层结构由18~20个平行横杆组成,每个横杆的长度为12~16mm,直径为0.3~0.5mm。
与现有技术相比,本发明具有以下有益效果:
本发明的制备方法,以络合铁盐和镁盐的聚多巴胺纳米颗粒为打印原料打印得到支架,金属络合物中的Fe3+发生芬顿反应产生活性氧的化学动力学治疗和聚多巴胺良好的光热治疗具有协同杀伤肿瘤细胞的作用,同时,金属络合物中的Mg2+具有高效的促成骨细胞分化作用,将该支架植入骨缺损部位可以进行骨再生。本发明制备得到的支架具有协同CDT/PTT杀伤肿瘤细胞和促进成骨细胞分化的作用,原位植入该支架可促进骨转移瘤的肿瘤消融以及缺损修复,为骨转移瘤治疗过程中避免二次手术和肿瘤复发提供了新的策略。
附图说明
图1为实施例1中双功能支架FeMg-SC的结构示意图。
图2为实施例1中双功能支架FeMg-SC的扫描电镜图。
图3为实施例和对比例中各种材料的抗压强度和弹性模量对比图。
图4为体内肿瘤消融实验结果图。
图5为体内促成骨实验结果图。
具体实施方式
为了便于理解本发明,以下将给出较佳实施例对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
以下实施例和对比例中涉及的原料均为市售购得。
实施例1
一种双功能支架FeMg-SC,通过以下方法制备得到:
(1)取6.2mg FeCl3·6H2O、142.5mg MgCl2和45mg盐酸多巴胺,在130mL纯水里搅拌1h后,快速注入20mL Tris溶液(22.5mg/ml),继续搅拌3h,10000rpm下离心20min,保留沉淀,用水洗涤3次,得FeMg-NPs(络合铁离子和镁离子的聚多巴胺纳米颗粒)。
(2)取3g聚乳酸羟基乙酸溶于10mL二氯乙烷中,得到PLAG/DCM溶液。
(3)取3gβ-TCP加入PLAG/DCM溶液中,冰浴超声处理30min,形成分散均匀的β-TCP/PLAG/DCM复合溶液。
(4)取0.3mg FeMg-NPs、50μL Tween 20和1mL超纯水,加入β-TCP/PLAG/DCM复合溶液中,超声处理5min,形成均匀的FeMg-PDA/DI water/TCP/PLGA/DCM复合乳化糊。
(5)将上述复合乳化糊转移至与V形喷嘴连接的注射器(容量20mL)中,V形喷嘴的内径为0.4mm,将注射器插入3D打印机的定位器中,调节环境温度为-30℃,使用预先设计的CAD模型进行逐层打印,冷冻干燥12h,得到支架FeMg-SC。其中,预先设计的CAD模型参数为:三维框架结构,每个支架具有8层结构,每层由19个平行的横杆组成,相邻两层的横杆相互垂直,每个横杆的长度为14mm,直径为0.4mm。
本实施例的双功能支架FeMg-SC成品如图1所示,扫描电镜图如图2所示。从图中可以看出本实施例的双功能支架FeMg-SC为具有规则方孔的三维框架结构,横杆直径约为0.4mm。
对比例1
一种支架Blank-SC,通过以下方法制备得到:
(1)取3g聚乳酸羟基乙酸溶于10mL二氯乙烷中,得到PLAG/DCM溶液。
(2)取3gβ-TCP加入PLAG/DCM溶液中,冰浴超声处理30min,形成分散均匀的β-TCP/PLAG/DCM复合溶液。
(3)取50μL Tween 20和1mL超纯水,加入β-TCP/PLAG/DCM复合溶液中,超声处理5min,形成均匀的DI water/TCP/PLGA/DCM复合乳化糊。
(4)将上述复合乳化糊转移至与V形喷嘴连接的注射器(容量20mL)中,V形喷嘴的内径为0.4mm,将注射器插入3D打印机的定位器中,调节环境温度为-30℃,使用预先设计的CAD模型进行逐层打印,冷冻干燥12h,得到支架Blank-SC。其中,预先设计的CAD模型参数为:三维框架结构,每个支架具有8层结构,每层由19个平行的横杆组成,相邻两层的横杆相互垂直,每个横杆的长度为14mm,直径为0.4mm。
对比例2
一种支架Mg-SC,通过以下方法制备得到:
(1)取142.5mg MgCl2和45mg盐酸多巴胺,在130mL纯水里搅拌1h后,快速注入20mLTris溶液(22.5mg/ml),继续搅拌3h,10000rpm下离心20min,保留沉淀,用水洗涤3次,得Mg-NPs(络合镁离子的聚多巴胺纳米颗粒)。
(2)取3g聚乳酸羟基乙酸溶于10mL二氯乙烷中,得到PLAG/DCM溶液。
(3)取3gβ-TCP加入PLAG/DCM溶液中,冰浴超声处理30min,形成分散均匀的β-TCP/PLAG/DCM复合溶液。
(4)取0.3mg Mg-NPs、50μL Tween 20和1mL超纯水,加入β-TCP/PLAG/DCM复合溶液中,超声处理5min,形成均匀的Mg-PDA/DI water/TCP/PLGA/DCM复合乳化糊。
(5)将上述复合乳化糊转移至与V形喷嘴连接的注射器(容量20mL)中,V形喷嘴的内径为0.4mm,将注射器插入3D打印机的定位器中,调节环境温度为-30℃,使用预先设计的CAD模型进行逐层打印,冷冻干燥12h,得到支架Mg-SC。其中,预先设计的CAD模型参数为:三维框架结构,每个支架具有8层结构,每层由19个平行的横杆组成,相邻两层的横杆相互垂直,每个横杆的长度为14mm,直径为0.4mm。
对比例3
一种支架Fe-SC,通过以下方法制备得到:
(1)取6.2mg FeCl3·6H2O和45mg盐酸多巴胺,在130mL纯水里搅拌1h后,快速注入20mL Tris溶液(22.5mg/ml),继续搅拌3h,10000rpm下离心20min,保留沉淀,用水洗涤3次,得Fe-NPs(络合铁离子的聚多巴胺纳米颗粒)。
(2)取3g聚乳酸羟基乙酸溶于10mL二氯乙烷中,得到PLAG/DCM溶液。
(3)取3gβ-TCP加入PLAG/DCM溶液中,冰浴超声处理30min,形成分散均匀的β-TCP/PLAG/DCM复合溶液。
(4)取0.3mg Fe-NPs、50μL Tween 20和1mL超纯水,加入β-TCP/PLAG/DCM复合溶液中,超声处理5min,形成均匀的Fe-PDA/DI water/TCP/PLGA/DCM复合乳化糊。
(5)将上述复合乳化糊转移至与V形喷嘴连接的注射器(容量20mL)中,V形喷嘴的内径为0.4mm,将注射器插入3D打印机的定位器中,调节环境温度为-30℃,使用预先设计的CAD模型进行逐层打印,冷冻干燥12h,得到支架Fe-SC。其中,预先设计的CAD模型参数为:三维框架结构,每个支架具有8层结构,每层由19个平行的横杆组成,相邻两层的横杆相互垂直,每个横杆的长度为14mm,直径为0.4mm。
实验例1
抗压强度和弹性模量测试。
对实施例1和对比例1-3的支架分别进行压缩试验测试,使用万能材料试验机测试不同支架的力学强度,根据测试所得的应力应变曲线计算得到相应的抗压强度和弹性模量。
测试结果如图3所示,从图3中可以看出,支架Blank-SC、Mg-SC、Fe-SC和FeMg-SC的抗压强度和弹性模量相当,抗压强度约为2.4±0.4MPa,弹性模量约为12.1±1.3MPa。
实验例2
体内肿瘤消融实验。
采用现有的常规方法建立4T1小鼠乳腺癌皮下模型,模型建立成功后,将实施例1和对比例1-3的支架分别原位植入肿瘤中。在相同环境中连续光照3天,光线波长为808nm,功率密度为1W/cm2,每次光照治疗时间为4min,随后继续正常饲养至第14天。每天定时测量肿瘤体积大小和小鼠体重,以评估打印支架的抗肿瘤效果。同时,设置两个不进行上述光照的对照组,即分别将PBS和实施例1的支架注入或植入肿瘤中,在其他环境条件相同的情况下,正常饲养14天,每天测量肿瘤重量和体积大小。
结果如图4所示,图4中向下的箭头表示第1-3天进行光照处理,Laser表示进行光照处理的实验组。从图4可以看出:在未进行光照处理时,与PBS组相比,FeMg-SC组可明显观察到肿瘤的增长速度被抑制。在进行光照处理后,Blank-SC组或Mg-SC组中肿瘤体积仍以较快速度增长,而Fe-SC组从第7天开始肿瘤逐渐消融,FeMg-SC组从第3天开始肿瘤就已经开始消融。
实验例3
体内促成骨实验。
采用现有的常规方法建立大鼠颅骨缺损模型,模型建立成功后,将实施例1和对比例1-3的支架分别植入缺损部位后进行缝合,正常喂养6周和12周后,收集大鼠的颅骨进行mirco-CT评价其成骨能力。
结果如图5所示,从图5可以看出,未治疗组(阴性对照组)成骨能力有限,在骨缺损边缘几乎没有新骨形成。相比之下,SC组植入材料的支撑杆与新骨均匀形成。Mg-SC和FeMg-SC治疗组在缺损中心区域均可见骨形成,说明Mg2+的存在极大地促进了缺损区域的骨再生。
从以上体内肿瘤消融实验和促成骨实验结果可以看出,支架FeMg-SC能够协同CDT/PTT有效杀伤肿瘤细胞,促进成骨细胞分化诱导成骨,为骨转移性乳腺癌的肿瘤消融以及骨组织缺损修复提供了新的治疗方法。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.一种具有抗肿瘤和组织缺损修复作用的双功能支架的制备方法,其特征在于,包括以下步骤:
制备纳米颗粒:将摩尔比为(0.020~0.025):(1.4~1.6):(0.20~0.25)的铁盐、镁盐、盐酸多巴胺混合均匀,得到聚多巴胺络合铁离子和镁离子的纳米颗粒;所述铁盐为氯化铁,镁盐为氯化镁;
制备乳化糊:将聚乳酸羟基乙酸、有机溶剂、磷酸三钙、表面活性剂以及上述纳米颗粒混合均匀,得到复合乳化糊;
打印成型:以上述复合乳化糊为打印墨水,打印形成支架,即得双功能支架。
2.根据权利要求1所述的制备方法,其特征在于,所述制备乳化糊步骤中,有机溶剂为二氯甲烷,表面活性剂为吐温20。
3.根据权利要求1所述的制备方法,其特征在于,所述打印成型步骤中,采用3D打印机进行打印。
4.根据权利要求1~3任一项所述的制备方法,其特征在于,所述制备纳米颗粒步骤具体为:将铁盐、镁盐、盐酸多巴胺、水混合均匀后,加入Tris溶液继续混合,离心,去除上清液,得到聚多巴胺络合铁离子和镁离子的纳米颗粒。
5.根据权利要求1~3任一项所述的制备方法,其特征在于,所述制备乳化糊步骤具体为:将聚乳酸羟基乙酸和有机溶剂混合均匀,加入磷酸三钙,冰浴超声处理25~35min,加入纳米颗粒、表面活性剂和水,超声混匀,得到复合乳化糊;其中,聚乳酸羟基乙酸、有机溶剂、磷酸三钙、纳米颗粒、表面活性剂和水的比例为(2~4)g:(8~12)mL:(2~4)g:(0.2~0.4)mg:(45~55)μL:(0.8~1.2)mL。
6.根据权利要求1~3任一项所述的制备方法,其特征在于,所述打印成型具体为:将复合乳化糊加入3D打印机的注射器中,调节环境温度为-32~-28℃,进行逐层打印,打印完成进行冷冻干燥,即得双功能支架。
7.一种采用权利要求1~6任一项所述的制备方法制备得到的具有抗肿瘤和组织缺损修复作用的双功能支架。
8.根据权利要求7所述的双功能支架,其特征在于,所述双功能支架为具有多孔的三维框架结构,所述三维框架结构由6~10层单层结构堆叠而成,每层单层结构由18~20个平行横杆组成,每个横杆的长度为12~16mm,直径为0.3~0.5mm。
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