CN115624653A - 双重缓释骨修复材料及其制备方法 - Google Patents
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Abstract
本发明涉及一种双重缓释骨修复材料，包括钙基生物陶瓷，所述钙基生物陶瓷具有多孔结构，所述孔洞中吸附CaO2@Co‑Fc纳米颗粒；所述CaO2@Co‑Fc纳米颗粒具有Co‑Fc配位化合物包覆CaO2的核壳结构。本发明巧妙利用恶性肿瘤骨缺损区的低氧酸化的特点，基于芬顿反应为原理的化学动力疗法，开发出具有“产ROS‑H+中和‑Ca2+双重缓释”特性的载CaO2@Co‑Fc纳米粒钙基生物陶瓷骨复合材料，可以同步解决肿瘤杀伤与骨修复的时序性问题，并克服了手术治疗、传统放化疗、光动力及光热疗法的局限性，可以安全、有效地实现微创、温和、同步的抗肿瘤‑促成骨联合治疗。
Description
技术领域
本发明涉及仿生材料，尤其涉及一种双重缓释骨修复材料。
背景技术
骨肿瘤的治疗及瘤性骨缺损的修复一直是临床治疗的难点，具有重大社会需求。然而目前普遍采用的手术+放化疗+骨再植的序列疗法存在骨缺损修复滞后的问题，也不可避免会造成骨缺损的二次损伤，增加了病理性骨折及感染的风险。而传统的化疗/放疗也存在多药毒性，耐药性，肿瘤细胞的无效清除等缺点，反而延缓了瘤性骨缺损的组织再生。而基于新型纳米材料开发的光动力疗法、光热疗法由于其组分难以降解、潜在毒性、光热转换效率低及高温导致的正常组织细胞损伤，不利于成骨进程。
发明内容
本发明巧妙利用恶性肿瘤骨缺损区的低氧酸化的特点，基于芬顿反应为原理的化学动力疗法，开发出具有“产ROS-H+中和-Ca2+双重缓释”特性的载CaO2@Co-Fc纳米粒钙基生物陶瓷骨复合材料，可以同步解决肿瘤杀伤与骨修复的时序性问题，并克服了手术治疗、传统放化疗、光动力及光热疗法的局限性，可以安全、有效地实现微创、温和、同步的抗肿瘤-促成骨联合治疗。
具体的，本发明采用如下技术方案：一种双重缓释骨修复材料，包括钙基生物陶瓷，所述钙基生物陶瓷具有多孔结构，所述孔洞中吸附CaO2@Co-Fc纳米颗粒；所述CaO2@Co-Fc纳米颗粒具有Co-Fc配位化合物包覆CaO2的核壳结构。
通过试验证明，CaO2@Co-Fc纳米粒和钙基生物陶瓷的复合，显著性的提高了CaO2@Co-Fc的肿瘤杀伤，带来了意想不到的技术效果，具体的，CaO2可通过氧化-还原反应产生超氧离子，Co-Fc壳又提供了酸性微环境下触发芬顿反应的催化剂。随着肿瘤微环境下H+的作用，Co-Fc壳降解，CaO2水解生成H2O2，并释放Ca2+。H2O2又在Co-Fc的催化下，生成大量·OH，持续诱导肿瘤细胞凋亡。同时，钙基生物陶瓷，如SA@nHA不断中和肿瘤微环境中的H+，释放Ca2+，持续纠正酸性微环境，抑制肿瘤细胞增殖。由于nHA结构的稳定性，这一过程可持续3周以上。同时，钙基生物陶瓷的pH调节效应减缓了Co-Fc壳的降解速率，延长了·OH及Ca2+的作用时间，共同强化肿瘤杀伤。
通过试验证明，CaO2@Co-Fc纳米粒和钙基生物陶瓷的复合，显著性的提高钙基生物陶瓷的成骨效应：以SA@nHA为例，肿瘤微环境下，SA@nHA不断释放OH-，中和H+，将酸性肿瘤微环境逆转为碱性成骨微环境；从离子环境来说，CaO2@Co-Fc水解及SA@nHA降解均释放大量Ca2+，实现Ca2+的双重缓释，可延长成骨细胞募集时间，为细胞外基质矿化供钙，共同加强成骨效应；从胞外界面来说，SA@nHA提供了成骨细胞分化必不可少的胞外物理界面，有利于成骨细胞的黏附、长入、分化。
在本发明的某些实施例中，超声下将CaO2(3.5～5.5mg)与PVP(110～220mg)溶解于DMF中，并加入(CH3COO)2Co·4H2O(0.1～0.3M)和Fc(COOH)2(0.1～0.3M)，80～100℃下搅拌4～6h，离心得到CaO2@Co-Fc纳米颗粒。二茂铁(Fc)及钴(Co)可交联形成的包裹粒子的“壳状”结构，以CaO2为核心，可以形成稳定的壳-核结构，保护CaO2在中性或碱性下的稳定性。同时，Co-Fc在n-HA酸性环境下可催化铁基芬顿反应，产生大量ROS。
SA@nHA具有疏松多孔的三维结构及巨大的比表面积，可稳定吸附CaO2@Co-Fc于材料内壁，本发明还提供上述双重缓释骨修复材料的制备方法如下：室温下混合海藻酸钙0.4～0.8g、纳米羟基磷灰石1.0～2.0g于水中，加入交联剂Ca-EDTA 3～6g及GDL 0.04～0.08g,搅拌均匀，得到SA@nHA；加入CaO2@Co-Fc纳米颗粒1～2g，混合均匀得到双重缓释骨修复材料。这种修复材料可以采用3D打印机上进行打印，冻干后获得特定形状的修复材料。作为本领域的公知常识，基于该方法，可以根据不同原料配比赋予SA@nHA不同的材料强度。
本发明的有益效果为：
1、同时具有肿瘤杀伤及成骨促进效应。杀肿瘤与成骨互相促进，用于肿瘤性骨缺损的治疗，缩减骨缺损修复时间，克服了传统治疗方式的“痛点”。
2、材料植入后无需后续附加治疗。基于局部铁基芬顿反应杀伤肿瘤，不产生全身化学、物理性毒副作用。
3、具备pH调节效应及pH响应性缓释效应，实现肿瘤微环境到成骨微环境的转变。
4、Ca2+双重缓释促进肿瘤杀伤，同时供应大量成骨相关离子，募集成骨细胞，促进成骨分化，具有优越的骨修复效应。
附图说明
图1.CaO2@Co-Fc合成反应机理图；
图2.a～b分别为不同放大倍数下的CaO2@Co-Fc扫描电镜成像；
图3.SA@nHA成功合成的特征性X射线衍射谱；
图4.a～b分别为不同放大倍数下的CaO2@Co-Fc/SA@nHA扫描电镜成像；
图5.CaO2@Co-Fc、CaO2@Co-Fc/SA@nHA体内抗肿瘤效果图；
图6.CaO2、CaO2@Co-Fc、CaO2@Co-Fc/SA@nHA植入后肿瘤体积缩小曲线；
图7.CaO2@Co-Fc、SA@nHA、CaO2@Co-Fc/SA@nHA修复骨缺损的microCT重建图；
图8.CaO2@Co-Fc、SA@nHA、CaO2@Co-Fc/SA@nHA修复骨缺损的骨体积分数定量图。
具体实施方式
为更进一步阐述本发明为实现预定发明目的所采取的技术手段及功效，以下结合附图及较佳实施例，对依据本发明的具体实施方式、结构、特征及其功效，详细说明如后。
实施例1，载CaO2@Co-Fc纳米粒SA@nHA
CaO2@Co-Fc纳米颗粒的制备：将CaCl2(0.1g)和PVP(0.35g)溶于15mL乙醇，连续搅拌下加入NH3·H2O(0.8M，1mL)并滴加H2O2(1M，0.2mL)，以12000rpm离心10分钟制备CaO2纳米颗粒。超声下将CaO2(3.5～5.5mg)与PVP(110～220mg)溶解于18mL DMF并加入(CH3COO)2Co·4H2O(0.1～0.3M，0.2mL)和Fc(COOH)2(0.1～0.3M，0.2mL)，80～100℃下搅拌4～6h，离心得到CaO2@Co-Fc纳米颗粒。其合成机制如图1所示(见)扫描电镜图如图2a和2b所示，从图中可以看出，具有Co-Fc配位化合物包覆CaO2的核壳结构。
SA@nHA包载CaO2@Co-Fc复合材料制备及3D打印：室温下混合海藻酸钙0.4g，纳米羟基磷灰石1.2g于20mL纯水，加入交联剂Ca-EDTA3～6g及GDL 0.04～0.08g,13000r/min下搅拌5min，其XRD如图3所示。加入CaO2@Co-Fc纳米颗粒1～2g，混合均匀后，即可采用3D打印机打印或置于固定形狀的容器内冻干，以获得具有特定形状的CaO2@Co-Fc包载SA@nHA复合植入材料，其SEM见图4，从图4可以看出，SA@nHA具有多孔结构，孔洞中吸附CaO2@Co-Fc纳米颗粒。
1)CaO2@Co-Fc/SA@nHA复合体系的抗肿瘤效应评估
CaO2@Co-Fc是本发明复合体系中的抗肿瘤作用部分，因此，将本发明的CaO2@Co-Fc/SA@nHA复合体系与CaO2@Co-Fc的抗肿瘤效果进行对比。
构建小鼠乳腺癌成瘤模型，分别将用于抗肿瘤部分CaO2@Co-Fc材料、本实施例得到的CaO2@Co-Fc/SA@nHA植入小鼠乳腺癌成瘤模型14天，进行5组平行对比试验，试验结果如图5所示。从图中可以看出，植入CaO2@Co-Fc/SA@nHA的模型的肿瘤体积相比于植入CaO2@Co-Fc的模型的肿瘤体积出现了显著缩小。进一步地，对肿瘤体积进行了跟踪，发现植入CaO2@Co-Fc/SA@nHA的模型的肿瘤生长速度相比于植入CaO2@Co-Fc的模型的肿瘤生长速度出现了显著区别，植入CaO2@Co-Fc的模型的肿瘤还保持生长，生长速度(斜率)为正；而植入CaO2@Co-Fc/SA@nHA的模型的肿瘤生长速度为负，表明CaO2@Co-Fc/SA@nHA复合材料相比于CaO2@Co-Fc具有显著增强的抗肿瘤效应。
这说明：CaO2@Co-Fc/SA@nHA相比于CaO2@Co-Fc，具有显著的抗肿瘤效果，这可能是因为CaO2可通过氧化-还原反应产生超氧离子，Co-Fc壳又提供了酸性微环境下触发芬顿反应的催化剂。随着肿瘤微环境下H+的作用，Co-Fc壳降解，CaO2水解生成H2O2，并释放Ca2+。H2O2又在Co-Fc的催化下，生成大量·OH，持续诱导肿瘤细胞凋亡。同时，SA@nHA不断中和肿瘤微环境中的H+，释放Ca2+，持续纠正酸性微环境，抑制肿瘤细胞增殖。由于nHA结构的稳定性，这一过程可持续3周以上。同时，钙基生物陶瓷的pH调节效应减缓了Co-Fc壳的降解速率，延长了·OH及Ca2+的作用时间，共同强化肿瘤杀伤。
2)CaO2@Co-Fc/SA@nHA复合体系的骨修复效应评估
SA@nHA是本发明复合体系中的骨修复作用部分，而CaO2@Co-Fc中由于其含有钙离子，也可能一定程度上促进骨修复。因此，将本发明的CaO2@Co-Fc/SA@nHA复合体系与CaO2@Co-Fc、CaO2@Co-Fc的骨修复效果进行对比。
构建兔股骨缺损模型，分别将CaO2@Co-Fc材料、SA@nHA材料、本实施例得到的CaO2@Co-Fc/SA@nHA植入兔股骨缺损模型，进行对比试验，12周后，micro CT三维重建结果显示，植入CaO2@Co-Fc/SA@nHA后，骨缺损位点的骨小梁成骨及皮质骨愈合显著增强，如图7所示。
对micro CT三维重建后进行骨小梁分析，发现CaO2@Co-Fc/SA@nHA复合材料植入后，骨体积分数BV/TV：7.0242±1.2302％，而CaO2@Co-Fc植入组为0.4840±0.0300％，SA@nHA植入组为3.9905±0.4630％，如图8所示。CaO2@Co-Fc/SA@nHA复合材料的骨体积分数显著大于CaO2@Co-Fc和SA@nHA的骨体积分数之和。这可能是因为：肿瘤微环境下，SA@nHA不断释放OH-，中和H+，将酸性肿瘤微环境逆转为碱性成骨微环境；从离子环境来说，CaO2@Co-Fc水解及SA@nHA降解均释放大量Ca2+，实现Ca2+的双重缓释，可延长成骨细胞募集时间，为细胞外基质矿化供钙，共同加强成骨效应；从胞外界面来说，SA@nHA提供了成骨细胞分化必不可少的胞外物理界面，有利于成骨细胞的黏附、长入、分化。
由上可知，本发明将CaO2@Co-Fc和SA@nHA结合，显著性提升了SA@nHA的骨修复性能和CaO2@Co-Fc的抗肿瘤性能，两者协效，带来了意想不到的技术效果。
实施例2
CaO2@Co-Fc纳米颗粒的制备：将CaCl2(0.1g)和PVP(0.35g)溶于15mL乙醇，连续搅拌下加入NH3·H2O(0.8M，1mL)并滴加H2O2(1M，0.2mL)，以12000rpm离心10分钟制备CaO2纳米颗粒。超声下将CaO2(3.5～5.5mg)与PVP(110～220mg)溶解于18mL DMF并加入(CH3COO)2Co·4H2O(0.1～0.3M，0.2mL)和Fc(COOH)2(0.1～0.3M，0.2mL)，80～100℃下搅拌4～6h，离心得到CaO2@Co-Fc纳米颗粒。其合成机制如图1所示(见)扫描电镜图如图2a和2b所示，从图中可以看出，具有Co-Fc配位化合物包覆CaO2的核壳结构。
SA@nHA包载CaO2@Co-Fc复合材料制备及3D打印：室温下混合海藻酸钙0.4g，纳米羟基磷灰石1.2g于20mL纯水，加入交联剂Ca-EDTA3～6g及GDL 0.04～0.08g,13000r/min下搅拌5min，其XRD如图3所示。加入CaO2@Co-Fc纳米颗粒1～2g，混合均匀后，即可采用3D打印机打印或置于固定形狀的容器内冻干，以获得具有特定形状的CaO2@Co-Fc包载SA@nHA复合植入材料，SEM图可以看出，SA@nHA具有多孔结构，孔洞中吸附CaO2@Co-Fc纳米颗粒。
参照实施例1的方案进行抗肿瘤效应和骨修复效应评估，试验结果表明，植入本实施例的CaO2@Co-Fc/SA@nHA的模型的肿瘤生长速度为负；植入本实施例的CaO2@Co-Fc/SA@nHA复合材料12周后，骨体积分数BV/TV：7.0242±1.2302％。
实施例3
CaO2@Co-Fc纳米颗粒的制备：将CaCl2(0.1g)和PVP(0.35g)溶于15mL乙醇，连续搅拌下加入NH3·H2O(0.8M，1mL)并滴加H2O2(1M，0.2mL)，以12000rpm离心10分钟制备CaO2纳米颗粒。超声下将CaO2(3.5～5.5mg)与PVP(110～220mg)溶解于18mL DMF并加入(CH3COO)2Co·4H2O(0.1～0.3M，0.2mL)和Fc(COOH)2(0.1～0.3M，0.2mL)，80～100℃下搅拌4～6h，离心得到CaO2@Co-Fc纳米颗粒。其合成机制如图1所示(见)扫描电镜图如图2a和2b所示，从图中可以看出，具有Co-Fc配位化合物包覆CaO2的核壳结构。
SA@nHA包载CaO2@Co-Fc复合材料制备及3D打印：室温下混合海藻酸钙0.4g，纳米羟基磷灰石1.2g于20mL纯水，加入交联剂Ca-EDTA3～6g及GDL 0.04～0.08g,13000r/min下搅拌5min，其XRD如图3所示。加入CaO2@Co-Fc纳米颗粒1～2g，混合均匀后，即可采用3D打印机打印或置于固定形狀的容器内冻干，以获得具有特定形状的CaO2@Co-Fc包载SA@nHA复合植入材料，SEM图可以看出，SA@nHA具有多孔结构，孔洞中吸附CaO2@Co-Fc纳米颗粒。
参照实施例1的方案进行抗肿瘤效应和骨修复效应评估，试验结果表明，植入本实施例的CaO2@Co-Fc/SA@nHA的模型的肿瘤生长速度为负；植入本实施例的CaO2@Co-Fc/SA@nHA复合材料12周后，骨体积分数BV/TV：7.0242±1.2302％。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭示如上，然而并非用以限定本发明，任何本领域技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的技术内容做出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简介修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (4)
1.一种双重缓释骨修复材料，其特征在于，包括钙基生物陶瓷，所述钙基生物陶瓷具有多孔结构，所述孔洞中吸附CaO2@Co-Fc纳米颗粒；所述CaO2@Co-Fc纳米颗粒具有Co-Fc配位化合物包覆CaO2的核壳结构。
2.根据权利要求1所述的双重缓释骨修复材料，其特征在于，钙基生物陶瓷为海藻酸钠-羟基磷灰石复合材料。
3.根据权利要求1所述的双重缓释骨修复材料，其特征在于，所述CaO2@Co-Fc纳米颗粒的制备方法如下：超声下将CaO2(3.5～5.5mg)与PVP(110～220mg)溶解于DMF中，并加入(CH3COO)2Co·4H2O(0.1～0.3M)和Fc(COOH)2(0.1～0.3M)，80～100℃下搅拌4～6h，离心得到CaO2@Co-Fc纳米颗粒。
4.如权利要求1所述的双重缓释骨修复材料的制备方法，其特征在于，该方法为：室温下混合海藻酸钙0.4～0.6g、纳米羟基磷灰石1.0～1.5g于水中，加入交联剂Ca-EDTA 3～4g及GDL 0.04～0.08g,搅拌均匀；加入CaO2@Co-Fc纳米颗粒1～2g，混合均匀得到双重缓释骨修复材料。
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