级联纳米复合材料用于抗肿瘤联合治疗

Cascade nanocomposite materials for combined tumor therapy

摘要

通过一锅法合成了树枝状介孔二氧化硅载体(DMSN),以共价键连方式实现了二茂铁分子对二氧化硅表面的后修饰改性,最后通过负载抗癌药物阿霉素(DOX)和乳酸氧化酶(LOD),成功构建了一种多功能级联抗肿瘤纳米药物 DMSN-Fc@LOD@DOX (MFDL).该复合纳米药物对肿瘤微环境具有显著的选择响应性,所负载的阿霉素和乳酸氧化酶均可在肿瘤细胞微环境条件得到有效释放;阿霉素的持续可控释放实现了对肿瘤的化学治疗;乳酸氧化酶可以消耗瘤内富集的乳酸,提升肿瘤微环境中过氧化氢的含量,进而促进基于二价铁离子的芬顿反应,上调肿瘤中的活性氧水平,通过这一酶级联反应设计增强了化学动力学疗效;该体系将酶催化级联反应、化学动力学治疗和化疗整合为一个高效抗肿瘤纳米平台,体外细胞实验和活体实验均显示出较好的肿瘤联合治疗效果,在肿瘤治疗的应用中有着巨大的潜力.

Abstract

Dendritic mesoporous silica (DMSN) carriers are synthesized via a one-pot method. After the post-modification of silica surface by covalently bonded ferrocene molecules and the loading of anticancer drugs doxorubicin (DOX) and lactate oxidase (LOD), a multicomponent cascade nanomedicine DMSN-Fc@LOD@DOX (MFDL) for anti-tumor therapy has been constructed successfully. This composite nanomedicine exhibits significant selective response to the tumor microenvironment, and both the loaded doxorubicin and lactate oxidase can be effectively released under tumor microenvironment. The sustainable and controllable release of DOX enables the chemotherapy for tumors. The LOD will consume the enriched lactate in the tumor, increase the content of H ₂O ₂ in the tumor microenvironment and finally promote the Fenton reaction derived from Fe ²⁺ to upregulate the level of reactive oxygen species (ROS) in the tumor. The chemodynamic therapy (CDT) efficacy can be enhanced through the design of this enzyme cascade reaction. This system integrates the enzyme catalyzed cascade reaction, chemodynamic therapy, and chemotherapy into one efficient antitumor nanoplatform. Both in vitro and in vivo experiments have shown excellent combined anti-tumor therapeutic effects by using this material, which has demonstrated great potential for application.

关键词

纳米复合材料 / 级联反应 / 联合治疗 / 抗肿瘤

Key words

nanocomposite materials / cascade reaction / combination therapy / anti-tumor

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基金资助

国家自然科学基金(21771058)

河南省高校科技创新人才支持计划(23HASTIT002)