Tumor Microenvironment-Responsive Nanococktails for Synergistic Enhancement of Cancer Treatment via Cascade Reactions
Tumor Microenvironment-Responsive Nanococktails for Synergistic Enhancement of Cancer Treatment via Cascade Reactions
复制标题
肿瘤微环境响应性纳米混合物通过级联反应协同增强癌症治疗
DOI：
10.1021/acsami.0c20268
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发表时间：
2021-01-20
影响因子：
9.5
通讯作者：
Li, Changming
中科院分区：
文献类型：
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作者：
Chen, Qiubing;Ma, Ya;Li, Changming
一种依赖不同治疗方法协同效应的联合治疗策略被认为是癌症治疗的一种有效方法。在此，将一种化疗药物（阿霉素，Dox）和锰离子（Mn²⁺）共同负载到基于再生丝素蛋白的纳米粒子（NPs）中，随后将藻蓝蛋白（PC）进行表面偶联，以构建肿瘤微环境激活的纳米鸡尾酒。所得的PC - Mn@Dox - NPs通过对各种刺激因素（酸性pH、过氧化氢（H₂O₂）和谷胱甘肽）做出响应，显示出药物释放速率增加，表明它们能够在肿瘤细胞中高效释放有效载荷（Dox和Mn²⁺）。释放的Dox不仅能够抑制肿瘤细胞的生长，还会产生大量的H₂O₂。升高的H₂O₂通过Mn²⁺介导的类芬顿反应分解为极具危害性的羟基自由基和氧气。此外，产生的氧气参与光动力疗法（PDT）并产生大量的单线态氧。我们的研究表明，这些PC - Mn@Dox - NPs表现出多种生物响应性和良好的生物安全性。通过级联反应整合Dox诱导的化疗、Mn²⁺介导的化学动力学疗法以及基于PC的PDT，与所有单一或双重治疗方法相比，PC - Mn@Dox - NPs在体外和体内都实现了增强的抗癌效果。这些发现表明，PC - Mn@Dox - NPs可被开发为一种有前景的用于级联反应介导的协同癌症治疗的纳米鸡尾酒。
A combination treatment strategy that relies on the synergetic effects of different therapeutic approaches has been considered to be an effective method for cancer therapy. Herein, a chemotherapeutic drug (doxorubicin, Dox) and a manganese ion (Mn2+) were co-loaded into regenerated silk fibroin-based nanoparticles (NPs), followed by the surface conjugation of phycocyanin (PC) to construct tumor microenvironment-activated nanococktails. The resultant PC-Mn@Dox-NPs showed increased drug release rates by responding to various stimulating factors (acidic pH, hydrogen peroxide (H2O2), and glutathione), revealing that they could efficiently release the payloads (Dox and Mn2+) in tumor cells. The released Dox could not only inhibit the growth of tumor cells but also generated a large amount of H2O2. The elevated H2O2 was decomposed into the highly harmful hydroxyl radicals and oxygen through an Mn2+-mediated Fenton-like reaction. Furthermore, the generated oxygen participated in photodynamic therapy (PDT) and produced abundant singlet oxygen. Our investigations demonstrate that these PC-Mn@Dox-NPs exhibit multiple bioresponsibilities and favorable biosafety. By integrating Dox-induced chemotherapy, Mn2+-mediated chemodynamic therapy, and PC-based PDT via cascade reactions, PC-Mn@Dox-NPs achieved enhanced in vitro and in vivo anticancer efficacies compared to all the mono- or dual-therapeutic approaches. These findings reveal that PC-Mn Dox-NPs can be exploited as a promising nanococktail for cascade reaction-mediated synergistic cancer treatment.