Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China.
Department of Radiology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China.
Int J Nanomedicine. 2023 Feb 21;18:933-948. doi: 10.2147/IJN.S390984. eCollection 2023.
Nanomaterials exhibited intrinsic enzyme-like properties due to the unique properties compared with natural enzyme. Carbon dots (CDs) are an important kind of quantum-sized nanomaterials, which have enormous application potential in bio-imaging, drug carrier, and nanosystems. Carbon dots possess intrinsic enzyme-like properties, such as glutathione (GSH) oxidase or peroxidase activities.
A co-delivery nanosystem that could carry siRNA and doxorubucin (DOX) simultaneously has been studied in this work. The co-delivery based on carbon dots was surface-modified with poly-ethylenimine (PEI) and loaded the siMRP1 with chemotherapeutics on the surface with pH-triggered drug release. The CD-PEI was synthesized by one-step microwave assisted method; the PEI was raw materials and passivator during the reaction process that makes CDs exhibit excellent optical property.
The CD-PEI was capable of loading and delivering siMRP1 and DOX to tumors and releasing them synchronously in cells in an acid-triggered manner. The particles exhibited GSH oxidase-like catalytic property, oxidizing GSH to oxidized glutathione with concomitant increase of reactive oxygen species (ROS). We found that silencing of MRP1 by co-delivery system antagonized chemoresistance by increasing DOX accumulation and significantly enhancing the inhibitory effect of cell viability induced by CD-PEI-DOX. The co-delivery system dramatically inhibited tumor growth in xenograft model, and CDs counteracted MRP1 function by siRNA-mediated knockdown of MRP1.
Taken together, we uncover the potential role of CDs with a combination of siRNA and chemotherapeutics in overcoming chemoresistance of lung cancer by suppressing MRP1 and oxidation of GSH. Our findings imply its potential of antagonizing chemoresistance to enhance therapeutic efficiency of doxorubicin in clinical practices of lung cancer treatment.
与天然酶相比，纳米材料具有独特的性质，表现出内在的酶样特性。碳点（CDs）是一种重要的量子纳米材料，在生物成像、药物载体和纳米系统中有巨大的应用潜力。碳点具有内在的酶样特性，如谷胱甘肽（GSH）氧化酶或过氧化物酶活性。
本研究中研究了一种能够同时携带 siRNA 和阿霉素（DOX）的共递药纳米系统。该共递药基于碳点，表面用聚乙二胺（PEI）进行修饰，并在表面加载载有化疗药物的 siMRP1，实现 pH 触发的药物释放。CD-PEI 通过一步微波辅助法合成；PEI 是反应过程中的原料和钝化剂，使 CDs 具有优异的光学性能。
CD-PEI 能够将 siMRP1 和 DOX 加载并递送到肿瘤中，并在酸性触发下在细胞中同步释放。该颗粒表现出 GSH 氧化酶样催化特性，将 GSH 氧化为氧化型谷胱甘肽，同时增加活性氧（ROS）。我们发现，共递药系统通过增加 DOX 积累和显著增强 CD-PEI-DOX 诱导的细胞活力抑制作用来沉默 MRP1，从而拮抗化学耐药性。共递药系统在异种移植模型中显著抑制肿瘤生长，并且 CDs 通过 siRNA 介导的 MRP1 敲低来拮抗 MRP1 功能。
综上所述，我们揭示了 CD 与 siRNA 和化疗药物联合应用在通过抑制 MRP1 和 GSH 氧化来克服肺癌化疗耐药性方面的潜在作用。我们的研究结果表明，它具有拮抗化学耐药性的潜力，从而提高阿霉素在肺癌治疗临床实践中的治疗效果。
