Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts 01609, United States.
ACS Appl Mater Interfaces. 2020 Mar 18;12(11):12407-12416. doi: 10.1021/acsami.9b20070. Epub 2020 Mar 6.
Combination therapies utilize multiple mechanisms to target cancer cells to minimize cancer cell survival. Graphene provides an ideal platform for combination therapy due to its photothermal properties and high loading capacity for cancer-fighting molecules. Lipid functionalization of graphene extends its potential as a therapeutic platform by improving its biocompatibility and functionality. Previous studies involving graphene demonstrated its usage as a therapeutic vehicle; however, the effect of bare and engineered graphene structures on oxidative stress has not been comprehensively investigated. Because oxidative stress has been linked to cancer progression, it is vital to examine the generation of reactive oxygen species (ROS) in response to therapeutic platforms. This study functionalizes reduced graphene oxide (rGO) with lipids and the antioxidant enzyme human manganese superoxide dismutase (hMnSOD) and presents a detailed characterization of cellular responses to bare and functionalized rGO nanostructures in tumorigenic and nontumorigenic breast cell lines. Each cell type displayed distinct responses depending on whether they were normal, nonmetastatic, or metastatic cells. Bare rGO significantly reduced cell growth and substantially increased ROS production in all cell lines and instigated necrosis in metastatic breast cancer cells. Cell proliferation decreased in cancerous breast cells upon introduction of lipid-rGO, which correlated with peroxidation of lipids coating the rGO. In contrast, lipid-rGO nanostructures had minimal impact on proliferation and lipid peroxidation for normal breast cells. Lipid-rGO nanostructures with bound hMnSOD inhibited the proliferation of metastatic cancer cells while preventing necrosis and avoiding the negative side effects on normal cells associated with chemotherapeutic agents. Together, the results confirm the importance of functionalizing rGO for therapeutic applications and present an additional modality for the usage of graphene to selectively target cancer cells.
联合疗法利用多种机制靶向癌细胞，以最大限度地减少癌细胞的存活。由于具有光热特性和高负载抗癌分子的能力，石墨烯为联合疗法提供了理想的平台。石墨烯的脂质功能化通过提高其生物相容性和功能，扩展了其作为治疗平台的潜力。以前涉及石墨烯的研究表明了其作为治疗载体的用途；然而，裸石墨烯和工程石墨烯结构对氧化应激的影响尚未得到全面研究。由于氧化应激与癌症进展有关，因此检查治疗平台对活性氧（ROS）的产生至关重要。本研究通过脂质和抗氧化酶人锰过氧化物酶（hMnSOD）对还原氧化石墨烯（rGO）进行功能化，并对肿瘤发生和非肿瘤发生的乳腺癌细胞系中裸和功能化 rGO 纳米结构的细胞反应进行了详细表征。每种细胞类型都根据它们是正常、非转移性还是转移性细胞而表现出不同的反应。裸 rGO 显著降低了所有细胞系的细胞生长，并大大增加了 ROS 的产生，并引发转移性乳腺癌细胞的坏死。引入脂质-rGO 后，癌细胞中的细胞增殖减少，与覆盖 rGO 的脂质过氧化有关。相比之下，脂质-rGO 纳米结构对正常乳腺细胞的增殖和脂质过氧化影响很小。与 hMnSOD 结合的脂质-rGO 纳米结构抑制了转移性癌细胞的增殖，同时防止了坏死，并避免了与化疗药物相关的对正常细胞的负面影响。总之，这些结果证实了对 rGO 进行功能化以用于治疗应用的重要性，并提出了一种使用石墨烯来选择性靶向癌细胞的新方法。
