School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin, 300072, China.
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, College of Chemistry, Nankai University, Tianjin, 300071, China.
Mater Sci Eng C Mater Biol Appl. 2020 Jan;106:110227. doi: 10.1016/j.msec.2019.110227. Epub 2019 Oct 14.
Organelle-targeting agents are promising in both fundamental and applied biomedicine research, but such materials are very limited. As a curved 2D carbon material, corannulene (Cor) displays an uneven intramolecular electron distribution, producing a large dipole moment that can favor the electrostatic interaction. Based on the large negative mitochondrial membrane potential and the presence of a connection structure between mitochondria and endoplasmic reticulum (ER), we hypothesized that Cor could simultaneously target both mitochondria and ER. Such hypothesis was well validated by using the fluorescence tag-labelled Cor. The co-localization analysis in a model cell line (PC3) revealed a preferred accumulation of Cor in both organelles, as evidenced by a large Pearson correlation coefficient. The large dipole also empowered Cor the ability of controlled production of reactive oxygen species (ROS) upon light irradiation. This feature plus mitochondria targeting of Cor induced depletion of adenosine triphosphate (ATP) and caspase 9/3 activation. The triggered ROS generation in ER caused the calcium dumping in the cytosol, as revealed by a calcium-specific fluorescence probe. A significant degree of apoptosis was induced by Cor as a result of the interplay of dual mitochondria/ER targeting and triggered organelle-specific ROS delivery. This study demonstrated the subcellular targeting ability of Cor for potential ROS-based therapy, and implied that the dipole could be a valuable parameter for efficient design and tailored screening of organelle-targeting materials for various biomedical applications.
细胞器靶向剂在基础和应用生物医学研究中都很有前景，但这类材料非常有限。作为一种弯曲的二维碳材料，corannulene（Cor）显示出不均匀的分子内电子分布，产生了很大的偶极矩，有利于静电相互作用。基于线粒体膜电位的负电性和线粒体与内质网（ER）之间存在连接结构，我们假设 Cor 可以同时靶向线粒体和 ER。这种假设通过荧光标记的 Cor 得到了很好的验证。在模型细胞系（PC3）中的共定位分析表明，Cor 优先积聚在这两个细胞器中，这一点可以从大的 Pearson 相关系数得到证明。大偶极矩还赋予了 Cor 在光照下产生活性氧（ROS）的能力。这一特性加上 Cor 对线粒体的靶向作用，导致三磷酸腺苷（ATP）的消耗和半胱天冬酶 9/3 的激活。在 ER 中引发的 ROS 生成导致细胞质中的钙流失，这可以通过钙特异性荧光探针来证明。Cor 诱导了细胞凋亡，这是由于双重线粒体/ER 靶向和触发的细胞器特异性 ROS 传递的相互作用。这项研究证明了 Cor 对潜在 ROS 治疗的亚细胞靶向能力，并暗示偶极矩可能是设计和筛选各种生物医学应用中靶向细胞器的材料的有效参数。
