Yang Mingdi, Li Kaiwen, Zhong Liangchen, Bu Yingcui, Ni Yingyong, Wang Ting, Huang Jing, Zhang Jingyan, Zhou Hongping
Anhui Key Laboratory of Advanced Building Materials, School of Materials and Chemical Engineering, Anhui Jianzhu University, Hefei, 230601, PR China.
School of Chemistry and Chemical Engineering, Anhui University, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Key Laboratory of Structure and Functional Regulation of Hybrid Materials (Anhui University) Ministry of Education, Hefei, 230601, PR China.
Anal Chim Acta. 2024 Jul 4;1311:342734. doi: 10.1016/j.aca.2024.342734. Epub 2024 May 16.
Photodynamic therapy (PDT), characterized by high treatment efficiency, absence of drug resistance, minimal trauma, and few side effects, has gradually emerged as a novel and alternative clinical approach compared to traditional surgical resection, chemotherapy and radiation. Whereas, considering the limited diffusion distance and short lifespan of reactive oxygen species (ROS), as well as the hypoxic tumor microenvironment, it is crucial to design photosensitizers (PSs) with suborganelle specific targeting ability and low-oxygen dependence for accurate and highly efficient photodynamic therapy. In this study, we have meticulously designed three PSs, namely CIH, CIBr, and CIPh, based on molecular engineering. Theoretical calculation demonstrate that the three compounds possess good molecular planarity with calculated S-T energy gaps (ΔE) of 1.04 eV for CIH, 0.92 eV for CIBr, and 0.84 eV for CIPh respectively. Notably, CIPh showcases remarkable dual subcellular targeting capability towards lipid droplets (LDs) and mitochondria owing to the synergistic effect of lipophilicity derived from coumarin's inherent properties combined with electropositivity conferred by indole salt cations. Furthermore, CIPh demonstrates exclusive release of singlet oxygen (O)and highly efficient superoxide anion free radicals(O) upon light irradiation supported by its smallest S1-T1 energy gap (ΔE = 0.84 eV). This leads to compromised integrity of LDs along with mitochondrial membrane potential, resulting in profound apoptosis induction in HepG2 cells. This successful example of molecular engineering guided by density functional theory (DFT) provides valuable experience for the development of more effective PSs with superior dual targeting specificity. It also provides a new idea for the development of advanced PSs with efficient and accurate ROS generation ability towards fluorescence imaging-guided hypoxic tumor therapy.
光动力疗法（PDT）具有治疗效率高、无耐药性、创伤小和副作用少等特点，与传统的手术切除、化疗和放疗相比，已逐渐成为一种新型的替代临床方法。然而，考虑到活性氧（ROS）的扩散距离有限和寿命较短，以及肿瘤微环境缺氧，设计具有亚细胞器特异性靶向能力和低氧依赖性的光敏剂（PSs）对于准确、高效的光动力疗法至关重要。在本研究中，我们基于分子工程精心设计了三种PSs，即CIH、CIBr和CIPh。理论计算表明，这三种化合物具有良好的分子平面性，CIH的计算S-T能隙（ΔE）为1.04 eV，CIBr为0.92 eV，CIPh为0.84 eV。值得注意的是，由于香豆素固有性质产生的亲脂性与吲哚盐阳离子赋予的正电性的协同作用，CIPh对脂滴（LDs）和线粒体具有显著的双亚细胞靶向能力。此外，CIPh在光照下表现出单线态氧（O）的独家释放和高效的超氧阴离子自由基（O），其最小的S₁-T₁能隙（ΔE = 0.84 eV）支持了这一点。这导致LDs的完整性以及线粒体膜电位受损，从而在HepG2细胞中诱导深度凋亡。这个由密度泛函理论（DFT）指导的分子工程成功实例为开发具有更优异双靶向特异性的更有效PSs提供了宝贵经验。它也为开发具有高效准确ROS生成能力的先进PSs用于荧光成像引导的缺氧肿瘤治疗提供了新思路。
