Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Laboratory for Advanced Fibers, Empa Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014 St. Gallen, Switzerland.
Int J Mol Sci. 2022 Aug 23;23(17):9525. doi: 10.3390/ijms23179525.
Phthalocyanines (Pcs) are promising candidates for photodynamic therapy (PDT) due to their absorption in the phototherapeutic window. However, the highly aromatic Pc core leads to undesired aggregation and decreased reactive oxygen species (ROS) production. Therefore, short PEG chain functionalized AB type asymmetric Pc photosensitizers (PSs) were designed in order to decrease aggregation and increase the aqueous solubility. Here we report the synthesis, characterization, optical properties, cellular localization, and cytotoxicity of three novel Pc-based agents (, , and ). The stepwise functionalization of the peripheral moieties has a strong effect on the distribution coefficient (log), cellular uptake, and localization, as well as photocytotoxicity. Additional experiments have revealed that the presence of the malonic ester moiety in the reported agent series is indispensable in order to induce photocytotoxicity. The best-performing agent, , showed mitochondrial targeting and an impressive phototoxic index (p.i.) of 748 in the cisplatin-resistant A2780/CP70 cell line, after a low-dose irradiation of 6.95 J/cm. This is the result of a high photocytotoxicity (IC = 157 nM) upon irradiation with near-infrared (NIR) light, and virtually no toxicity in the dark (IC = 117 μM). Photocytotoxicity was subsequently determined under hypoxic conditions. Additionally, a preliminarily pathway investigation of the mitochondrial membrane potential (MMP) disruption and induction of apoptosis by was carried out. Our results underline how agent design involving both hydrophilic and lipophilic peripheral groups may serve as an effective way to improve the PDT efficiency of highly aromatic PSs for NIR light-mediated cancer therapy.
酞菁（Pcs）因其在光疗窗口中的吸收而成为光动力疗法（PDT）的有前途的候选物。然而，高度芳香的 Pc 核导致不希望的聚集和减少的活性氧（ROS）产生。因此，设计了短的 PEG 链功能化 AB 型不对称 Pc 光敏剂（PS），以减少聚集并增加水溶解度。在这里，我们报告了三种新型基于 Pc 的试剂（，和）的合成，表征，光学性质，细胞定位和细胞毒性。外围部分的逐步功能化对分配系数（log），细胞摄取和定位以及光细胞毒性有很强的影响。进一步的实验表明，在所报道的试剂系列中，马来酸酯部分的存在对于诱导光细胞毒性是必不可少的。表现最佳的试剂，表现出线粒体靶向性和令人印象深刻的光毒性指数（p.i.），在顺铂耐药 A2780/CP70 细胞系中，在 6.95 J/cm 的低剂量照射后。这是由于在近红外（NIR）光照射下具有高的光细胞毒性（IC = 157 nM），并且在黑暗中几乎没有毒性（IC = 117 μM）。随后在缺氧条件下测定了光细胞毒性。此外，还对通过进行线粒体膜电位（MMP）破坏和诱导细胞凋亡的初步途径进行了研究。我们的结果强调了如何通过设计涉及亲水性和疏水性外围基团的试剂来提高高度芳香 PS 的 PDT 效率，从而为近红外光介导的癌症治疗提供有效的方法。
