Feasibility of Photodynamic Therapy for Glioblastoma with the Mitochondria-Targeted Photosensitizer Tetramethylrhodamine Methyl Ester (TMRM)

Abstract

One of the most challenging problems in the treatment of glioblastoma (GBM) is the highly infiltrative nature of the disease. Infiltrating cells that are non-resectable are left behind after debulking surgeries and become a source of regrowth and recurrence. To prevent tumor recurrence and increase patient survival, it is necessary to cleanse the adjacent tissue from GBM infiltrates. This requires an innovative local approach. One such approach is that of photodynamic therapy (PDT) which uses specific light-sensitizing agents called photosensitizers. Here, we show that tetramethylrhodamine methyl ester (TMRM), which has been used to asses mitochondrial potential, can be used as a photosensitizer to target GBM cells. Primary patient-derived GBM cell lines were used, including those specifically isolated from the infiltrative edge. PDT with TMRM using low-intensity green light induced mitochondrial damage, an irreversible drop in mitochondrial membrane potential and led to GBM cell death. Moreover, delayed photoactivation after TMRM loading selectively killed GBM cells but not cultured rat astrocytes. The efficacy of TMRM-PDT in certain GBM cell lines may be potentiated by adenylate cyclase activator NKH477. Together, these findings identify TMRM as a prototypical mitochondrially targeted photosensitizer with beneficial features which may be suitable for preclinical and clinical translation.

Recent Development of Advanced Fluorescent Molecular Probes for Organelle-Targeted Cell Imaging

“…For example, the membrane potential of mitochondria is vital to maintaining respiratory chain reactions, ion transfer, and other bioactivities. Several commercial probes, including TMRM and JC-1, have been widely applied to detect the mitochondria membrane potential [ 78 , 79 ]. Chemical reagents are also important for the normal activity of mitochondria.…”

Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics

“…Organelle targeting becomes a more practical and efficient approach to minimize the reoccurrence of tumors. Vasilev et al worked on a mitochondria-targeted photosensitizer, namely tetramethylrhodamine methyl ester (TMRM), to evaluate the mitochondria capability [94]. They used a small dose of this photosensitizer approach and observed that this dye was excited by the green/yellow spectrum having better tissue penetration.…”

Mitochondrial NIR imaging probe mitigating oxidative damage by targeting HDAC6

“…For instance, tetramethylrhodamine methyl ester (TMRM), the least toxic of all widely used trackers for mitochondria, can only be employed at doses up to 0.5 μM without having an inhibitory effect on respiration. 17,18 Additionally, the most popular cyanine-based mitochondria-targeting probe, JC-1, can only exhibit red emission when introduced in micromolar concentrations forming J-aggregates, which results in high cytotoxicity. 19…”

“…For instance, tetramethylrhodamine methyl ester (TMRM), the least toxic of all widely used trackers for mitochondria, can only be employed at doses up to 0.5 mM without having an inhibitory effect on respiration. 17,18 Additionally, the most popular cyanine-based mitochondria-targeting probe, JC-1, can only exhibit red emission when introduced in micromolar concentrations forming J-aggregates, which results in high cytotoxicity. 19 Given the above considerations, we proposed a precisely designed non-toxic mitochondria-targetable NIR-emitting (l em E 830 nm) probe, T2, by conjugating a cationic cyaninebased dye and a HDAC6 inhibitor (Scheme 1b).…”