Cyanoarylporphyrazines with High Viscosity Sensitivity: A Step towards Dosimetry-Assisted Photodynamic Cancer Treatment

Abstract

Despite the significant relevance of photodynamic therapy (PDT) as an efficient strategy for primary and adjuvant anticancer treatment, several challenges compromise its efficiency. In order to develop an “ideal photosensitizer” and the requirements applied to photosensitizers for PDT, there is still a need for new photodynamic agents with improved photophysical and photobiological properties. In this study, we performed a detailed characterization of two tetracyanotetra(aryl)porphyrazine dyes with 4-biphenyl (pz II) and 4-diethylaminophenyl (pz IV) groups in the periphery of the porphyrazine macrocycle. Photophysical properties, namely, fluorescence quantum yield and lifetime of both photosensitizers, demonstrate extremely high dependence on the viscosity of the environment, which enables them to be used as viscosity sensors. PzII and pz IV easily enter cancer cells and efficiently induce cell death under light irradiation. Using fluorescence lifetime imaging microscopy, we demonstrated the possibility of assessing local intracellular viscosity and visualizing viscosity changes driven by PDT treatment with the compounds. Thus, pz II and pz IV combine the features of potent photodynamic agents and viscosity sensors. These data suggest that the unique properties of the compounds provide a tool for PDT dosimetry and tailoring the PDT treatment regimen to the individual characteristics of each patient.

Unraveling of Functional Activity of Primary Hippocampal Neuron-Glial Networks in Photodynamic Therapy Based on Tetracyanotetra(aryl)porphyrazines

“…The assessment of viscosity characteristics by measuring the lifetime of fluorescent molecular rotor excitation using time-resolved microscopy allows for early monitoring of tumor cells’ sensitivity to photoinduction, and the efficiency of cell death during PDT procedure or immediately after its termination. The functions of molecular rotors were shown for pz I – IV in our previous studies [ 18 , 27 , 28 , 42 , 45 , 46 ]. That means that pz can provide promising prospects for personalized PDT dosimetry aiming to achieve the highest treatment efficacy with minimal cytotoxic effect for surrounding normal tissues.…”

“…We have previously shown that pz I – IV effectively kills murine glioma GL261 cells and causes different long-term dark toxicity effects on primary neuronal cultures [ 18 , 19 ]. Herein, we assessed the influence of pz I – IV on the functional network activity of primary hippocampal cultures in a normal state and after PDT.…”

“…On day 14 of cultivation (14 DIV), the culture medium was replaced to a serum-free medium containing porphyrazines at concentrations of 1.18 µM for pz I , 0.19 µM for pz II , and 0.54 µM and 0.37 µM for pz III and pz IV , respectively. Since we consider pz I – IV as potential photodynamic agents for PDT treatment of brain tumors, the concentrations we used corresponded to the IC 50 for murine glioma GL261 cells, which were experimentally established in our previous studies [ 18 , 19 ]. After 4 h of incubation, the medium was replaced with a pz-free complete culture medium.…”

“…We recently presented a novel group of tetracyanotetra(aryl)porphyrazines (hereinafter, pz ) as promising photosensitizers for PDT [ 18 , 19 ]. These compounds have unique properties providing an elegant combination of photophysical and cytotoxic properties (e.g., stable production of cytotoxic singlet oxygen), which function as sensors and molecular rotors.…”

“…These compounds have unique properties providing an elegant combination of photophysical and cytotoxic properties (e.g., stable production of cytotoxic singlet oxygen), which function as sensors and molecular rotors. The action of these photosensitizers is dependent on fluorescence of the rate of intramolecular rotation that opens up an ability to detect tumor cells’ sensitivity to photoinduction and timely optimizes the treatment modes for each patient, allowing for the opportunity to have more personalized cancer therapy [ 18 ]. We have previously shown the effectiveness of four pz ( pz I – IV ) in PDT treatment of glioma in vitro.…”