Novel porphyrazine-based photodynamic anti-cancer therapy induces immunogenic cell death

Abstract

The immunogenicity of dying cancer cells determines the efficacy of anti-cancer therapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD), which is characterized by the emission of damage-associated molecular patterns (DAMPs) from dying cells. This emission can trigger effective anti-tumor immunity. Only a few photosensitizers are known to induce ICD and, therefore, there is a need for development of new photosensitizers that can induce ICD. The purpose of this work was to analyze whether photosensitizers developed in-house from porphyrazines (pz I and pz III) can induce ICD in vitro and in vivo when used in PDT. We indetified the optimal concentrations of the photosensitizers and found that, at a light dose of 20 J/cm2 (λex 615–635 nm), both pz I and pz III efficiently induced cell death in cancer cells. We demonstrate that pz I localized predominantly in the Golgi apparatus and lysosomes while pz III in the endoplasmic reticulum and lysosomes. The cell death induced by pz I-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) but not by ferrostatin-1 and DFO (ferroptosis inhibitors) or by necrostatin-1 s (necroptosis inhibitor). By contrast, the cell death induced by pz III-PDT was inhibited by z-VAD-fmk and by the necroptosis inhibitor, necrostatin-1 s. Cancer cells induced by pz I-PDT or pz III-PDT released HMGB1 and ATP and were engulfed by bone marrow-derived dendritic cells, which then matured and became activated in vitro. We demonstrate that cancer cells, after induction of cell death by pz I-PDT or pz III-PDT, are protective when used in the mouse model of prophylactic tumor vaccination. By vaccinating immunodeficient mice, we prove the role of the adaptive immune system in protecting against tumours. All together, we have shown that two novel porphyrazines developed in-house are potent ICD inducers that could be effectively applied in PDT of cancer.

Immunogenic cell death and its therapeutic or prognostic potential in high-grade glioma

“…To induce cell death with increased immunogenicity, an ICD inducer is necessary in the first place [19][20][21][22][23][24][25][26][27]. Known therapeutic treatments associated with ICD comprise a variety of cellular stressors, including (but not limited to) conventional chemotherapies (e.g.…”

“…Besides, different types of RCD can exist simultaneously in ICD induced by a single inducer. Turubanova et al showed that in photosens -PDT induced ICD, cell death can be inhibited by both zVAD-fmk (apoptosis inhibitor) and ferrostatin-1 and DFO (ferroptosis inhibitors), which means apoptosis and ferroptosis are co-existing during the process [ 22 ]. Further research on the cross-talk of different RCDs is warranted [ 63 ].…”

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

“…The power of these particular compounds to induce ICD needs to be further investigated; however, we can now assert that tetracyanotetra(aryl)porphyrazines fulfill this requirement. In our previous study, we showed that cancer cells subjected to PDT with two compounds of cyanoarylporphyrazine group with 9-phenanthrenyl and 4-(4-fluorobenzyoxy)phenyl substituted in the aryl frame of the macrocycle demonstrate typical features of ICD: release of crucial DAMPs (e.g., ATP and HMGB1), which induce activation and maturation of dendritic cells in vitro [ 11 ]. Moreover, cancer cells stimulated with pz-PDT served as a potent vaccine in a prophylactic tumor vaccination model in vivo, activating the adaptive immune system, thereby ensuring effective protection of mice from tumor growth after challenge with the viable cancer cells.…”

“…The excited photosensitizer reacts with cellular oxygen, resulting in the generation of cytotoxic reactive oxygen species (e.g., singlet oxygen ( 1 O 2 ), superoxide anion (O 2 −• ), hydroperoxide radical (HOO • ), peroxides (H 2 O 2 , ROOH), and hydroxyl radical (HO • )), and initiating molecular mechanisms which lead to tumor tissue destruction and vascular damage [ 1 , 2 , 3 ]. The efficient development of photodynamic reaction depends primarily on the photophysical and photochemical properties of the photosensitizer [ 4 , 5 , 6 ], its tissue distribution [ 7 , 8 ], its uptake by cancer cells and subcellular localization [ 4 , 9 , 10 , 11 ], and the irradiation dose [ 12 , 13 ].…”

Investigation of Structural and Optical Properties of Some [1,4]Dithiine-porphyrazine Dyes

“…Tetra-(1,4-dithiin)porphyrazine is one of the phthalocyanine derivatives having two sulfur atoms at equivalent 1,4-positions of the phthalocyanine benzene units [ 2 ]. Zinc, aluminium, and other metal porphyrazine complexes have anticancer characteristics and are used in photodynamic treatment [ 3 ]. In a multi-step reaction sequence, novel tetra-(1,4-dithiin) metal-free (H2-Pz) and metallo-porphyrazines (M-Pz, M = Mg, Fe) carrying peripheral tetra propyl-bromine were synthesized from 2,3-dicyano-5-propyl-bromine-1,4-dithiin and disodiomaleonitrile [ 4 ].…”