Photodynamic therapy (PDT) has emerged as a promising and evolving modality in cancer treatment leveraging light-sensitive compounds known as photosensitizers to selectively induce cell death in malignant tissues through the generation of reactive oxygen species (ROS). This review delves into the intricate mechanisms of PDT highlighting the pivotal role of photosensitizers and the resultant oxidative stress that damages cancer cells. It explores the versatile applications of PDT across various cancer types alongside the advantages and limitations inherent to this therapy. Recent technological advancements including improved photosensitizers and novel light delivery systems are also discussed. Additionally the review examines the critical role of arachidonic acid (AA) metabolism in cancer progression detailing the cyclooxygenase, lipoxygenase and cytochrome P450 pathways and their contributions to tumor biology. By elucidating the interplay between PDT and AA metabolism the review underscores the potential of targeting AA metabolic pathways to enhance PDT efficacy. Finally it provides clinical and translational perspectives highlighting ongoing research and future directions aimed at optimizing PDT for improved cancer treatment outcomes.

SignificanceProstate cancer is a major health issue (second most common cancer in men worldwide). Despite therapeutic advances and early detection, many side effects are often observed during treatment. Photodynamic therapy (PDT) is a promising therapy to reduce side effects, many 2nd and 3rd generation of photosensitizer (PS) are poorly soluble in aqueous media, limiting their attractiveness.ApproachWe have developed and tested 3rd generation of PS vectorized by arene-ruthenium (Ru) complexes coordinated to tetrapyridylporphin (tpp-2H), Zn-tetrapyridylporphin (tpp-Zn) or Co-tetrapyridylporphin (tpp-Co).ResultsTwo of the three complexes show a good efficacy. The compounds localize into the cytoplasm. An analysis of the apoptotic process shows a cleavage of poly-ADP ribose polymerase (PARP) and a strong induction of DNA fragmentation following irradiation.ConclusionsArene-ruthenium tetrapyridylporphin complexes are excellent candidates for PDT application. The addition of the metal shows a decrease (tpp-Zn) or no effects (tpp-Co), compared to the metal free photosentizer (tpp-2H).

PDF file - 131K, The effect of Alpha5 integrin on p53 activity and resistance to temozolomide is restricted to p53wt expressing cells

PDF file - 23K, Proportion of grade III and grade IV glioma in the subgroups of patients with high and low Alpha5 integrin mRNA expression in the 3 cohorts of patients included in this study

Prostate cancer is the second most common cancer for men and a major health issue. Despite treatments, a lot of side effects are observed. Photodynamic therapy is a non-invasive method that uses photosensitizers and light to induce cell death through the intramolecular generation of reactive oxygen species, having almost no side effects. However, some of the PSs used in PDT show inherent low solubility in biological media, and accordingly, functionalization or vectorization is needed to ensure internalization. To this end, we have used arene–ruthenium cages in order to deliver PSs to cancer cells. These metalla-assemblies can host PSs inside their cavity or be constructed with PS building blocks. In this study, we wanted to determine if the addition of metals (Mg, Co, Zn) in the center of these PSs plays a role. Our results show that most of the compounds induce cytotoxic effects on DU 145 and PC-3 human prostate cancer cells. Localization by fluorescence confirms the internalization of the assemblies in the cytoplasm. An analysis of apoptotic processes shows a cleavage of pro-caspase-3 and poly-ADP-ribose polymerase, thus leading to a strong induction of DNA fragmentation. Finally, the presence of metals in the PS decreases PDT’s effect and can even annihilate it.

PDF file - 48K, Nutlin-3a decreases the total expression of Beta1 integrin subunit in U87MG cells but not its expression at the cell membrane

PDF file - 32K, Nutlin-3a does not modulate the Alpha5 integrin expression in U373 cells

PDF file - 25K, Mean fluorescence intensities of Alpha5 and Beta1 integrin subunits at the cell membrane

PDF file - 27K, Relationship between Alpha5 mRNA level and p53 status in human biopsies and in human xenografts in nude mice

Low oxygen concentration in solid cancer tumors leads to resistance, especially when dealing with photodynamic therapy (PDT) treatments. In fact, the presence of oxygen is mandatory to obtain an efficient PDT treatment. The synthesis of new oxygen carriers, specifically targeting cancer cells, appears to be an elegant strategy to tackle this issue. With this in mind, we have synthetized 15 arene ruthenium(II) assemblies containing different anthracenyl-based ligands in which the anthracenyl moieties were used to capture O2. We present their synthesis and characterization, as well as their photo-oxygenation and their toxicity/phototoxicity behavior on DU145 prostatic cancer cells. The possibility to transport oxygen via the formation of endoperoxides was further confirmed by mass spectrometry.

The effect of dimethyl sulfoxide (DMSO) in rheumatoid arthritis (RA) human fibroblast-like synoviocytes (FLSs) has been studied on five different samples harvested from the joints (fingers, hands and pelvis) of five women with RA. At high concentrations (>5%), the presence of DMSO induces the cleavage of caspase-3 and PARP-1, two phenomena associated with the cell death mechanism. Even at a 0.5% concentration of DMSO, MTT assays show a strong toxicity after 24 h exposure (≈25% cell death). Therefore, to ensure a minimum impact of DMSO on RA FLSs, our study shows that the concentration of DMSO has to be below 0.05% to be considered safe.

Ruthenium-based assemblies containing tetrapyridylporphyrins (TPyP) in their structure have been evaluated as photosensitizers (PS) to treat rheumatoid arthritis (RA) by photodynamic therapy (PDT). TPyP is useless by itself as a PS due to its low solubility in biological media, however, incorporated in metallacages it can be internalized in cells. The study shows a cellular antiproliferative activity in fibroblast-like synoviocyte (FLS) in the lower nanomolar range in the presence of light, and no dark toxicity at 1 μM concentration, thus having an excellent photoactivity index. The presence of diamagnetic (Zn2+) and paramagnetic (Co2+) metals in the center of TPyP impairs the effectiveness of PDT, showing no (Co) or reduced (Zn) photoactivity. A total of five metallacages with different structural characteristics have been evaluated, and our results suggest that the incorporation of PS in metalla-assemblies is not only an elegant method to increase solubility in biological media for TPyP but also appears to be an efficient hybrid system to treat RA by PDT.

Tumor cells have a modified glycosylation profile that promotes their evolution and/or their maintenance in the tumor. Sialylation is a type of glycosylation that is often altered in cancers. RNA-Seq database analysis revealed that the sialyltransferase gene ST3GAL2 is significantly overexpressed at all stages of colorectal cancer (CRC). ST3GAL2 sialylates both glycoproteins and glycolipids. The aim of this work was to investigate the involvement of ST3GAL2 in CRC. Using the HT29 tumor cell line derived from a stage II of CRC, we decreased the expression of ST3GAL2 by specific shRNA, and then characterized these cells by performing functional tests. We found that ST3GAL2 knock down (KD) significantly decreases tumor cell proliferation, cell migration and invasiveness properties in vitro. The cell cycle of these cells is affected with a change in cell cycle distribution and an increase of cell apoptosis. The effect of ST3GAL2 KD was then studied in vivo, following xenografts into nude mice, in which the tumor progression was significantly reduced. This work demonstrates that ST3GAL2 is a major player in the behavior of colorectal tumor cells, by modifying the sialylation state of glycoproteins and glycolipids which remain to be specifically identified.

Four tetrapyridylporphyrin and four dipyridylporphyrin arene ruthenium complexes have been synthesized and characterized. In these complexes, the porphyrin core is either metal-free or occupied by zinc, and the arene ligand of the arene ruthenium units are either the standard methyl-isopropyl-benzene ([Formula: see text]cymene) or the less common phenylpropanol (PhPrOH) derivative. The porphyrin derivatives are coordinated to four arene ruthenium units or only two, in accordance with the number of pyridyl substituents at the periphery of the porphyrins, 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine (TPyP) and 5,15-diphenyl-10,20-di(pyridin-4-yl)porphyrin (DPhDPyP). All eight complexes were evaluated as anticancer agents on synovial sarcoma cells, in the presence and absence of light, suggesting that both the arene ligand and the porphyrin core substituent can play a crucial role in fine-tuning the photodynamic activity of such organometallic photosensitizers.

Most photosensitizers (PS) suffer from a lack of water solubility and from a low selectivity toward tumor cells. Delivery systems using nanoparticles make it possible to improve PS water solubility, and also tumor targeting via the enhanced permeability and retention (EPR) effect. Among the organelles, mitochondria are attractive target sites for drug-delivery strategies since they perform a variety of key cellular processes. Our study was aimed at synthesizing nanoparticles consisting of xylan-carrying poi phyrins attached to a triphenylphosphonium moiety, in order to enhance the PDT effect through mitochondria' targeting. Hybrid nanoparticles were designed that consisted of a silica core coated with xylan substituted with porphyrin derivatives carrying a triphenylphosphonium moiety. These hybrid nanoparticles have been constructed, along with their counterparts devoid of silica core, taking into consideration the controversy surrounding the use of silica nanoparticles. Phototoxicity experiments, conducted against the HCT-116 and HT-29 colorectal cancer cell lines, showed that nanoparticles with porphyrins bearing a triphenylphosphonium moiety exhibited an enhanced photocytotoxic effect in comparison with free porphyrin or nanoparticles with porphyrins without the triphenylphosphonium moiety.

The poor solubility of most photosensitizers (PS) hampers their practical use as clinical agents. Conjugation of PS with water-soluble nanoparticles has been often used to bypass this hurdle. We describe in this study the extraction of glucuronoacetylxylan from chestnut sawdust, the hemisynthesis of pheophorbide-a (Pha) and its covalent attachment to xylan. The resulting conjugates (xyl-Pha) spontaneously form water-soluble spherical nanoparticles (xyl-Pha NPs) ranging between 100 and 250 nm in diameter. Assayed against the HT-29 colorectal cancer cell line, xyl-Pha NPs exhibited a dose-dependent phototoxicity only when irradiated with red light.

Photodynamic therapy (PDT) using porphyrins has been approved for treatment of several solid tumors due to the generation of cytotoxic reactive oxygen species (ROS).www.videleaf.comHowever, low physiological solubility and lack of selectivity towards tumor sites are the main limitations of their clinical use.Nanoparticles are able to spontaneously accumulate in solid tumors through an enhanced permeability and retention (EPR) effect due to leaky vasculature, poor lymphatic drainage, and increased vessel permeability.Herein, we proved the added value of nanoparticle vectorization on anticancer efficacy and tumor-targeting by 5-(4-hydroxyphenyl)-10,15,20triphenylporphyrin (TPPOH).Using 80 nm silica nanoparticles (SNPs) coated with xylan-TPPOH conjugate (TPPOH-X), we first showed very significant phototoxic effects of TPPOH-X SNPs mediated by post-PDT ROS generation and stronger cell uptake in human colorectal cancer cell lines compared to free TPPOH.Additionally, we demonstrated apoptotic cell death induced by TPPOH-X SNPs-PDT and the interest of autophagy inhibition to increase anticancer efficacy.Finally, we highlighted in vivo, without toxicity, elevated anticancer efficacy of TPPOH-X SNPs through improvement of tumor-targeting compared to a free TPPOH protocol.Our work demonstrated for the first time the strong anticancer efficacy of TPPOH in vitro and in vivo and the merit of SNPs vectorization.

Colorectal cancer (CRC) is a leading cause of cancer-related death. The demand for new therapeutic approaches has increased attention paid toward therapies with high targeting efficiency, improved selectivity and few side effects. Porphyrins are powerful molecules with exceptional properties and multifunctional uses, and their special affinity to cancer cells makes them the ligands par excellence for anticancer drugs. Porphyrin derivatives are used as the most important photosensitizers (PSs) for photodynamic therapy (PDT), which is a promising approach for anticancer treatment. Nevertheless, the lack of solubility and selectivity of the large majority of these macrocycles led to the development of different photosensitizer complexes. In addition, targeting agents or nanoparticles were used to increase the efficiency of these macrocycles for PDT applications. On the other hand, gold tetrapyrrolic macrocycles alone showed very interesting chemotherapeutic activity without PDT. In this review, we discuss the most important porphyrin derivatives, alone or associated with other drugs, which have been found effective against CRC, as we describe their modifications and developments through substitutions and delivery systems.

For the first time, ruthenium-based assemblies have been used as carriers for photosensitizers in the treatment of rheumatoid arthritis by photodynamic therapy (PDT). These metallacages are totally soluble in physiological media and can transport photosensitizers (PS) in their cavity. After an incubation period, the PS is released in the cytoplasm and irradiation can take place. This strategy allows photosensitizers with low or null solubility in biological media to be evaluated as PDT agents in rheumatoid arthritis. The systems in which 21H,23H-porphine and 29H,31H-phthalocyanine are encapsulated show excellent photocytotoxicity and no toxicity in the dark. On the other hand, systems in which metalated derivatives such as Mg(II)-porphine and Zn(II)-phthalocyanine are used show good photocytotoxicity, but to a lesser extent than the previous two. Furthermore, the presence of Zn(II)-phthalocyanine significantly increases the toxicity of the system. Overall, fifteen different host–guest systems have been evaluated, and based on the results obtained, they show high potential for treating rheumatoid arthritis by PDT.