Search

Glioblastoma multiforme is one of the most common intracranial tumors. It is distinguished by a high degree of malignancy and aggressiveness. It is difficult to diagnose and treat, which is why it is so important to introduce new therapeutic solutions that will enhance the effects of treatment and more accurately visualize neoplastic changes in the brain. Several treatments, including radiotherapy and PDT, strongly rely on the presence of oxygen before and during the therapy. Moreover, the changes in tumor oxygenation post-treatment have prognostic significance in the outcome of photodynamic therapy. The aim of the study was to measure non-invasively oxygen partial pressure (pO 2) in an orthotopic model of glioma in mice. For this purpose, electron paramagnetic resonance (EPR) imaging with microspheres based on lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) was used. Mapping the oxygen concentration in tumor tissue is possible because tumor cells were mixed with LiNc-BuO crystal microspheres before implantation into the brain. The murine glioma cell line GL261 was used to inoculate a brain tumor in C57bl/6J mice orthotopically. The probe microcrystals containing unpaired electron spins allow for obtaining a repeated oxygen concentration from a small area around the site of tumor cell implantation. This can be corelated with anatomical magnetic resonance (MRI) images visualizing the size of the glioma tumor. In order to induce the photodynamic effect, it is planned to use nanoparticles that can cross the blood-brain barrier. This solution seems to be a great way of delivering drugs directly to brain tumors. AGuIX nanocarriers with a TPP photosensitizer are linked to a peptide that specifically binds to endothelial cells of blood vessels supplying blood to the tumor. After irradiation with 650 nm light, a photodynamic action of photosensitizer destroys the tumor's vascularization, thus depriving cancer cells of nutrients and changing the oxygenation level of the tumor. Oxygen partial pressure mapping of brain tumors brings an understanding of the degree of oxygenation of gliomas in the orthotopic model and in the future will provide valuable information that will allow tracking of the effectiveness of the therapy. Non-invasive methods of measuring pO 2 in tumors may have immense potential in assessing the degree of effectiveness of anti-cancer therapies. ACKNOWLEDGEMENTS: NCBiR grant no DWM/ENM3-IV/425/2021 [ABSTRACT FROM AUTHOR]

A method of automated synthesis of [18F]fluoromisonidazole ([18F]FMISO) for application in preclinical studies on small animals was presented. A remote-controlled synthesizer Synthra RNplus was used for nucleophilic substitution of NITTP (1′-(2′-nitro-1-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonyl-propanediol) with 18F anion. Labeling of 5 mg of precursor was performed in anhydrous acetonitrile at 100°C for 10 min, and the hydrolysis with HCl was performed at 100°C for 5 min. Final purification was done with high-performance liquid chromatography (HPLC) and the radiochemical purity of radiotracer was higher than 99%. Proposed [18F]FMISO synthesis was used as a reliable tool in studies on hypoxia in Lewis lung carcinoma (LLC) in mouse models. [ABSTRACT FROM AUTHOR]

Clinical trials to ameliorate hypoxia as a strategy to relieve the radiation resistance it causes have prompted a need to assay the precise extent and location of hypoxia in tumors. Electron paramagnetic resonance oxygen imaging (EPR O2 imaging) provides a noninvasive means to address this need. To obtain a preclinical proof-of-principle that EPR O2 images could predict radiation control, we treatedmouse tumors at or near doses required to achieve 50% control (TCD50). Mice with FSa fibrosarcoma or MCa4 carcinoma were subjected to EPR O2 imaging and immediately radiated to a TCD50 or TCD50 10Gy. Statistical analysiswas permitted by collection of approximately 1,300 tumor pO2 image voxels, including the fraction of tumor voxels with pO2 less than 10mmHg (HF10). Tumors were followed for 90 days (FSa) or 120 days (MCa4) to determine local control or failure. HF10 obtained fromEPR images showed statistically significant differences between tumors thatwere controlled by the TCD50 and those that were not controlled for both FSa andMCa4. Kaplan-Meier analysis of both types of tumors showed that approximately 90%ofmildly hypoxic tumorswere controlled (HF10% 10%), and only 37%(FSA) and 23% (MCa4) tumors controlled if hypoxic. EPR pO2 image voxel distributions in these approximately 0.5 mL tumors provide a prediction of radiation curability independent of radiation dose. These data confirm the significance of EPR pO2 hypoxic fractions. The 90% control of low HF10 tumors argue that 0.5 mL subvolumes of tumors may be more sensitive to radiation and may need less radiation for high tumor control rates. [ABSTRACT FROM AUTHOR]

Epilepsy is a pathophysiological condition displaying a highly diverse phenotype. Consequently, comprehending the mechanisms underlying seizures necessitates moving beyond a simplistic model focused on the imbalance between the classical excitatory and inhibitory neurotransmitter systems. Nitric oxide (NO), a nonclassical and multifunctional gaseous neurotransmitter, has the potential to exert a profound influence on epileptic reactivity. Unfortunately, numerous studies have not provided clear answers about its involvement in the pathophysiology of epilepsy. The objective of our study was to delineate the temporal dynamics of alterations in nitrergic system activation after experimentally induced seizures. Seizures were induced in 2-month-old male Wistar rats by an administration of pilocarpine. Over a 6-hour observation period, seizure behaviour intensity was continuously evaluated using a modified Racine scale. At intervals of 6, 12, 24, 48, or 96 h post-chemoconvulsant administration, NO spin trapping was conducted with ferrous-diethyldithiocarbamate complexes (Fe(DETC) 2 ). Electron paramagnetic resonance (EPR) spectroscopy was employed to quantify mononitrosyl iron complexes (NO-Fe(DETC) 2 ) in the brain. The temporal kinetic of NO release after seizures revealed a rise in NO synthesis during the initial 12 h. Subsequently, a sharp decline occurred, returning to baseline 96 h after pilocarpine injection. Notably, our research suggests that the level of NO synthesis does not interfere with the severity of the epileptic seizures that occur. In light of this, we propose that the nitrergic system is quickly activated in the epileptic brain as a compensatory mechanism of the central nervous system. However, under usual conditions, this activation is insufficient to effectively attenuate seizures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The importance of epigenetic changes as a measurable endpoint in nanotoxicological studies is getting more and more appreciated. In the present work, we analyzed the epigenetic effects induced by citrate- and PEG-coated 20 nm silver nanoparticles (AgNPs) in a model consisting of 4T1 breast cancer tumors in mice. Animals were administered with AgNPs intragastrically (1 mg/kg b.w. daily-total dose 14 mg/kg b.w.) or intravenously (administration twice with 1 mg/kg b.w.-total dose 2 mg/kg b.w.). We observed a significant decrease in 5-methylcytosine (5-mC) level in tumors from mice treated with citrate-coated AgNPs regardless of the route of administration. For PEG-coated AgNPs, a significant decrease in DNA methylation was observed only after intravenous administration. Moreover, treatment of 4T1 tumor-bearing mice with AgNPs decreased histone H3 methylation in tumor tissue. This effect was the most pronounced for PEG-coated AgNPs administered intravenously. No changes in histone H3 Lys9 acetylation were observed. The decrease in methylation of DNA and histone H3 was accompanied by changes in expression of genes encoding chromatin-modifying enzymes (Setd4, Setdb1, Smyd3, Suv39h1, Suv420h1, Whsc1, Kdm1a, Kdm5b, Esco2, Hat1, Myst3, Hdac5, Dnmt1, Ube2b, and Usp22) and genes related to carcinogenesis (Akt1, Brca1, Brca2, Mlh1, Myb, Ccnd1, and Src). The significance of the observed changes and the mechanisms responsible for their development are unclear, and more research in this area is warranted. Nevertheless, the present work points to the epigenetic effects as an important level of interaction between nanomaterials and biological systems, which should always be taken into consideration during analysis of the biological activity of nanomaterials and development of nanopharmaceuticals.

Low tissue oxygenation significantly impairs the effectiveness of cancer therapy and promotes a more aggressive phenotype. Many strategies to improve tissue oxygenation have been proposed throughout the years, but only a few showed significant effects in clinical settings. We investigated stability and ultrasound pulse (UP) triggered oxygen release from phospholipid coated oxygen microbubbles (OMB) in vitro and in murine tumors in vivo using EPR oximetry. In solution, the investigated microbubbles are stable and responsive to ultrasound pulse. The addition of the OMB solution alone resulted in an increase in pO 2 of approximately 70 mmHg which was further increased for an additional 80 mmHg after the application of UP. The in vivo kinetic study revealed a substantial, up to 120 mmHg, increase in tumor pO 2 after UP application and then pO 2 was decreasing for 20 min for intravenous injection and 15 min for intratumoral injection. A significant increase was also observed in groups that received microbubbles filled with nitrogen and ultrasound pulse and OMB without UP, but the effect was much lower. Oxygen microbubbles lead to a decrease in HIF-1a and VEGF-A both at the level of mRNA and protein. Toxicity analysis showed that intravenous injection of OMB does not cause oxidative damage to the heart, liver, or kidneys. However, elevated levels of oxidative damage to lipids and proteins were observed short-term in tumor tissue. In conclusion, we have demonstrated the feasibility of oxygen microbubbles in delivering oxygen effectively and safely to the tumor in living animals. Such treatment might enhance the effectiveness of other anticancer therapies., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Combinations of metabolic blockers (incl. fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133 high and/or CD44 high cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44 negative "bulk" cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44 high SCL cells. However, the CD44 negative offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44 high SCL prostate cells and their "bulk" progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment., (© 2020 The Authors. STEM CELLS published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

We demonstrated that a quickly growing hamster skin melanoma developed a tumor after autologous implantation into the anterior chamber of the eye. Tumor cells were seen invading all the surrounding tissues, including the iris, ciliary body, choroid and cornea. Histological examination confirmed the presence of numerous blood vessels of large diameter. Their walls were very thin, thus only the endothelium could be identified using light microscopy. Macrophages, microemboli and extravasations were present within the tumor mass.