Graphene-Based Photodynamic Therapy and Overcoming Cancer Resistance Mechanisms: A Comprehensive Review.

Photodynamic therapy (PDT) is a non-invasive therapy that has made significant progress in treating different diseases, including cancer, by utilizing new nanotechnology products such as graphene and its derivatives. Graphene-based materials have large surface area and photothermal effects thereby making them suitable candidates for PDT or photo-active drug carriers. The remarkable photophysical properties of graphene derivates facilitate the efficient generation of reactive oxygen species (ROS) upon light irradiation, which destroys cancer cells. Surface functionalization of graphene and its materials can also enhance their biocompatibility and anticancer activity. The paper delves into the distinct roles played by graphene-based materials in PDT such as photosensitizers (PS) and drug carriers while at the same time considers how these materials could be used to circumvent cancer resistance. This will provide readers with an extensive discussion of various pathways contributing to PDT inefficiency. Consequently, this comprehensive review underscores the vital roles that graphene and its derivatives may play in emerging PDT strategies for cancer treatment and other medical purposes. With a better comprehension of the current state of research and the existing challenges, the integration of graphene-based materials in PDT holds great promise for developing targeted, effective, and personalized cancer treatments.

Plastic response of macrophages to metal ions and nanoparticles in time mimicking metal implant body environment.

The paradigm of using metal biomaterials could be viewed from two sides - treatment of wide spectrum of degenerative diseases, and debris release from materials. After implant insertion, metal nanoparticles (NPs) and ions are released not only upon the first contact with cells/tissues, but in continual manner, which is immediately recognized by immune cells. In this work, the effects of metal nanoparticles (TiO2, Ni) and ions (Ni2+, Co2+, Cr3+, Mo6+) on primary human M0 macrophages from the blood samples of osteoarthritic patients undergoing total arthroplasty were studied in order to monitor immunomodulatory effects on the cells in a real-time format. The highest NiNPs concentration of 10 µg/ml had no effect on any of macrophage parameters, while the Ni2+ ions cytotoxicity limit for the cells is 0.5 mM. The cytotoxic effects of higher Ni2+ concentration revealed mitochondrial network fragmentation leading to mitochondrial dysfunction, accompanied by increased lysosomal activity and changes in pro-apoptotic markers. The suppression of M2 cell formation ability was connected to presence of Ni2+ ions (0.5 mM) and TiO2NPs (10 µg/ml). The immunomodulatory effect of Mo6+ ions, controversially, inhibit the formation of the cells with M1 phenotype and potentiate the thread-like shape M2s with increased chaotic cell movement. To summarize, metal toxicity depends on the debris form. Both, metal ions and nanoparticles affect macrophage size, morphological and functional parameters, but the effect of ions is more complex and likely more harmful, which has potential impact on healing and determines post-implantation reactions.

Photodynamic therapy: Innovative approaches for antibacterial and anticancer treatments.

Photodynamic therapy is an alternative treatment mainly for cancer but also for bacterial infections. This treatment dates back to 1900 when a German medical school graduate Oscar Raab found a photodynamic effect while doing research for his doctoral dissertation with Professor Hermann von Tappeiner. Unexpectedly, Raab revealed that the toxicity of acridine on paramecium depends on the intensity of light in his laboratory. Photodynamic therapy is therefore based on the administration of a photosensitizer with subsequent light irradiation within the absorption maxima of this substance followed by reactive oxygen species formation and finally cell death. Although this treatment is not a novelty, there is an endeavor for various modifications to the therapy. For example, selectivity and efficiency of the photosensitizer, as well as irradiation with various types of light sources are still being modified to improve final results of the photodynamic therapy. The main aim of this review is to summarize anticancer and antibacterial modifications, namely various compounds, approaches, and techniques, to enhance the effectiveness of photodynamic therapy.

Restoration of antibacterial activity of inactive antibiotics via combined treatment with a cyanographene/Ag nanohybrid.

The number of antibiotic-resistant bacterial strains is increasing due to the excessive and inappropriate use of antibiotics, which are therefore becoming ineffective. Here, we report an effective way of enhancing and restoring the antibacterial activity of inactive antibiotics by applying them together with a cyanographene/Ag nanohybrid, a nanomaterial that is applied for the first time for restoring the antibacterial activity of antibiotics. The cyanographene/Ag nanohybrid was synthesized by chemical reduction of a precursor material in which silver cations are coordinated on a cyanographene sheet. The antibacterial efficiency of the combined treatment was evaluated by determining fractional inhibitory concentrations (FIC) for antibiotics with different modes of action (gentamicin, ceftazidime, ciprofloxacin, and colistin) against the strains Escherichia coli, Pseudomonas aeruginosa, and Enterobacter kobei with different resistance mechanisms. Synergistic and partial synergistic effects against multiresistant strains were demonstrated for all of these antibiotics except ciprofloxacin, which exhibited an additive effect. The lowest average FICs equal to 0.29 and 0.39 were obtained for colistin against E. kobei and for gentamicin against E. coli, respectively. More importantly, we have experimentally confirmed for the first time, that interaction between the antibiotic's mode of action and the mechanism of bacterial resistance strongly influenced the combined treatment's efficacy.

Silver Covalently Bound to Cyanographene Overcomes Bacterial Resistance to Silver Nanoparticles and Antibiotics.

The ability of bacteria to develop resistance to antibiotics is threatening one of the pillars of modern medicine. It was recently understood that bacteria can develop resistance even to silver nanoparticles by starting to produce flagellin, a protein which induces their aggregation and deactivation. This study shows that silver covalently bound to cyanographene (GCN/Ag) kills silver-nanoparticle-resistant bacteria at concentrations 30 times lower than silver nanoparticles, a challenge which has been so far unmet. Tested also against multidrug resistant strains, the antibacterial activity of GCN/Ag is systematically found as potent as that of free ionic silver or 10 nm colloidal silver nanoparticles. Owing to the strong and multiple dative bonds between the nitrile groups of cyanographene and silver, as theory and experiments confirm, there is marginal silver ion leaching, even after six months of storage, and thus very high cytocompatibility to human cells. Molecular dynamics simulations suggest strong interaction of GCN/Ag with the bacterial membrane, and as corroborated by experiments, the antibacterial activity does not rely on the release of silver nanoparticles or ions. Endowed with these properties, GCN/Ag shows that rigid supports selectively and densely functionalized with potent silver-binding ligands, such as cyanographene, may open new avenues against microbial resistance.

Ni and TiO2 nanoparticles cause adhesion and cytoskeletal changes in human osteoblasts.

Titanium-based alloys have established a crucial role in implantology. As material deteriorates overtime, nanoparticles of TiO2 and Ni are released. This study is focused on the impact of TiO2 and Ni nanoparticles with size of 100 nm on cytoskeletal and adhesive changes in human physiological and osteoarthritic osteoblasts. The impact of nanoparticles with concentration of 1.5 ng/mL on actin and tubulin expression and gene expression of FAK and ICAM-1 was studied. The cell size and actin expression of physiological osteoblasts decreased in presence of Ni nanoparticles, while TiO2 nanoparticles caused increase in cell size and actin expression. Both cell lines expressed more FAK as a response to TiO2 nanoparticles. ICAM-1 gene was overexpressed in both cell lines as a reaction to both types of nanoparticles. The presented study shows a crucial role of Ni and TiO2 nanoparticles in human osteoblast cytoskeletal and adhesive changes, especially connected with the osteoarthritic cells. Graphical abstract.

Relationship of epigenetic variability of miR-124 to extracellular matrix remodelling and age-related MMP-3 expression in rheumatoid arthritis.

The aim of study was to examine relation among miR-124 and serum levels of selected cytokines and chemokines, MMP-3, production of auto-antibodies, and factors describing clinical activity (DAS28) and radiographic progression in rheumatoid arthritis (RA). A total of 80 RA patients according to the ACR classification criteria, and 32 control subjects were recruited into study. The measurements of miR-124 and U-6 expression, CRP, anti-CCP, rheumatoid factors (RFs), radiographs of both hands with calculation of total sharp score (TSS), DAS28 and cytokines, chemokines and MMP levels in serum were obtained from all RA patients. miR-124 was down-regulated in RA patients compared to controls (7-fold decrease). The miR-124 expression correlated to MMP-3 levels (p < 0.001), which were in multivariate analysis associated to age of RA onset. Higher levels were detected in younger subjects. No relation of miR-124 expression to measures of RA activity (DAS28 score; TSS), auto-antibodies (anti-CCP, RF, RF IgG, RF IgA, RF IgM), acute inflammatory markers (CRP, IL-6), and other cytokine and chemokines (IL-13, IL-15, IL-8, TNF-α, MCP-1, RANTES) was observed. In conclusion, we present a down-regulation of miR-124 in RA patients and its correlation to MMP-3 levels, which associated to age of RA onset.

Osteoarthritic process modifies expression response to NiTi alloy presence.

Nickel-titanium alloy (nitinol, NiTi) is a biomaterial with unique thermal shape memory, superelasticity and high damping properties. Therefore NiTi has been used in medical applications. In this in vitro study, the effect of NiTi alloy (with two surface modifications - helium and hydrogen) on gene expression profile of selected interleukins (IL-1ß, IL-6 and IL-8) and matrix metalloproteinases (MMP-1 and MMP-2) in human physiological osteoblasts and human osteoarthritic osteoblasts was examined to respond to a question of the different behavior of bone tissue in the implantation of metallic materials in the presence of cells affected by the osteoarthritic process. The cells were cultivated in contact with NiTi and with or without LPS (bacterial lipolysaccharide). Changes in expression of target genes were calculated by 2-ΔΔCt method. An increased gene expression of IL-1ß in osteoarthritic osteoblasts, with even higher expression in cells collected directly from the metal surface was observed. In case of physiological osteoblasts, the change in expression was detected after LPS treatment in cells surrounding the disc. Higher expression levels of IL-8 were observed in osteoarthritic osteoblasts after NiTi treatment in contact with alloy, and in physiological osteoblasts without relation to location in combination of NiTi and LPS. IL-6 was slightly increased in physiological osteoblastes after application of LPS. MMP-1 expression level was obviously significantly higher in osteoarthritic osteoblasts with differences regarding the metal surface and location. MMP-2 expression was decreased in both cell lines after LPS treatment. In conclusion, results of present study show that the NiTi alloy and the treatment by LPS, especially repeated doses of LPS, change the gene expression of selected ILs and MMPs in human osteoblast cell cultures. Some of the changes were depicted solely to osteoarthritic osteoblasts.

Do human B-lymphocytes avoid aging until 60 years?

Broad changes in human innate and adaptive immunity are associated with advanced age. The age-related alteration of gene expression was reported for both T and B lymphocytes. We analysed the genome-wide expression profiles (n=20) of naive and whole B cell populations from young and early aged healthy donors under 60 years. We revealed large homogeneity of all analysed genome-wide expression profiles but did not identified any significant gene deregulation between young (30-45 years) and early aged healthy donors (50-60 years). We argue that B cells avoid the aging program on molecular level until 60 years of age. Our results demonstrate the potential of hematopoietic stem cells to generate uncompromised lymphocytes in early elderly. These are very encouraging findings for the general health and the immunity maintenance would not need any intervention to naive B cells. Rather, a suitable immune stimulation in healthy body environment warrants further research into aging of older elderly.