Graphene-based materials (GBMs) have shown significant promise in cancer therapy due to their unique physicochemical properties, biocompatibility, and ease of functionalization. Their ability to target solid tumors, penetrate the tumor microenvironment (TME), and act as efficient drug delivery platforms highlights their potential in nanomedicine. However, the complex and dynamic nature of the TME, characterized by metabolic heterogeneity, immune suppression, and drug resistance, poses significant challenges to effective cancer treatment. GBMs offer innovative solutions by enhancing tumor targeting, facilitating deep tissue penetration, and modulating metabolic pathways that contribute to tumor progression and immune evasion. Their functionalization with targeting ligands and biocompatible polymers improves their biosafety and specificity, while their ability to modulate immune cell interactions within the TME presents new opportunities for immunotherapy. Given the role of metabolic reprogramming in tumor survival and resistance, GBMs could be further exploited in metabolism-targeted therapies by disrupting glycolysis, mitochondrial respiration, and lipid metabolism to counteract the immunosuppressive effects of the TME. This review focuses on discussing research studies that design GBM nanocomposites with enhanced biodegradability, minimized toxicity, and improved efficacy in delivering therapeutic agents with the intention to reprogram the TME for effective anticancer therapy. Additionally, exploring the potential of GBM nanocomposites in combination with immunotherapies and metabolism-targeted treatments could lead to more effective and personalized cancer therapies. By addressing these challenges, GBMs could play a pivotal role in overcoming current limitations in cancer treatment and advancing precision oncology.

• MeSH
• Graphite * chemistry   therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Tumor Microenvironment * drug effects   MeSH
• Neoplasms * drug therapy   metabolism   MeSH
• Nanocomposites * chemistry   therapeutic use   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

• MeSH
• Apoptosis * drug effects   MeSH
• Centrosome * drug effects   metabolism   MeSH
• Phenylethyl Alcohol * analogs & derivatives   pharmacology   chemistry   MeSH
• Caffeic Acids * pharmacology   chemistry   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: A critical step preceding the potential biomedical application of nanoparticles is the evaluation of their immunomodulatory effects. Such nanoparticles are expected to enter the bloodstream where they can be recognized and processed by circulating monocytes. Despite the required biocompatibility, this interaction can affect intracellular homeostasis and modulate physiological functions, particularly inflammation. This study focuses on titanium dioxide (TiO2) as an example of relatively low cytotoxic nanoparticles with potential biomedical use and aims to evaluate their possible modulatory effects on the inflammasome-based response in human primary monocytes. METHODS: Monocyte viability, phenotypic changes, and cytokine production were determined after exposure to TiO2 (diameter, 25 nm; P25) alone. In the case of the modulatory effects, we focused on NLRP3 activation. The production of IL-1β and IL-10 was evaluated after (a) simultaneous activation of monocytes with bacterial stimuli muramyl dipeptide (MDP), or lipopolysaccharide (LPS), and TiO2 (co-exposure model), (b) prior activation with TiO2 alone and subsequent exposure to bacterial stimuli MDP or LPS. The differentiation of TiO2-treated monocytes into macrophages and their polarization were also assessed. RESULTS: The selected TiO2 concentration range (30-120 μg/mL) did not induce any significant cytotoxic effects. The highest dose of TiO2 promoted monocyte survival and differentiation into macrophages, with the M2 subset being the most prevalent. Nanoparticles alone did not induce substantial production of inflammatory cytokines IL-1β, IL-6, or TNF-α. The immunomodulatory effect on NLRP3 depended on the type of costimulant used. While co-exposure of monocytes to MDP and TiO2 boosted NLRP3 activity, co-exposure to LPS and TiO2 inhibited NLRP3 by enhancing IL-10 release. The inhibitory effect of TiO2 on NLRP3 based on the promotion of IL-10 was confirmed in a post-exposure model for both costimulants. CONCLUSION: This study confirmed a non-negligible modulatory effect on primary monocytes in their inflammasome-based response and differentiation ability.

• MeSH
• Acetylmuramyl-Alanyl-Isoglutamine pharmacology   MeSH
• Cell Differentiation drug effects   MeSH
• Cytokines metabolism   MeSH
• Inflammasomes drug effects   MeSH
• Interleukin-10 metabolism   MeSH
• Interleukin-1beta metabolism   MeSH
• Metal Nanoparticles chemistry   toxicity   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Lipopolysaccharides * pharmacology   MeSH
• Macrophages drug effects   MeSH
• Monocytes * drug effects   MeSH
• Nanoparticles chemistry   toxicity   MeSH
• NLR Family, Pyrin Domain-Containing 3 Protein * metabolism   MeSH
• Titanium * chemistry   pharmacology   toxicity   MeSH
• Cell Survival * drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Bio-nano interactions have been extensively explored in nanomedicine to develop selective delivery strategies and reduce systemic toxicity. To enhance the delivery of nanocarriers to cancer cells and improve the therapeutic efficiency, different nanomaterials have been developed. However, the limited clinical translation of nanoparticle-based therapies, largely due to issues associated with poor targeting, requires a deeper understanding of the biological phenomena underlying cell-nanoparticle interactions. In this context, we investigate the molecular and cellular mechanobiology parameters that control such interactions. We demonstrate that the pharmacological inhibition or the genetic ablation of the key mechanosensitive component of the Hippo pathway, i.e., yes-associated protein, enhances nanoparticle internalization by 1.5-fold. Importantly, this phenomenon occurs independently of nanoparticle properties, such as size, or cell properties such as surface area and stiffness. Our study reveals that the internalization of nanoparticles in target cells can be controlled by modulating cell mechanosensing pathways, potentially enhancing nanotherapy specificity.

• MeSH
• Adaptor Proteins, Signal Transducing metabolism   MeSH
• Mechanotransduction, Cellular drug effects   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Nanoparticles * chemistry   MeSH
• Nanomedicine MeSH
• Hippo Signaling Pathway MeSH
• YAP-Signaling Proteins MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Retroviral gene transfer is the preferred method for stable, long-term integration of genetic material into cellular genomes, commonly used to generate chimeric antigen receptor (CAR)-T cells designed to target tumor antigens. However, the efficiency of retroviral gene transfer is often limited by low transduction rates due to low vector titers and electrostatic repulsion between viral particles and cellular membranes. To overcome these limitations, peptide nanofibrils (PNFs) can be applied as transduction enhancers. Among these, PNFs derived from the 12-mer peptide EF-C are well-investigated and commercially available. EF-C PNFs enhance transduction by forming EF-C PNFs/virus complexes that overcome electrostatic repulsion through their polycationic surface and interaction with cellular protrusions. However, the safe application of PNFs as transduction enhancers in gene therapeutic applications requires a fundamental understanding of their transduction-enhancing mechanisms, uptake, and degradation. In this study, we demonstrate that EF-C PNFs induce plasma membrane invaginations, increasing the membrane surface for viral attachment and reducing the distance to the nuclear membrane, thereby facilitating viral entry and transport to the nucleus. Furthermore, we identified macropinocytosis as the main entry pathway for EF-C PNFs and their subsequent degradation by lysosomal peptidases. The lysosomal degradation of EF-C PNFs prevents their accumulation as amyloid deposits, mitigating potential side effects and supporting their safe use in clinical applications.

• MeSH
• Endocytosis MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mice MeSH
• Nanofibers * chemistry   MeSH
• Peptides * chemistry   metabolism   MeSH
• Pinocytosis * MeSH
• Transduction, Genetic methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. METHODS: In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells' distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. RESULTS: Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).

• MeSH
• Cell Culture Techniques methods   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * pathology   metabolism   MeSH
• Gels chemistry   MeSH
• Collagen * chemistry   pharmacology   MeSH
• Humans MeSH
• Polyethylene Glycols * chemistry   MeSH
• Receptors, CXCR4 metabolism   MeSH
• Carboxymethylcellulose Sodium * chemistry   pharmacology   MeSH
• Cell Culture Techniques, Three Dimensional methods   MeSH
• Tissue Scaffolds * chemistry   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Introduction: The use of Cannabis sativa L. in health care requires stringent care for the optimal production of the bioactive compounds. However, plant phenotypes and the content of secondary metabolites, such as phytocannabinoids, are strongly influenced by external factors, such as nutrient availability. It has been shown that phytocannabinoids can exhibit selective cytotoxicity against various cancer cell lines while protecting healthy tissue from apoptosis. Research Aim: This study aimed to clarify the cytotoxic effect of cannabis extracts on colorectal cell lines by identifying the main active compounds and determining their abundance and activity across all developmental stages of medical cannabis plants cultivated under hydroponic conditions. Materials and Methods: Dimethyl sulfoxide extracts of medical cannabis plants bearing the genotype classified as chemotype I were analyzed by high-performance liquid chromatography, and their cytotoxic activity was determined by measuring cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay on the human colon cancer cell lines, Caco-2 and HT-29, and the normal human epithelial cell line, CCD 841 CoN. Results: The most abundant phytocannabinoid in cannabis extracts was tetrahydrocannabinolic acid (THCA). Its maximum concentrations were reached from the 7th to the 13th plant vegetation week, depending on the nutritional cycle and treatment. Almost all extracts were cytotoxic to the human colorectal cancer (CRC) cell line HT-29 at lower concentrations than the other cell lines. The phytocannabinoids that most affected the cytotoxicity of individual extracts on HT-29 were cannabigerol, Δ9-tetrahydrocannabinol, cannabidiol, cannabigerolic acid, and THCA. The tested model showed almost 70% influence of these cannabinoids. However, THCA alone influenced the cytotoxicity of individual extracts by nearly 65%. Conclusions: Phytocannabinoid extracts from plants of the THCA-dominant chemotype interacted synergistically and showed selective cytotoxicity against the CRC cell line, HT-29. This positive extract response indicates possible therapeutic value.

• MeSH
• Caco-2 Cells MeSH
• Cannabis * chemistry   MeSH
• Hydroponics MeSH
• Humans MeSH
• Medical Marijuana * MeSH
• Dronabinol analysis   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.

• MeSH
• Amino Acids, Diamino MeSH
• Angiotensin-Converting Enzyme 2 metabolism   MeSH
• COVID-19 * prevention & control   MeSH
• Cytokines metabolism   MeSH
• Epithelial Cells * drug effects   virology   MeSH
• Fullerenes * pharmacology   chemistry   MeSH
• Spike Glycoprotein, Coronavirus * metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Nanoparticles * chemistry   MeSH
• Nasal Mucosa drug effects   cytology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• SARS-CoV-2 * drug effects   MeSH
• Cytokine Release Syndrome * prevention & control   MeSH
• Cell Survival * drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell-nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple-negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.

• MeSH
• Humans MeSH
• Nanoparticles * MeSH
• YAP-Signaling Proteins MeSH
• Signal Transduction physiology   MeSH
• Triple Negative Breast Neoplasms * drug therapy   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.

• MeSH
• Antigens, CD34 analysis   MeSH
• ADP-ribosyl Cyclase 1 MeSH
• Bone Marrow chemistry   MeSH
• Humans MeSH
• Multiple Myeloma * therapy   MeSH
• Hematopoietic Stem Cell Mobilization MeSH
• Flow Cytometry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH