Ferenc Fenyvesi

Background: Uveal melanoma is the most common intraocular malignancy in adults with a poor prognosis. Although local therapies are effective, treatment options for advanced disease remain limited. Combination strategies using chemotherapeutic agents and natural compounds, such as quercetin, are in focus for their potential to enhance antitumor efficiency and overcome resistance. Methods: The effects of doxorubicin, quercetin, and their combination were investigated in uveal melanoma cell lines. Cell viability was determined by an MTT assay, and apoptosis and cell cycle distribution by flow cytometry. Invasion assays were performed to evaluate metastatic potential, while modifications in signaling pathways were analyzed by Western blotting and qPCR. Results: Both doxorubicin and quercetin significantly reduced cell viability and induced apoptotic and necrotic cell death. The combination treatment demonstrated additional inhibitory effects in both cell lines, shown by increased SubG1 populations, reduced invasive capacity, and modulation of signaling pathways. Cell cycle analysis indicated treatment-induced growth inhibition. Notably, pathway modifications varied between cell lines, suggesting heterogeneous responses. Conclusions: Quercetin may potentiate certain antitumor effects of doxorubicin in uveal melanoma, particularly by reducing post-treatment invasiveness and modulating certain PI3K/AKT pathway-related proteins. These results support the possibility of quercetin-based combination therapies, although further molecular and in vivo studies are required.

Background/Objectives: Intracellular delivery of RNA molecules is challenging. To solve this problem, many carrier systems are available, which are based on liposomes or polymers. Cyclodextrins are widely used excipients to increase the solubility of small molecules, but their polymer derivatives are able to deliver macromolecules. In the present study, we aimed to investigate and compare the siRNA and mRNA carrying capacity of a cationic quaternary ammonium β-cyclodextrin polymer (QABCDPS) and polyethylenimine (PEI). Methods: Cytotoxicity of the polymers was tested by the MTT method. Polyplexes were formulated with different nitrogen/phosphate ratios (NP), and their physicochemical properties were examined using dynamic light scattering and zeta potential measurements. Cellular internalization and intracellular effects of the polyplexes were investigated by confocal microscopy and flow cytometry. Results: QABCDPS exhibited lower toxicity compared to PEI, effectively binding both siRNA and mRNA and delivering them into vesicles in the cytoplasm, but showing different internalization patterns. Polyplexes formed with PEI showed stronger biological effect than those with QABCDPS, which can be attributed to the strength of interactions facilitated by the polymers. Conclusions: In summary, QABCDPS is a low-toxicity carrier that shows some promise for mRNA delivery but is ineffective for siRNA silencing under the tested conditions and requires further structural optimization.

Background: Menopause is characterised by a decline in oestrogen levels, leading to physical and psychological symptoms that significantly affect quality of life. Current parenteral oestradiol ester therapies, while effective, are often associated with side effects due to their oil-based formulations, including injection-site reactions and immune responses. Methods: In this study, we developed a water-soluble, polyethylene glycol cross-linked β-cyclodextrin (PEG–β-CD) polymer-based system for parenteral oestradiol delivery and evaluated its biocompatibility, solubility enhancement, immune compatibility, and pharmacokinetics. Results: Cytotoxicity assays using NIH-3T3 fibroblasts and RAW 264.7 macrophages showed minimal toxicity up to 10% (w/w). Phase-solubility studies demonstrated a significant increase in oestradiol solubility with the PEG–β-CD polymer, surpassing that of β-cyclodextrin or PEG alone. Dynamic light scattering and FTIR analyses confirmed successful complex formation, with submicron particles averaging 271 nm and physical incorporation of oestradiol into the polymer matrix. Macrophage activation assays and RT-qPCR analyses indicated an absence of immunogenic responses or pro-inflammatory cytokine induction. In vivo toxicity testing in Galleria mellonella larvae confirmed safety, while pharmacokinetic studies in Wistar rats revealed rapid initial absorption followed by stable, low-level serum concentrations comparable to those of commercially used oestradiol esters. Conclusions: These findings indicate that the PEG–β-CD polymer–oestradiol complex provides a safe, water-based alternative to traditional oil-based injections, with the potential to reduce side effects and improve patient compliance in postmenopausal hormone therapy.

Given the increasing incidence and mortality of breast cancer, the development of target‐specific imaging probes for early disease detection seems straightforward. Prostaglandin E2 (PGE2) and its receptors have a crucial role in tumor angiogenesis; therefore, radiolabelled cyclodextrins targeting such biomolecules may serve as selective vectors for positron emission tomography (PET) imaging of breast cancer. Herein, we aimed to monitor PGE2 production in MDA‐MB‐HER2‐positive and 4 T1 triple‐negative breast cancer xenografts using ⁶⁸ Ga‐labeled randomly methylated beta cyclodextrin (RAMEB) and 2‐hydroxypropyl‐beta‐cyclodextrin (HPβCD) and PET technique. After the injection of [ ⁶⁸ Ga]Ga‐NODAGA‐HPβCD and [ ⁶⁸ Ga]Ga‐DOTAGA‐RAMEB, CB17 SCID mice bearing breast tumors underwent weekly PET imaging with subsequent quantitative data assessment and ex vivo biodistribution studies. Both cyclodextrin compounds were suitable to identify the tumors, though tracer accumulation varied with tumor size. Significantly higher [ ⁶⁸ Ga]Ga‐NODAGA‐HPβCD uptake was observed in the MDA‐MB‐HER2+ tumors across all sizes (small, medium, and large‐sized) compared to the 4 T1 counterparts. In contrast, [ ⁶⁸ Ga]Ga‐DOTAGA‐RAMEB accumulated to a greater extent in small and midsized 4 T1 tumors in comparison with size‐matched MDA‐MB‐HER2+ tumors, while it showed higher uptake in the large HER2+ lesions than in 4 T1. The presented results indicate notable radioactivity in both 4 T1 and MDA‐MB‐HER2+ tumors designating [ ⁶⁸ Ga]Ga‐DOTAGA‐RAMEB and [ ⁶⁸ Ga]Ga‐NODAGA‐HPβCD as effective PET probes for the identification of breast cancer.

Flavonoids play an important role in preventive and therapeutic research due to their significant antioxidant properties. However, their application is limited by several pharmacokinetic drawbacks, such as poor water solubility and low bioavailability. Cyclodextrin-based delivery systems offer an opportunity to overcome these disadvantages. Cyclodextrins are able to form stable, water-soluble inclusion complexes with flavonoids, thereby improving their solubility, chemical stability, and antioxidant activity. This review summarizes the structural characteristics and complexation mechanisms of various flavonoid–cyclodextrin complexes and examines how these interactions influence biological activity. Special attention is given to nanotechnological formulations—such as liposomes, nanofibers, and nanosponges—that enable targeted drug delivery and enhanced therapeutic efficacy. The aim of this review is to provide a comprehensive overview of the role of cyclodextrin-based carriers in the formulation of flavonoids and to highlight the future potential of these systems in modern therapeutics and functional product development.