2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Despite substantial progress in anticancer drug discovery, the therapeutic potential of many biologically active small molecules is compromised by poor aqueous solubility and limited bioavailability, preventing effective intracellular delivery and clinical translation. This challenge is particularly pronounced for lipophilic, redox-active compounds, which often exhibit potent anticancer activity in vitro but fail to reach therapeutically relevant concentrations in vivo. Selenium-containing compounds represent a compelling class of anticancer agents due to their ability to modulate redox homeostasis, induce apoptosis, interfere with oncogenic signaling pathways, and influence immune-related mechanisms.

These biological effects make selenium derivatives especially attractive for cancer therapy. However, their hydrophobic character and unfavorable physicochemical properties significantly restrict solubility, absorption, and systemic exposure, thereby limiting their therapeutic applicability. Self-Emulsifying Drug Delivery Systems (SEDDS) can offer a rational and highly suitable formulation strategy for selenium-based small molecules. By spontaneously forming fine oil-in-water nanoemulsions under physiological conditions, SEDDS enhance the solubilization, membrane permeability, and cellular uptake of poorly water-soluble compounds, particularly those with intermediate lipophilicity - such as selenium derivatives. This approach not only improves bioavailability but also enables more efficient intracellular delivery of redox-active agents, which is critical for achieving their anticancer effects.

In this context, we designed and synthesized a series of novel 1,3-selenazole-2-one derivatives and hypothesized that their incorporation into Self-Emulsifying Drug Delivery Systems (SEDDS) would overcome key formulation barriers and enhance anticancer efficacy. The aim of the present study was to evaluate the anticancer activity and selectivity of these selenium-based compounds toward breast cancer cells and to assess the impact of SEDDS formulation on their biological performance. To first establish anticancer efficacy and formulation-dependent enhancement, cytotoxicity and cellular uptake of the novel 1,3-selenazole-2-one derivatives were evaluated in breast cancer cell models.

A series of newly synthesized derivatives (including Les-903, Les-957, Les-1986, Les-2013, and Les-2187) was examined in vitro using human breast cancer cell lines MCF-7 and MDA-MB-231, as well as normal breast epithelial cells MCF-10A. Cytotoxicity was assessed using MTT assays after 24 h exposure. Selected lead compounds were incorporated into optimized SEDDS formulations, and their anticancer activity was compared with non-formulated derivatives and the reference drug cisplatin. Cellular uptake of SEDDS-formulated compounds was visualized using confocal microscopy in Caco-2 cells. Subsequently, to provide a mechanistic rationale for future studies and to explore a potential immunomodulatory component beyond direct cytotoxicity, molecular docking was performed to assess the ability of selected compounds to interact with the immune checkpoint protein PD-L1.

Several 1,3-selenazole-2-one derivatives demonstrated significantly higher cytotoxicity against breast cancer cells than cisplatin at comparable concentrations, while exhibiting lower toxicity toward normal MCF-10A cells. Les-903 and Les-957 showed particularly high selectivity indices, indicating preferential anticancer activity. Incorporation into SEDDS markedly enhanced cytotoxic effects, likely due to improved cellular uptake, as confirmed by confocal imaging. Molecular docking revealed strong and stable binding of selected derivatives to PD-L1, with binding energies comparable or superior to known selenium-based reference compounds.

These preliminary findings indicate that novel 1,3-selenazole-2-one derivatives possess potent and selective anticancer activity against breast cancer cells. SEDDS formulation significantly enhances their efficacy, supporting this delivery strategy as a promising approach to overcome solubility and bioavailability limitations.