Volume 9 ; Issue 2 ; in Month : July-Dec (2025) Article No : 197
Noushin Golzar

Abstract

Sulfur-containing heterocycles (SHCs) have emerged as an important class of bioactive compounds with promising applications in cancer therapy, owing to their structural diversity, redox activity, and ability to interfere with multiple oncogenic pathways. However, their therapeutic potential is often limited by poor aqueous solubility, instability in circulation, and reduced efficacy against multidrug-resistant (MDR) tumors. In this study, we aimed to evaluate the anticancer activity of a novel SHC previously developed by our team and to enhance its performance through a redox-responsive nanodelivery system. Chitosan–stearic acid (CS–SA) was synthesized via EDC-mediated amidation and subsequently conjugated to SHC through a disulfide linker, yielding SHC–ss–CS–SA micelles. Structural verification by ^1H NMR confirmed successful conjugation, and UV–visible spectrophotometry determined the SHC content to be 11.3% (w/w). The amphiphilic conjugates self-assembled into stable micelles with a mean diameter of 56 nm, low polydispersity, and positive zeta potential, exhibiting a reduced critical micelle concentration compared to CS–SA alone. Redox-responsiveness was confirmed by dithiothreitol-triggered release, where SHC–ss–CS–SA micelles displayed rapid cleavage of disulfide bonds and efficient drug liberation under intracellular-like reductive conditions, but remained stable in extracellular-like environments. Cytotoxicity assays in T47D breast cancer cells and their resistant counterpart T47D/SN150 demonstrated that SHC–ss–CS–SA micelles significantly enhanced anticancer potency compared to free SHC, reducing IC₅₀ values and achieving a resistance reversal index of 3.62. The improved efficacy may be attributed to endocytic uptake, bypass of MRP/BCRP efflux, redox-triggered intracellular release, and potential nuclear enrichment facilitated by chitosan’s GlcNAc structure. Collectively, these findings show that SHC–ss–CS–SA micelles not only potentiate the anticancer activity of a novel sulfur-containing heterocyclic compound but also effectively overcome transporter-mediated MDR, offering a promising and safe platform for targeted cancer therapy.

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