ArticleFrontiers in pharmacology2026
A dual edge-activation strategy for rhein bilosomes enhances intradermal delivery and anti-melanoma efficacy.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: The therapeutic potential of rhein (RH) in topical melanoma management is constrained by its poor aqueous solubility and limited intradermal bioavailability. This study proposes an innovative mechanism-driven formulation strategy to address these limitations and improve the therapeutic performance of RH against melanoma. Methods: A rhein-phospholipid complex (RH-PLC) was first prepared and and confirmed through solid-state characterization. The complex was subsequently encapsulated into two nanovesicular systems: bilosomes (BIL) engineered using sodium tauroglycocholate (STGC) as a bioactive edge activator, and limobilosomes (L-BIL), additionally containing limonene to further enhance dermal permeation. The developed formulations were evaluated for particle size, entrapment efficiency, physicochemical stability, in vitro drug release, ex vivo skin permeation, intradermal deposition, and cytotoxic activity against A375 melanoma cells. Results: Both nanovesicular systems exhibited nanoscale particle sizes (∼300 nm), high drug entrapment efficiencies (>90%), and favorable physicochemical stability. Compared with free RH, the developed systems significantly enhanced in vitro drug release, ex vivo human skin permeation (10.2-fold increase), and intradermal drug deposition (9.9-fold increase). In addition, cytotoxicity studies against A375 melanoma cells demonstrated a marked improvement in anticancer activity with IC50 values decreasing from 434.8 μg/mL for free RH to 50.4 μg/mL for BIL and 30.9 μg/mL for L-BIL. Furthermore, nanovesicular delivery improved melanoma cell selectivity and widened the therapeutic window, achieving a selectivity index (SI) of 2.4 despite the known selectivity limitations of anthraquinone derivatives. Conclusions: Rational modulation of edge-activation mechanisms can substantially improve the dermal delivery, and anticancer efficacy of RH. Among the developed systems, L-BIL demonstrated superior performance and represents a promising nanoplatform for topical melanoma therapy.
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