Development of a nanomedicine approach to improve the therapeutic index of bexarotene.

Abstract

Bexarotene (BEX), a retinoid X receptor (RXR) agonist, has demonstrated therapeutic potential in oncology, neurodegenerative diseases and inflammatory conditions, including multiple sclerosis (MS). However, its broader clinical application is limited by poor aqueous solubility, low bioavailability, and dose-limiting adverse effects, most notably hypertriglyceridaemia. In this study, we investigated whether conjugation of BEX to dextrin, a biodegradable polysaccharide, could improve its physicochemical properties and therapeutic index. A dextrin-BEX conjugate was synthesised using succinoylated dextrin (30 mol%) and characterised by gel permeation chromatography (GPC), Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (1H-NMR) and dynamic light scattering (DLS). The effects of conjugation on solubility, aggregation behaviour and biological activity were evaluated using in vitro cytotoxicity assays in leukaemia, liver and fibroblast cell lines, alongside measurements of intracellular triglyceride levels. The impact on lipid metabolism and toxicity was further assessed in an in vivo murine model of hyperlipidaemia. Dextrin conjugation significantly increased the aqueous solubility of BEX (from <0.004 mg/mL to 9.88 mg/mL) and led to the formation of nanoscale aggregates in solution. This was associated with a marked increase in in vitro potency, with IC50 values reduced by up to 14-fold across multiple cell lines. However, the increased cytotoxicity was not selective for cancer cells and was also observed in normal fibroblast and hepatic cell models. The dextrin-BEX conjugate did not induce intracellular triglyceride accumulation in vitro. In vivo, dextrin conjugation did not mitigate BEX-associated lipid dysregulation, while serum triglyceride levels and markers of liver injury remained unchanged. However, although free BEX led to a significant increase in liver weight after 14 days, the dextrin-BEX conjugate did not produce a statistically significant effect. In conclusion, dextrin conjugation markedly improves the solubility and in vitro potency of BEX but does not enhance its selectivity or reduce its metabolic toxicity in vivo. These findings suggest that while polymer conjugation is an effective strategy for addressing physicochemical limitations, it is insufficient to overcome the inherent dyslipidaemia associated with systemic RXR activation. Future strategies should focus on integrating targeting and controlled release mechanisms, alongside approaches that address the underlying pharmacological drivers of lipid dysregulation.