Re-purposed phenobarbital-loaded squarticles: A novel approach for the topical management of chemotherapy-induced alopecia

Document Type

Article

Publication Date

Spring 4-4-2026

Abstract

Background

Chemotherapy-induced alopecia (CIA) causes significant psychological distress, prompting the need for effective prophylactic or therapeutic interventions. Phenobarbital, a potential agent for re-purposing towards CIA prophylaxis and/or treatment, activates ABC receptors to expel chemotherapeutic agents from hair follicles. Squarticles, nanostructured lipid carriers enriched with squalene, are emerging nanocarriers that selectively target hair follicles via interaction with physiological sebum.

Methods

This study developed phenobarbital-loaded squarticles using a cost-effective high-speed stirring-ultrasonication method. Key formulation variables included total lipid amount (1% or 2%), precirol-to-squalene ratio (0:1, 3:1, 1:1, 1:0), and surfactant concentration (0.25% or 0.5%)

Results

The optimized formulation displayed a particle size of 229 ± 16.7 nm and drug entrapment efficiency of 82.72 ± 3.02%. Further characterization of the optimized formula demonstrated controlled drug release following the Higuchi pharmacokinetic model, with ∼ 11% of the drug deposited in hair follicles. Confocal laser scanning examination of skin specimens with DiI-loaded squarticles confirmed follicular targeting. In vivo studies on cyclophosphamide-induced alopecia in mice showed that both phenobarbital-loaded and blank squarticles provided a degree of hair follicle protection, accelerated recovery, and promoted cellular proliferation, as verified by histopathology, SEM imaging, and Ki-67 immunohistochemistry.

Conclusions

Both blank and drug-loaded squarticles demonstrated potential as prophylactic/therapeutic agents against CIA.

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