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Purpose <p>Hesperetin (HET) is a flavonoid that shows potential as an anticancer agent; nevertheless, it is poorly soluble and bioavailable, so nature makes it challenging to administer orally. These limitations prompted the development and optimisation of PEGylated bilosomes (PEG-Bilo-HET) using a Box-Behnken Design.</p> Methods <p>PEG-Bilo-HET were prepared using thin-film hydration and optimized through BBD. The optimized bilosomal formulation was characterized for vesicle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), and morphology through Transmission Electron Microscopy (TEM).</p> Results <p>As evidence of effective formulation, the PEG-Bilo-HET exhibited nanoscale vesicle size (174.71 ± 2.43&#xa0;nm), homogeneous distribution (PDI 0.196 ± 0.03), zeta potential (˗31.09 ± 0.73 mV), and high drug encapsulation efficiency (83.19 ± 2.21%). Compared to the HET suspension, the in vitro drug release experiments performed at simulated stomach and intestinal pH conditions showed a sustained, enhanced release profile. Studies on <i>ex vivo</i> permeation in non-everted rat intestines showed that PEG-Bilo-HET had far greater permeability than an HET suspension, as seen by the higher apparent permeability coefficient (Papp) and increased cumulative drug permeation (~ 2-fold). In addition, the formulation’s robustness over 12 months was confirmed through stability testing under conditions recommended by the ICH guidelines. The PEG-Bilo-HET showed greater cytotoxicity against MCF-7 breast cancer cells than free HET (The IC₅₀ value of PEG-Bilo-HET was 95.50 ± 3.84 µM/mL, whereas 161.86 ± 5.85 µM/mL for HET-suspension), suggesting it could improve oral bioavailability and therapeutic outcomes in breast cancer.</p> Conclusion <p>The Optimised PEGylated bilosomes present a viable approach for the oral administration of HET, integrating increased solubility, enhanced intestinal permeability, and substantial anticancer efficacy.</p> Novelty of the Work <p>The distinctive aspect of this study resides in the development of a PEGylated bilosomal system for the oral administration of hesperetin. PEGylation improved vesicle stability and intestine residence time, whereas Box–Behnken formulation modification controlled key quality metrics. This study examines pH-dependent release, <i>ex vivo</i> intestinal penetration, and in vitro anticancer activity in MCF-7 cells, establishing PEGylated bilosomes as an improved oral nanocarrier for breast cancer treatment.</p> Graphical Abstract <p></p>

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Optimized PEGylated Bilosomes for Oral Delivery of Hesperetin: Formulation and In Vitro Evaluation in Breast Cancer

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Bjad K. Almutairy,
  • Abdullah Alshetaili,
  • Mohammed Aldawsari,
  • Munerah Alfadhel,
  • Aftab Alam,
  • Mohd Imran

摘要

Purpose

Hesperetin (HET) is a flavonoid that shows potential as an anticancer agent; nevertheless, it is poorly soluble and bioavailable, so nature makes it challenging to administer orally. These limitations prompted the development and optimisation of PEGylated bilosomes (PEG-Bilo-HET) using a Box-Behnken Design.

Methods

PEG-Bilo-HET were prepared using thin-film hydration and optimized through BBD. The optimized bilosomal formulation was characterized for vesicle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), and morphology through Transmission Electron Microscopy (TEM).

Results

As evidence of effective formulation, the PEG-Bilo-HET exhibited nanoscale vesicle size (174.71 ± 2.43 nm), homogeneous distribution (PDI 0.196 ± 0.03), zeta potential (˗31.09 ± 0.73 mV), and high drug encapsulation efficiency (83.19 ± 2.21%). Compared to the HET suspension, the in vitro drug release experiments performed at simulated stomach and intestinal pH conditions showed a sustained, enhanced release profile. Studies on ex vivo permeation in non-everted rat intestines showed that PEG-Bilo-HET had far greater permeability than an HET suspension, as seen by the higher apparent permeability coefficient (Papp) and increased cumulative drug permeation (~ 2-fold). In addition, the formulation’s robustness over 12 months was confirmed through stability testing under conditions recommended by the ICH guidelines. The PEG-Bilo-HET showed greater cytotoxicity against MCF-7 breast cancer cells than free HET (The IC₅₀ value of PEG-Bilo-HET was 95.50 ± 3.84 µM/mL, whereas 161.86 ± 5.85 µM/mL for HET-suspension), suggesting it could improve oral bioavailability and therapeutic outcomes in breast cancer.

Conclusion

The Optimised PEGylated bilosomes present a viable approach for the oral administration of HET, integrating increased solubility, enhanced intestinal permeability, and substantial anticancer efficacy.

Novelty of the Work

The distinctive aspect of this study resides in the development of a PEGylated bilosomal system for the oral administration of hesperetin. PEGylation improved vesicle stability and intestine residence time, whereas Box–Behnken formulation modification controlled key quality metrics. This study examines pH-dependent release, ex vivo intestinal penetration, and in vitro anticancer activity in MCF-7 cells, establishing PEGylated bilosomes as an improved oral nanocarrier for breast cancer treatment.

Graphical Abstract