Enhanced Bioavailability by Orally Administered Sirolimus Nanocrystals

Area of Science:

• Pharmaceutical Sciences
• Nanotechnology
• Immunology

Background:

• Insoluble drugs present challenges in administration and bioavailability.
• Nanocrystallization is a promising strategy to enhance drug properties.
• Sirolimus (SRL) is an important immunosuppressive drug with poor solubility.

Purpose of the Study:

• To investigate the transport mechanism and efficacy of nanocrystallized sirolimus (SRL NCs).
• To compare the in vitro and in vivo performance of SRL NCs against conventional SRL formulation.
• To evaluate the impact of SRL NCs on immune responses.

Main Methods:

• Sirolimus was nanocrystallized to achieve 120 nm nanocrystals (SRL NCs).
• In vitro studies involved Caco-2 cell monolayer transport assays.
• In vivo studies included administration in normal mice and an ovalbumin-sensitized mouse model to assess immune effects.

Main Results:

• SRL NCs demonstrated enhanced permeability across Caco-2 cell monolayers.
• Cellular uptake involved multiple endocytosis pathways, with ER, Golgi, and microtubules crucial for drug expulsion.
• In vivo, SRL NCs reduced CD4+/CD8+ ratios and increased regulatory T cells (Tregs), enhancing immune tolerance.

Conclusions:

• Nanocrystallization significantly improves sirolimus oral bioavailability and transcytosis.
• SRL NCs exhibit enhanced efficacy by modulating immune responses and increasing drug residence time.
• This study highlights the potential of SRL nanocrystals for improved drug delivery and therapeutic outcomes.