Sirolimus-loaded polymeric micelles with honokiol for oral delivery

ObjectivesThe aims of the present study were to design polymeric micelles loading sirolimus with honokiol to increase drug solubility and to gain an insight into the effect of honokiol on oral transport of P-glycoprotein substrate (P-gp). MethodsParticle size distribution, encapsulation efficiency, drug-loading content and in-vitro release of sirolimus-loaded micelles with honokiol were determined. Transport of sirolimus-loaded micelles across Caco-2 cell monolayers and jejunum segment of rats were investigated. In-vitro cytotoxicity experiments and the cellular uptake study were carried out via sulforhodamine B assay and flow cytometry, respectively. Key findingsA coadministration of honokiol with sirolimus in micelles did not significantly modify the particle size, polydispersity index and release of drugs demonstrating successful loading within the micelles. The apparent transport coefficients (P-app) and effective permeability (P-eff) of sirolimus were increased with more amount of honokiol loaded in micelles. Cellular uptake study demonstrated that rhodamine123 uptake rate was enhanced by honokiol-loaded micelles, indicating substantial P-gp inhibition action by honokiol and mPEG-PLA-based micelles. ConclusionOral transport of sirolimus was significantly improved by coadministration with honokiol, an inhibitor of the P-gp, in polymeric micelles formulation.