Bioadhesive chitosan-coated cyclodextrin-based superamolecular nanomicelles to enhance the oral bioavailability of doxorubicin

Abstract

In order to improve the oral bioavailability of doxorubicin (Dox), a novel bioadhesive nanomicelle based on host–guest interaction was developed in this study. Hyaluronic acid-linked β-cyclodextrin (HA–CD) was synthesized. The primary nanomicelles were formed through the self-assemble of HA–CD and retinoic acid (RA) which was included as the hydrophobic core to anchor CD cavity by host–guest interaction. Chitosan (CS) was then coated on the surface of primary nanomicelles by ionic interaction with the negatively charged HA. The critical micellar concentration of HA–CD–RA was as low as 22.5 μg/mL. Dox was successfully encapsulated into the hydrophobic core of CS-coated HA–CD–RA nanomicelles (CS/HA–CD–RA–Dox), with encapsulation efficiency as high as 89.2 %. The CS/HA–CD–RA–Dox particle size was 234 nm and was stable over 30 days. In vitro Dox release showed that CS/HA–CD–RA nanomicelles were more sustained than HA–CD–RA nanomicelles, and Dox encapsulated into CS-coated nanomicelles was stable at low pH. The in situ single pass intestinal perfusion revealed that encapsulation of Dox into CS/HA–CD–RA nanomicelles could significantly improve the intestinal permeability of Dox. The mucoadhesion results indicated that the retention percentage of CS/HA–CD–RA nanomicelles was significantly higher than that of HA–CD–RA nanomicelles in gastrointestinal tract. In vivo pharmacokinetic study revealed that AUC(0−∞) of CS/HA–CD–RA nanomicelles was about fourfold higher than that of Dox solution. The present study suggested that CS/HA–CD–RA nanomicelles as biodegradable, biocompatible, and bioadhesive nanostructure can be a promising nanocarrier in improving the bioavailability of anticancer drugs to facilitate the oral chemotherapy.