Design and Evaluation of Innovative Oral Delivery Vehicle of Daunorubicin Using Particle-Stabilized Antibubbles

Abstract

Daunorubicin (DNR) is a DNA intercalating anticancer drug that is used to treat various types of cancer and is administered intravenously. DNR is highly cytotoxic to healthy mucosal tissue in the gastrointestinal tract and its oral availability is low, primarily due to P-gp-mediated efflux. Therefore, the development of a viable oral formulation of DNR is highly desirable. The aim of this study was to encapsulate DNR in silica-stabilized antibubbles. Additionally, tariquidar (TAR) was used as a P-gp inhibitor to inhibit the efflux of DNR and achieve a higher bioavailability. Empty core, DNR, TAR, and co-loaded antibubbles were produced. Microscopic images showed that the antibubbles were spherical and multi-cored, indicating that the manufacturing process was successful. Subsequently, the encapsulation efficiency (EE%) of DNR in the antibubbles was determined, which ranged from 93-99% for the DNR antibubbles and 86-91% for the co-loaded antibubbles. DNR release was induced by bile salts in a concentration-dependent manner by destabilizing the antibubbles. However, this release was not complete due to co-precipitation of DNR, bile salts, and silica particles. Finally, a transport experiment in a 2D Caco-2 cell model was performed in which cells were incubated with solutions of free DNR and TAR and/or rehydrated DNR, TAR, and co-loaded antibubbles. A trend was observed that TAR could inhibit DNR efflux leading to a higher DNR cellular accumulation, and that encapsulation of TAR did not affect its effectiveness. Overall, antibubbles are a very interesting delivery vehicle and this study has planted the first seeds for an oral administration form of DNR, while highlighting the need for more research and further optimization.