Multilayer micro-dispersing system as oral carriers for co-delivery of doxorubicin hydrochloride and P-gp inhibitor.

ABSTRACT

The primary constraints for efficient oral delivery of anticancer drugs include the efflux pump function of the multidrug transporter P-glycoprotein (P-gp) for anticancer drugs and the barriers to drug absorption in gastrointestinal (GI) tract. To improve bypassing P-gp drug efflux pumps and oral bioavailability of doxorubicin hydrochloride (DOX), Multilayer micro-dispersing system (MMS) was constructed by co-immobilization of DOX loaded chitosan/carboxymethyl chitosan nanogels (DOXCS/CMCS-NGs), along with quercetin (Qu) in the core of multilayer sodium alginate beads (DOXNGs/Qu-M-ALG-Beads). The obtained DOXNGs/Qu-M-ALG-Beads possessed layer-by-layer structure and porous core with many nanoscale particles. The swelling characteristic and drug release results indicated that DOXNGs/Qu-M-ALG-Beads exhibited favorable gastric acid tolerance and targeting release of intact DOXCS/CMCS-NGs and Qu in small intestine. After oral administration of DOXNGs/Qu-M-ALG-Beads in rats, DOX was effectively delivered into systemic circulation due to P-gp inhibitory properties of Qu. The absolute bioavailability reached 55.75%, about 18.65 folds higher than oral DOX. Tissue distribution results showed that the liver exhibited the highest DOX level, followed by kidney, heart, lung, and spleen. These results implied that DOXNGs/Qu-M-ALG-Beads had great potential to be applied as dual drug delivery for oral chemotherapy.