Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation

To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX-ES complex was in an amorphous form. An in vitro release (pH 6.8 PBS) study showed the excellent sustained-release characteristics of DOX-loaded EPNs (DOX-EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX-EPNs, and caveolin- and clathrin-mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco-2 cells, compared with DOX-Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOXEPNs internalized by Caco-2 cells was higher than that of DOX-Sol showing that P-glycoprotein-mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco-2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX-EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC((0-t)) and t(1/2) of DOX-EPNs were increased to 3.63-fold and 2.47-fold in comparison with DOX solution (DOX-Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability. (C) 2016 Elsevier B.V. All rights reserved.