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 DOX-EPNs 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 t1/2 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.

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