Functionalized PEG-PLA nanoparticles for brain targeted delivery of ketoconazole contribute to pregnane X receptor overexpressing in drug-resistant epilepsy

Objective: To develop a functionalized PEG-PLA nanoparticle system containing ketoconazole (KCZ) to overcome the overactivity of pregnane X receptor (PXR) for the treatment of drug-resistant epilepsy (DRE). Significance: KCZ was developed as a therapy strategy for DRE limited by its lethal hepatotoxicity and minute brain concentration. KCZ-incorporated nanoparticles modified with angiopep-2 (NPs/KCZ) could reduce adverse effects of KCZ and achieve epileptic foci-targeted drug delivery. Methods: NPs/KCZ was prepared by thin-film hydration method and characterized in vitro and in vivo. The efficacy evaluation of NPs/KCZ was evaluated in a kainic acid (KA)-induced mice model of epilepsy with carba-mazepine (CBZ) treatment. Results: The mean particle size and Zeta potential of NPs/KCZ were 17.84 +/- 0.33 nm and -2.28 +/- 0.12 mV, respectively. The drug-loading (DL%) of KCZ in nanoparticles was 8.96 +/- 0.12 % and the entrapment efficiency (EE%) was 98.56 +/- 0.02 %. The critical value of critical micelle concentration was 10- 3.3 mg/ml. No obvious cytotoxicity was found in vitro. The behavioral and electrographic seizure activities were obviously attenuated in NPs/KCZ+CBZ group. The CBZ concentration of brain tissues in mice treated with NPs/KCZ+CBZ was significantly increased than those treated with CBZ alone (P = 0.0028). A significantly decreased expression level of PXR and its downstream proteins was observed in NPs/KCZ+CBZ group compared with that in the control and CBZ group (All P < 0.05). Conclusion: Our results showed that NPs/KCZ achieved the epileptic foci-targeted delivery of KCZ and amelio-rated the efficacy of CBZ on DRE by attenuating the overactivity of PXR.