Calcium Phosphate-Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures.
Small
; 19(29): e2300395, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37029709
ABSTRACT
Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca2+ and PHT into the cytosol. Ca2+ ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenitoína
/
Epilepsia
Limite:
Humans
Idioma:
En
Revista:
Small
Ano de publicação:
2023
Tipo de documento:
Article