Calcium Phosphate‐Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures

Abstract

to temporally block the sodium-dependent action potentials for inhibiting seizure activities. However, the unique pathological features of epilepsy create additional challenges for PHT-based seizure treatment. Typically, the blood-brain-barrier (BBB) is a formidable obstacle that severely limits the translocation of PHT from the bloodstream to epileptic neurons, which often warrants large PHT dosage to ensure sufficient brain PHT accumulation and causes unneglectable side effects. [2] The prevalent adverse reactions with PHT treatment for epilepsy include gingival hyperplasia and hirsutism and rare but serious cutaneous eruptions such as Stevens-Johnson syndrome. [3] These toxic effects bring great clinical challenges regarding the usage of PHT. Moreover, epileptic neurons are usually overexpressed with p-glycoprotein (P-gp) (coded by the gene Abcb1 in mice) drug efflux pumps, leading to the rapid excretion of internalized PHT molecules and compromising their therapeutic efficacy. [4][5][6] Consequently, it is important to develop new strategies to improve the brain-targeted delivery efficacy of PHT for enhanced epilepsy treatment efficacy.The P-gp-mediated drug efflux is a well-recognized adenosine triphosphate (ATP)-consuming process. [7][8][9][10] Therefore, an ideal PHT delivery system should be able to simultaneously inhibit the P-gp expression in epileptic neurons, as well 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 Ca 2+ and PHT into the cytosol. Ca 2+ 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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“…[ 160 ] Representative CPPs include TAT, penetratin and oligoarginine, etc. [ 163 , 190 ] In contrast to CPPs, various ligands act on transporters and/or receptors to trigger transcellular pathways. An ideal targeted receptor/transporter for delivering cargoes to the brain parenchyma should possess the following features: 1) high expression on the luminal side of brain vasculature and low expression in other tissues; 2) mediation of transcytosis rather than confining cargoes inside endothelial cells; 3) high turnover from cell membranes; 4) broad substrate recognition and resistance to saturation by endogenous substrates.…”

“…The reversal of PHT resistance is achieved through Ca 2+ release following lysosomal degradation of CaP@PHT‐PEG‐TAT, which downregulated P‐gp expression and enhanced the brain retention of PHT. [ 190 ]…”

“…The reversal of PHT resistance is achieved through Ca 2+ release following lysosomal degradation of CaP@PHT-PEG-TAT, which downregulated P-gp expression and enhanced the brain retention of PHT. [190] Although brain-targeting nanomedicines can enhance the brain delivery of antiepileptic drugs, most of these nanoplatforms lack the capability for on-demand drug release. Since seizures often occur in an abrupt, unpredicted manner and may last for a relatively long time, ideal nanocarriers should possess the ability to promptly control seizure spreading and maintain sustained drug release to suppress continuous seizures.…”