Angiopep‐Conjugated Electro‐Responsive Hydrogel Nanoparticles: Therapeutic Potential for Epilepsy

Abstract

A safe and effective therapy for epilepsy requires a drug delivery system that can penetrate the blood-brain barrier and subsequently release antiepileptic drugs rapidly to suppress neuronal discharges in a timely manner. We have developed electro-responsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiepileptic drug phenytoin sodium. The resulting ANG-ERHNPs had an average diameter of (102.3±16.8) nm and were electro-sensitive with regard to particle size and drug release in vitro. ANG-ERHNPs have the characteristics of penetrate the BBB easily, resulting in a higher distribution in the central system. The improved antiepileptic effects were investigated with the amygdala kindling model. The results demonstrate that the ANG-ERHNPs were able to transport antiepileptic drugs into the brain and release them under electroencephalograph epileptiform abnormalities to greatly improve the therapeutic index of existing drugs in clinical use.

Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems

“…In this study in vitro triggering and increased drug release with potential application in epilepsy treatment was shown. 146 …”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…Liposomes were used to deliver AEDs such as gamma-aminobutyric acid and phenytoin to show suppressed epileptic seizures (203). Polymeric NPs with advantages of higher stability, controlled drug release, and higher circulatory half-life were also used to deliver AEDs such as thyrotropin-releasing hormone, clonazepam (204), ethosuximide (205), valproate (206), loperamaide (207), phenytoin (205, 208), and carbamazepine (205). …”

Design strategies for physical-stimuli-responsive programmable nanotherapeutics

“…Besides this result, the release of piroxicam and insulin from the nanoparticles increased linearly from about 1.5 to about 2.2 and 7.0 µg mL −1 when the number of pulses increased from 0 to 3 (−100 µA for 25 seconds) and 2 (−1 V for 4 min), respectively. Ying et al (2014) [124] synthesized phenytoin sodium-loaded electro-responsive nanogels using sodium 4-vinylbenzene sulfonate-based polyelectrolyte that swelled from 102.3 ± 16.8 to 388.0 ± 20.4 nm when exposed to 500 µA for 1 min. Phenytoin sodium release from the nanogels also increased from 34.6% to 60.8% and 87.3% upon exposure to 100 and 200 µA current for 4 h, respectively.…”

“…For example, Ying et al . (2014) [124] modified the surfaces of phenytoin sodium-loaded electro-responsive nanogels using brain-targeting angiopep-2 peptide, a ligand of the low-density lipoprotein receptor-related protein, to improve the blood brain barrier penetration of the nanogels for the treatment of epilepsy. In comparison to the free drug, the concentration of phenytoin sodium in the brain from the non-modified and surface-modified nanogels increased by 1.49- and 1.97-fold, respectively, in vivo in rats.…”