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

Ying, Xiaoying; Wang, Yi; Liang, Jing; Yue, Jiaxing; Xu, Cenglin; Lu, Lina; Xu, Zhenghao; Du, Yong‐Zhong; Chen, Zhong

doi:10.1002/ange.201403846

Cited by 38 publications

(25 citation statements)

References 25 publications

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“…Under an external electric field, the particle size of the ANG-HNP remained stable, while the particle size of the ANG-ERHNP increased dramatically as the current increased from 50 to 500 μA (Fig. 1B), results consistent with our previous study [8]. The increase in diameter happened as quickly as within 1 min of exposure to the electric field (Fig.…”

Section: Resultssupporting

confidence: 91%

“…This effect may be due to the brain targeting effect of ANG [39], and/or nanoparticle characteristics such as small size and prolonged blood circulation owing to PEGylation [40]. In addition, our previous study in a kindling model further verified that the antiseizure effects of the ANG-PHT-ERHNP could last as long as 8 h; the effect of the PHT solution only lasted for 2 h [8]. This sustainedrelease characteristic of the carrier can effectively reduce the number of times the medicine needs to be administered.…”

Section: Discussionmentioning

confidence: 71%

“…We previously designed electroresponsive hydrogel nanoparticles (ERHNP) based on the abnormal electrical activity characteristics of epileptic seizures, and further modified ERHNP with the brain-targeting angiopep-2 peptide (ANG), a ligand of the low-density lipoprotein receptor-related protein, to improve penetration of the BBB [8]. However, the optimal preparation formula for electroresponsive ability is still unclear and the in vivo electroresponsive characteristics of ANG-PHT-ERHNP during seizures has been limited by the challenges of performing molecular studies in the face of generalized convulsions.…”

Section: Introductionmentioning

confidence: 99%

“…However, the optimal preparation formula for electroresponsive ability is still unclear and the in vivo electroresponsive characteristics of ANG-PHT-ERHNP during seizures has been limited by the challenges of performing molecular studies in the face of generalized convulsions. Although the improved antiepileptic effect of ANG-PHT-ERHNP compared with the PHT solution was demonstrated in the kindling model [8], it is highly likely that the improved antiepileptic effect may be caused by a higher concentration of PHT in the central nervous system (CNS) owing to the brain-targeting effect of ANG. Moreover, PHT is highly bound to proteins both in plasma and in the brain, so only the free (nonprotein-bound) levels of PHT are relevant for its pharmacological effects [9].…”

Section: Introductionmentioning

confidence: 99%

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Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

et al. 2016

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Previously, we developed electroresponsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiseizure drug phenytoin sodium (PHT). However, the electroresponsive characteristics were not verified directly in epileptic mice and the optimal preparation formula for electroresponsive ability is still unclear. Here, we further synthesized PHT-loaded ANG-ERHNPs (ANG-PHT-HNPs) and PHT-loaded nonelectroresponsive hydrogel nanoparticles (ANG-PHTHNPs) by changing the content of sodium 4-vinylbenzene sulfonate in the preparation formulae. In vivo microdialysis analysis showed that ANG-PHT-ERHNPs not only have the characteristics of a higher distribution in the central nervous system, but also have electroresponsive ability, which resulted in a strong release of nonprotein-bound PHT during seizures.In both electrical-(maximal electrical shock) and chemicalinduced (pentylenetetrazole and pilocarpine) seizure models, ANG-PHT-ERHNPs lowered the effective therapeutic doses of PHT and demonstrated the improved antiseizure effects compared with ANG-PHT-HNPs or PHT solution. These results demonstrate that ANG-ERHNPs are able to transport PHT into the brain efficiently and release them when epileptiform activity occurred, which is due to the content of sodium 4-vinylbenzene sulfonate in formula. This may change the therapeutic paradigm of existing drug treatment for epilepsy into a type of on-demand control for epilepsy in the future.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

et al. 2016

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“…Further downscaling the hydrogel into nanoscale particles, Chen et al . demonstrated that hydrogels nanoparticles could penetrate the blood‐brain barrier and then release drugs rapidly with real‐time control as shown in Figure G . These dispersed hydrogel micro/nanoparticles have great advantages for in vivo drug delivery.…”

Section: Biochemical Release Controlled By Electrochemical Actuationmentioning

confidence: 99%

Electrically Controlled Biochemical Release from Micro/Nanostructures for in vitro and in vivo Applications: A Review

Guo

Fan

2018

ChemNanoMat

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To release biosubstances, including drug molecules, DNAs, and proteins, at prescribed cellular and tissue locations with controllable rates is the Holy Grail of drug delivery that could enable an array of unprecedented in vitro and in vivo applications. Extensive research efforts have been focused on exploring innovative mechanisms and approaches for controlling biochemical release with prescribed dose, timing, and dynamics. Particularly, the utilization of electric fields to stimulate the release of biomolecules from synthesized micro/nanostructures has received considerable interest. In this review, we focus on the recent progresses in controlling the release of biomolecules with electric fields by a variety of mechanisms, including electrochemical desorption and actuation, electrically triggered erosion, and electrically driven nanopumps and mechanical motions. The research on external electric stimuli trigged biorelease has progressed rapidly and could make remarkable impact in single‐cell biology, cell‐cell communication, and drug discovery.

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MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

et al. 2015

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Drug delivery across the blood-brain barrier (BBB) is af ormidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively,t heir application is partly limited by lability to proteases.T he present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, aneurotoxinf rom bee venom, was minimized by reducing its complexity,t oxicity,a nd immunogenicity,w hile preserving brain targeting,a ctive transport, and protease resistance. Among the analogues designed, the monocyclic lactambridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in ah uman-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver ac argo across the BBB into the brain parenchyma of mice.The incidence of brain diseases is increasing mainly because of population aging.Unfortunately,most molecules intended for therapy and with high in vitro efficiency fail to reach their targets because they are unable to cross the blood-brain barrier (BBB) in adequate amounts.[1] One of the most promising non-invasive strategies under investigation for drug delivery to the central nervous system (CNS) is the use of BBB shuttles.[2] These vectors are able to enhance the passage of compounds across the BBB without altering its integrity.In the last few years,m uch research effort has been devoted to identifying peptide shuttles because these molecules are more economical, less immunogenic,a nd have higher chemical versatility than large proteins,such as Tr ojan horse antibodies. Nevertheless,animportant drawback of existing sequences is their high lability to serum proteases.W ea nd others have recently shown that peptides with reversed sequences and damino acids (retro-enantio approach) can be more efficient carriers than their l-counterparts.[3] Nonetheless,this strategy is relatively costly and may decrease the affinity of the peptide for the receptor that mediates its transport. Away to circumvent these drawbacks could be the use of natural cyclic peptides targeting the CNS,s uch as those found in venoms. However,a ni nconvenience of using these compounds as BBB shuttles is their high toxicity.I np articular,t he bicyclic peptide apamin, found in bee venom, crosses the BBB and blocks calcium-mediated potassium channels.[4] Despite the proven CNS-targeting capacity of apamin, [5] the extended application of this molecule has been limited by its toxicity, high immunogenicity, [6] and relatively complex structure.T wo years ago,w er eported that the replacement of arginines by ornithines yielded anon-toxic apamin analogue that is able to cross atight monolayer of bovine endothelial cells mimicking the BBB.[7] Our present study aimed to obtain all-l-proteaseresistant shuttles by minimizing apamin, while reducing its toxicity and immunogenicity.F urthermore,w es tudied the ability of these shuttles to carry large cargoes in ahuman-c...

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

Cited by 38 publications

References 25 publications

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

Electrically Controlled Biochemical Release from Micro/Nanostructures for in vitro and in vivo Applications: A Review

MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

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