Current options for drug delivery to the spinal cord

Introduction: Spinal cord disorders (SCDs) are among the most devastating neurological diseases, due to their acute and long-term health consequences, the reduced quality of life and the high economic impact on society. Here, drug administration is severely limited by the blood–spinal cord barrier (BSCB) that impedes to reach the cord from the bloodstream. So, developing a suitable delivery route is mandatory to increase medical chances.

Areas covered: This review provides an overview of drug delivery systems used to overcome the inaccessibility of the cord. On one side, intrathecal administration, either with catheters or with biomaterials, represents the main route to administer drugs to the spinal cord; on the other side, more recent strategies involve chemical or electromagnetic disruption of the barrier and synthesis of novel functionalized compounds as nanoparticles and liposomes able to cross BSCB.

Expert opinion: Both the multifactorial pathological progression and the restricted access of therapeutic drugs to the spine are probably the main reasons behind the absence of efficient therapeutic approaches for SCDs. Hence, very recent highlights suggest the use of original strategies to overcome the BSCB, and new multidrug delivery systems capable of local controlled release of therapeutic agents have been developed. These issues can be addressed by using nanoparticles technology and smart hydrogel drug delivery systems, providing an increased therapeutic compound delivery in the spinal cord environment and multiple administrations able to synergize treatment efficacy.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8–1?µm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

miR-196b-5p减轻大鼠脊髓损伤后组织水肿和星形胶质细胞活化机制探讨

目的 探讨miR-196b-5p靶向水通道蛋白4(AQP4)促进大鼠脊髓损伤（SCI）后组织修复和神经元轴突再生的机制。方法 双荧光素酶报告检测miR-196b-5p与AQP4靶向关系;实时定量聚合酶链反应（RT-qPCR）检测SCI后1 d、2 d、3 d、5 d和7 d miR-196b-5p与AQP4变化;RT-qPCR检测假手术（Sham）组、单纯脊髓损伤（SCI）组、agomiR-196b-5p干预（miRNA）组和miR-196b-5p阴性对照（NC）组脊髓miR-196b-5p与AQP4 m RNA相对表达水平,Western blot检测各组脊髓AQP4、胶质纤维酸性蛋白（GFAP）、增殖细胞核抗原（PCNA）和生长相关蛋白43(GAP-43)蛋白相对表达水平,干湿质量法和苏木精-伊红（HE）染色检测脊髓含水量及脊髓空洞大小。结果 双荧光素酶报告显示AQP4是miR-196b-5p的靶基因。与Sham组比较,SCI后各时间点miR-196b-5p表达水平降低（P<0.05）,而AQP4 mRNA表达升高并在2 d时达到高峰,随后逐渐降低。与Sham组比较,SCI组...     

Nanotechnology-based drug delivery of ropinirole for Parkinson’s disease

A new drug delivery system is developed for ropinirole (RP) for the treatment of Parkinson’s disease (PD) consisting of biodegradable poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). The formulation selected was prepared with 8?mg RP and 50?mg PLGA 502. This formulation exhibited mean encapsulation efficiency of 74.8?±?8.2%, mean particle size lower than 155?nm, the zeta potential of ?14.25?±?0.43?mV and zero-order in vitro release of RP (14.13?±?0.17?μg/h/10?mg NPs) for 5?d. Daily doses of the neurotoxin rotenone (2?mg/kg) given i.p. to male Wistar rats induced neuronal and behavioral changes similar to those of PD. Once neurodegeneration was established (15?d) animals received RP in saline (1?mg/kg/d for 35?d) or encapsulated within PLGA NPs (amount of NPs equivalent to 1?mg/kg/d RP every 3 d for 35?d). Brain histology and immunochemistry (Nissl-staining, glial fibrillary acidic protein and tyrosine hydroxylase immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that RP-loaded PLGA NPs were able to revert PD-like symptoms of neurodegeneration in the animal model assayed.     

Comparative study of kanamycin sulphate microparticles and nanoparticles for intramuscular administration: preparation in vitro release and preliminary in vivo evaluation

Kanamycin sulphate (KS) is a Mycobacterium tuberculosis protein synthesis inhibitor. KS is polycationic, a property responsible for KS poor oral absorption half-life (2.5?h) and rapid renal clearance, which results in serious nephrotoxicity/ototoxicity. The current study aimed to develop KS-loaded PLGA vitamin-E-TPGS microparticles (MPs) and nanoparticles (NPs) to reduce the dosing frequency and dose-related adverse effect. In vitro release was sustained up to 10 days for KS PLGA–TPGS MPs and 13 days for KS PLGA–TPGS NPs in phosphate-buffered saline (PBS) pH 7.4. The in vivo pharmacokinetic test in Wistar rats showed that the AUC_0–∞ of KS PLGA–TPGS NPs (280.58?μg/mL*min) was about 1.62-fold higher than that of KS PLGA–TPGS MPs (172.30?μg/mL*min). Further, in vivo protein-binding assay ascribed 1.20-fold increase in the uptake of KS PLGA–TPGS NPs through the alveolar macrophage (AM). The studies, therefore, could provide another useful tool for successful development of KS MPs and NPs.     

选择性线粒体分裂抑制剂对大鼠急性脊髓损伤后神经细胞的保护作用及其机制

【摘要】目的 检测选择性线粒体分裂抑制剂-1（Mdivi-1）对大鼠急性脊髓损伤（ASCI）后神经细胞线粒体中丙二醛（MDA）、谷胱甘肽（GSH）、细胞色素C（Cyt-C）及神经细胞凋亡的影响。方法成年雌性SD大鼠36只,体质量 250~300g,随机分为假手术组（Sham组）、单纯脊髓损伤组（SCI组）、Mdivi-1预处理组（1.20mg/kg,Mdivi-1组）,各12 只。Sham组只暴露脊髓,不打击。SCI组和Mdivi-1组采用Allen’s方法制备脊髓损伤模型。Mdivi-1组在脊髓打击之前15min尾静脉给予Mdivi-1,而SCI组给予等量二甲基亚砜（DMSO）。Sham组在暴露脊髓8h后立即处死,SCI组和Mdivi-1组均于脊髓损伤后8h处死;然后取出脊髓节段T9~T11,用分光光度计检测各组脊髓组织线粒体中MDA 和GSH的含量,Western Blot法检测线粒体及胞浆内Cyt-C表达情况,荧光TUNEL法观察神经细胞凋亡情况。结果与Sham组相比,SCI组线粒体中Cyt-C和GSH明显减少,但线粒体中的MDA,胞浆中Cyt-C及神经细胞凋亡数目明显增多（P<0.01）;与SCI组相比,Mdivi-1组线粒体中Cyt-C和GSH明显增多,但线粒体中MDA,胞浆中Cyt-C以及神经细胞凋亡数目明显减少（P<0.01）。结论Mdivi-1具有减轻ASCI后神经细胞线粒体氧化损伤,抑制线粒体中Cyt-C 的释放及神经细胞凋亡的作用,促进了脊髓功能恢复。     

Preparation,statistical optimisation and in vitro characterisation of poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/poly (lactic-co-glycolic acid) blend nanoparticles for prolonged delivery of teriparatide

The purpose of this study was the preparation, optimisation and in vitro characterisation of PHBV and PLGA blend nanoparticles (NPs) for prolonged delivery of Teriparatide. Double emulsion solvent evaporation technique was employed for the fabrication of NPs. The nanoformulation was optimised using the Box–Behnken methodology. The morphological properties of NPs were assessed by both SEM and transmission electron microscopy (TEM). Encapsulation of Teriparatide within the NPs and lacking of chemical bonds between drug and copolymers were proved by XRPD, FTIR and DSC. The structural stability of Teriparatide after processing was confirmed by fluorescence spectrometry. The average size of optimised NPs was 250.0?nm with entrapment efficiency (EE) of 89.5% and drug loading (DL) of 5.0%. Teriparatide release from optimised NPs led to 64.4% release over 30 days and it showed a diffusion-based mechanism. Based on the favourable results, PHBV/PLGA blend NPs could be a promising candidate for designing a controlled release formulation of Teriparatide.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8-1?μm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In?vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

Novel optimized drug delivery systems for enhancing spinal cord injury repair in rats

Effective and accurate delivery of drugs to tissue with spinal cord injury (SCI) is the key to rehabilitating neurological deficits. Sustained-release microspheres (MS) have excellent degradability and can aid in the long-term release of drugs. However, the burst release phenomenon can cause unexpected side effects. Herein, we developed and optimized an injectable poly(lactic-co-glycolic acid) (PLGA) MS loaded with melatonin(Mel), which were mixed further with Laponite hydrogels (Lap/MS@Mel, a micro-gel compound) in order to reduce the burst release of MS. Thus, these MS were able to achieve stable and prolonged Mel release, as well as synergistic Lap hydrogel in order to repair neural function in SCI by in situ injection. In clinical practice, patients with SCI have complicated conditions and significant inter-individual differences, which means that a single route of administration does not meet actual clinical needs. Thus, the nanospheres are synthesized and subsequently coated with platelet membrane (PM) in order to form PM/MS@Mel (nano-PM compound) for sustained and precision-targeted delivery of Mel intravenously in the SCI. Notably, optimized microsphere delivery systems have improved Mel regulation polarization of spinal microglial/macrophages, which can reduce loss of biomaterials due to macrophage-induced immune response during implantation of spinal cord tissue. These two new delivery systems that are based on MS provide references for the clinical treatment of SCI, according to different requirements.     

PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency

The natural product berberine (BBR), present in various plants, arouses great interests because of its numerous pharmacological effects. However, the further development and application of BBR had been hampered by its poor oral bioavailability. In this work, we report on polymer–lipid hybrid nanoparticles (PEG–lipid–PLGA NPs) loaded with BBR phospholipid complex using a solvent evaporation method for enhancing the oral BBR efficiency. The advantage of this new drug delivery system is that the BBR–soybean phosphatidylcholine complex (BBR–SPC) could be used to enhance the liposolubility of BBR and improve the affinity with the biodegradable polymer to increase the drug-loading capacity and controlled/sustained release. The entrapment efficiency of the PEG–lipid–PLGA NPs/BBR–SPC was observed to approach approximately 89% which is more than 2.4 times compared with that of the PEG–lipid–PLGA NPs/BBR. To the best of our knowledge, this is the first report on using polymer material for effective encapsulation of BBR to improve its oral bioavailability. The prepared BBR delivery systems demonstrated a uniform spherical shape, a well-dispersed core-shell structure and a small particle size (149.6?±?5.1?nm). The crystallographic and thermal analysis has indicated that the BBR dispersed in the PEG–lipid–PLGA NPs matrix is in an amorphous form. More importantly, the enhancement in the oral relative bioavailability of the PEG–lipid–PLGA NPs/BBR–SPC was ～343% compared with that of BBR. These positive results demonstrated that PEG–lipid–PLGA NPs/BBR–SPC may have the potential for facilitating the oral drug delivery of BBR.     

In vivo tissue distribution and efficacy studies for cyclosporin A loaded nano-decorated subconjunctival implants

Biodegradable implants are promising drug delivery systems for sustained release ocular drug delivery with the benefits such as minimum systemic side effects, constant drug concentration at the target site and getting cleared without surgical removal. Dry eye syndrome (DES) is a common disease characterized with the changes in ocular epithelia surface and results in inflammatory reaction that might lead to blindness. Cyclosporin A (CsA) is a cyclic peptide that is frequently employed for the treatment of DES and it needs to be applied several times a day in tear drops form. The aim of this study was to evaluate in vivo behavior and efficacy of the developed nano-decorated subconjunctival implant systems for sustained release CsA delivery. Biodegradable Poly-?-caprolactone (PCL) implant or micro-fiber implants containing CsA loaded poly-lactide-co-glycolide (85:15) (PLGA) or PCL nanoparticles were prepared in order to achieve sustained release. Two of the formulations PCL–PLGA–NP-F and PCL-PCL-NP-I were selected for in vivo evaluation based on their in vitro characteristics determined in our previous study. In this study, formulations were implanted to Swiss Albino mice with induced dry eye syndrome to investigate the ocular distribution of CsA following subconjunctival implantation and to evaluate the efficacy. Tissue distribution study indicated that CsA was present in ocular tissues such as cornea, sclera and lens even 90 days after the application and blood CsA levels were found lower than ocular tissues. Efficacy studies also showed that application of CsA-loaded fiber implant formulation resulted in faster recovery based on their staining scores.     

Doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) nanoparticles as hepatocyte-targeting drug carrier

The objective of this work is to produce doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to be specifically recognised by human hepatoma cellular carcinoma (Hep G2) cells and assess NPs cytotoxicity. Doxorubicin-unloaded and doxorubicin-loaded galactose-conjugated PLGA NPs were prepared using an emulsion method and characterised for morphology, size, drug release behaviour, Hep G2 recognition and cell cytotoxicity. The produced doxorubicin-loaded PLGA-galactose-conjugate nanoparticles (PLGA-GAL NPs) are spherical in shape with a size of 365?±?74?nm, a drug encapsulation efficiency of 69% and released in a biphasic pattern with higher release rates at pH 5. In vitro cell studies confirmed the specific interaction between the receptors of Hep G2 and the PLGA-GAL NPs. Cell cytotoxicity tests showed that unloaded NPs are non-toxic and that doxorubicin-loaded NPs caused a cellular viability decrease of around 80%, therefore representing a promising approach to improve liver-specific drug delivery.     

Intracellular drug delivery in Leishmania-infected macrophages: Evaluation of saponin-loaded PLGA nanoparticles

Drug delivery systems present an opportunity to potentiate the therapeutic effect of antileishmanial drugs. Colloidal carriers are rapidly cleared by the phagocytic cells of the reticuloendothelial system (RES), rendering them ideal vehicles for passive targeting of antileishmanials. This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin β-aescin. NPs were prepared using the combined emulsification solvent evaporation/salting-out technique. Confocal microscopy was used to visualise the internalisation and intracellular trafficking of fluorescein- and nile red-labelled PLGA NPs in J774A.1 macrophages infected with GFP-transfected Leishmania donovani. The in vitro activity of aescin and aescin-loaded NPs on L. infantum was determined in the axenic model as well as in the ex vivo model. The developed PLGA NPs were monodispersed with Z_ave<300?nm, exhibited negative zeta potentials and had relatively high drug loadings ranging from 5.80 to 8.68% w/w PLGA. The fluorescent NPs were internalised by the macrophages and trafficked towards the lysosomes after 2?h in vitro incubation. Co-localisation of the NPs and the parasite was not shown. A two-fold increase in activity was observed in the ex vivo macrophage model by encapsulating β-aescin in PLGA NPs (IC₅₀, 0.48–0.76 µg/mL vs. 1.55?±?0.32 µg/mL for the free drug).     

Novel multifunctional polyethylene glycol-transactivating-transduction protein-modified liposomes cross the blood-spinal cord barrier after spinal cord injury

The blood-spinal cord barrier (BSCB) prevents many macromolecular agents from passing through to reach sites of injury in the spinal cord. This study evaluated the ability of a novel multifunctional liposome modified with polyethylene glycol (PEG) and transactivating-transduction protein (TAT) containing an iron core to cross the BSCB using a rat model of spinal cord injury. Rats were examined daily for a period of three days after spinal cord injury and injection of either the multifunctional modified liposome or control formulations using a 3.0 T magnetic resonance imaging spectrometer. A low signal was observed in the T2-weighted images. Prussian blue staining and flame atomic absorption spectrophotometry revealed that significantly more iron accumulated around the lesion site in the experimental group than the control groups (P?<?0.05). The findings from this study suggest that this multifunctional liposome carrier can cross the BSCB to accumulate around the lesion site.     

Oral Paracetamol Bioavailability in Rats Subjected to Experimental Spinal Cord Injury

The purpose of the present study was to examine the time dependence of oral paracetamol (acetaminophen) bioavailability in an experimental model of spinal cord injury (SCI). Female Sprague–Dawley rats were subjected to spinal cord contusion at the T8–T9 level by the weight drop method producing permanent paraplegia. Oral paracetamol bioavailability after administration of a single 100 mg kg⁻¹ dose was determined 1, 12, and 50 d after SCI. C_max and AUC were significantly decreased 1 d after SCI compared to sham-injured controls. This reduction, however, was temporary, as there was a recovery of bioavailability parameters which was partial 12 d after SCI, being complete by day 50. The present results confirm the usefulness of animal models for the characterization of the effect of SCI in drug kinetics. Data show that SCI induces significant changes in paracetamol pharmacokinetics. Nonetheless, despite the fact of a permanent loss of functions related to locomotion, pharmacokinetic alterations evolved with time. © 1997 John Wiley & Sons, Ltd.     

L-type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids

Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.     

脐血干细胞移植对大鼠脊髓损伤后轴突再生的影响

目的:探讨脐血千细胞移植对大鼠脊髓损伤后轴突再生的影响.方法:收集脐带血,分离提取,制备成合适浓度的CD34阳性细胞.Allen重物坠击法制作SD大鼠急性脊髓损伤动物模型30只,随机分成2组.A组为损伤对照组,B组为细胞移植组,1周后再次手术,细胞移植组将体外培养的脐血干细胞用微量注射器分别注入于脊髓损伤区域头侧和尾侧各10x105个细胞,损伤对照组予以同样体积的PBS,于移植后1周、2周、6周时分别取材,进行组织学检查及免疫组织化学检杏以评估损伤区域脊髓形态学变化,并于移植后1周、2周、4周、6周采用BBB评分及斜板实验,以观察大鼠后肢运动神经功能恢复情况.结果:与对照组比较,细胞移植组大鼠脊髓损伤区域空腔面积显著减小,生长相关蛋白(GAP-43)和神经丝蛋白(NF200)表达显著增加,并且后肢运动功能均有较明显的恢复.结论:脐血干细胞移植可以促进脊髓损伤大鼠轴突再生和后肢运动功能恢复.     

Targeted delivery of monoclonal antibody conjugated docetaxel loaded PLGA nanoparticles into EGFR overexpressed lung tumour cells

The aim of this study was to develop anti-EGFR antibody conjugated poly(lactide-co-glycolide) nanoparticles (NPs) to target epidermal growth factor receptor, highly expressed on non-small cell lung cancer cells to improve cytotoxicity and site specificity. Cetuximab was conjugated to docetaxel (DTX) loaded PLGA NPs by known EDC/NHS chemistry and characterised for size, zeta potential, conjugation efficiency and the results were 128.4?±?3.6?nm, –31.0?±?0.8?mV, and 39.77?±?3.4%, respectively. In vitro release study demonstrated sustained release of drug from NPs with 25% release at pH 5.5 after 48?h. In vitro cytotoxicity studies demonstrated higher anti-proliferative activity of NPs than unconjugated NPs. Cell cycle analysis and apoptosis study were performed to evaluate extent of cell arrest at different phases and apoptotic potential for the formulations, respectively. In vivo efficacy study showed significant reduction in tumour growth and so antibody conjugated NPs present a promising active targeting carrier for tumour selective therapeutic treatment.     

Brain-targeted delivery of Tempol-loaded nanoparticles for neurological disorders

Brain-targeted Tempol-loaded poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) conjugated with a transferrin antibody (OX 26) were developed using the nanoprecipitation method. These NPs may have utility in treating neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Central to these diseases is an increased production of reactive oxygen and nitrogen species which may take part in the development of these conditions. As proof of principle, the NPs were loaded with Tempol, a free radical scavenger that has been shown to be protective against oxidative insults. To enhance the delivery of NPs to the central nervous system (CNS), we conjugated the transferrin receptor antibody covalently to PLGA NPs using the NHS-PEG3500-Maleimide crosslinker. The NPs showed a particle size suitable for blood brain barrier (BBB) permeation (particle size 80–110?nm) and demonstrated a sustained drug release behavior. A high cellular uptake of antibody-conjugated NPs was demonstrated in RG2 rat glioma cells. The ability of the Tempol-loaded NPs to prevent cell death by resveratrol in RG2 cells was determined using the MTT assay. The conjugated NPs containing Tempol were more effective in preventing cell viability by resveratrol when compared with unconjugated NPs or free Tempol in solution. Our findings suggest that transferrin-conjugated NPs containing antioxidants may be useful in the treatment of neurodegenerative diseases.     

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano‐vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification–solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl‐lactic‐co‐glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP‐PLGA‐NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP‐PLGA‐NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma‐aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme‐linked immunosorbent assay. The maximal electroshock‐induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP‐loaded NPs. The prepared ZP‐PLGA NPs were negatively charged spherical particles with an average size of 120–300 nm. Optimized ZP‐PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42‐fold augmentation in oral drug bioavailability in comparison to ZP‐marketed products. Moreover, parenteral administration of ZP‐NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP‐PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.