Dataset Information

Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

ABSTRACT: Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.

SUBMITTER: Zhang C

PROVIDER: S-EPMC5595130 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

Zhang Chun C Ling Cheng-Li CL Pang Liang L Wang Qi Q Liu Jing-Xin JX Wang Bing-Shan BS Liang Jian-Ming JM Guo Yi-Zhen YZ Qin Jing J Wang Jian-Xin JX

Theranostics 20170723 13

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ...[more]

PMID: 28900508

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Project description:ObjectiveThis study sought to evaluate the feasibility of multifunctional gastrodin (GAS)-containing nano-drug carrier system against cerebral ischemia-reperfusion injury (CIRI).MethodsThe drug-loaded nanocomposite (Au-G5.NHAc-PS/GAS) with certain encapsulation efficiency (EE) was prepared by physical adsorption method using different proportions of GAS and drug-carrying system (Au-G5.NHAc-PS). High-performance liquid chromatography was used to determine the drug loading and EE. Cultured rat astrocytes and hypothalamic neurons were assigned into four groups: PBS, Au-G5.NHAc-PS, Au-G5.NHAc-PS/GAS, and GAS. CCK-8 assay, flow cytometry, and quantitative real-time PCR were performed to examine the cell viability, apoptosis, and the expression of tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 in the astrocytes and hypothalamic neurons, respectively. Cellular uptake of GAS and Au-G5.NHAc-PS/GAS was analyzed by using Hoechst 33342 staining. The animal model with focal cerebral ischemia was generated by middle cerebral artery occlusion (MCAO) in healthy male Sprague Dawley (SD) rats, and pathological changes of brain tissue and major organs in the rats were identified by hematoxylin and eosin (HE) staining. Apoptosis in rat astrocytes and hypothalamic neurons was detected by TUNEL staining and flow cytometry.ResultsAu-G5.NHAc-PS had a spherical shape with a uniform size of 157.3 nm. Among the nanoparticles, Au-G5.NHAc-PS/GAS with an EE of 70.3% displayed the best release delay effect. Moreover, we observed that in vitro cytotoxicity and cellular uptake of Au-G5.NHAc-PS/GAS were higher than those of GAS, whereas the expression of TNF-α, IL-1β, and IL-6 was significantly downregulated in Au-G5.NHAc-PS/GAS group as compared to G5.NHAc-PS group. Notably, HE staining revealed that although Au-G5.NHAc-PS/GAS had no toxic and side effects on the main organs of rats, it alleviated the damage of brain tissue in the MCAO rats. Besides, Au-G5.NHAc/GAS markedly reduced MCAO-induced apoptosis.ConclusionAu-G5.NHAc-PS showed favorable surface morphology, sustained drug release ability, no measurable toxicity, and good biocompatibility, indicating that GAS exerts anti-inflammatory and antiapoptotic effects on CIRI.

Project description:Neuroprotection in cerebral ischemia (CI) has received increasing attention. However, efficient delivery of therapeutic agents to the brain remains a major challenge due to the complex environment of the brain. Nose-to-brain-based delivery is a promising approach. Here, we optimized a nanocarrier formulation of neuroprotective agents that can be used for nose-to-brain delivery by obtaining RVG29 peptide-modified polyethylene glycol-polylactic acid-co-glycolic acid nanoparticles (PEG-PLGA RNPs) that have physicochemical properties that lead to stable and sustained drug release and thereby improve the bioavailability of neuroprotective agents. The brain-targeting ability of PEG-PLGA RNPs administered through nasal inhalation was verified in a rat model of CI. It was found that delivery to the whole brain can be achieved with little delivery to the peripheral circulation. Baicalin (BA) was selected as the neuroprotective agent for delivery. After intranasal administration of BA-PEG-PLGA RNPs, the neurological dysfunction of rats with ischemic brain injury was significantly alleviated, the cerebral infarction area was reduced, and nerve trauma and swelling were relieved. Furthermore, it was demonstrated that the neuroprotective effects of BA in a rat model of CI may be mediated by inhibition of inflammation and alleviation of oxidative stress. The immunohistochemical results obtained after treatment with nanoparticles loaded with BA showed that Nrf2/HO-1 was activated in the area in which ischemic brain damage had occurred and that its expression was significantly higher in the group treated with BA-PEG-PLGA RNPs than in the other groups. The ELISA results showed that the levels of IL-1β, IL-6, and TNF-α were abnormally increased in the serum of rats with cerebral ischemia. After treatment with BA-loaded nanoparticles, IL-1β, IL-6, and TNF-α levels decreased significantly. Oxidative stress was alleviated; the levels of glutathione and superoxide dismutase increased; and the levels of reactive oxygen species and malondialdehyde decreased, in animals to which BA-PEG-PLGA RNPs were delivered by intranasal inhalation. In conclusion, BA-PEG-PLGA RNPs can effectively deliver BA to rats and thereby exert neuroprotective effects against CI.

Dataset Information

Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

Publications

Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

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