EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2016
·
IF 3.773
XiuLing Xu,JingJing Li,ShunPing Han,ChengHao Tao,Luo Fang,Yue Sun,JiaZhen Zhu,ZeHua Liang,FanZhu Li
Effective targeting drug delivery system for glioma treatment is still greatly challenged by the existence of the blood–brain barrier (BBB) and the intracranial overspreading of anti-tumor drug. Herein, we presented a dual-functional glioma targeting delivery of doxorubicin based on the PAMAM G5 dendrimer , modified with folic acid (FA) to target tumor cell, also borneol (BO), a well known safe material derived from traditional Chinese medicine , to facilitate the BBB permeability and reduce the toxicity of naked PAMAM. The intracranial transportation and glioma targeting ability were evaluated on the BBB model and C6 glioma cells in vitro . Also, pharmacokinetics and biodistribution were studied on C6 glioma-bearing rats in vivo . It indeed reduced the cytotoxicity of PAMAM against both HBMEC and C6 cells by coupling BO on the surface, while efficiently boosted BBB permeability with the improvement of transportation ratio by 2 folds to the BO-unmodified conjugates. Furthermore, conjugated FA increased total uptake amount by C6 cells leading to strong inhibition with the 3-fold lower IC 50 value than FA-unmodified DOX conjugate. In comparison with DOX solution, FA-BO-PAMAM/DOX exhibited significantly prolonged half-life time and increased area under the curve and improved DOX accumulation in brain tumor. The tumor growth inhibition, in vivo , was significantly increased up to 57.4%. The median survival time of xenograft rats after administering FA-BO-PAMAM/DOX (28 days) was significantly prolonged compared to free DOX (18 days, P < 0.05) or other controls. In conclusion, this strategy of novel targeting nanocarrier provides a promising method to increase the drug accumulation in the tumor site for therapy of glioma.
研究领域:
药理学
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Oncotarget
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2017
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IF 5.168
Na Huang,Shuai Lu,Xiao-Ge Liu,Jie Zhu,Yu-Jiong Wang,Rui-Tian Liu
Alzheimer's disease (AD) is the most common form of dementia, characterized by the formation of extracellular senile plaques and neuronal loss caused by amyloid β (Aβ) aggregates in the brains of AD patients. Conventional strategies failed to treat AD in clinical trials, partly due to the poor solubility, low bioavailability and ineffectiveness of the tested drugs to cross the blood-brain barrier (BBB). Moreover, AD is a complex, multifactorial neurodegenerative disease; one-target strategies may be insufficient to prevent the processes of AD. Here, we designed novel kind of poly(lactide-co-glycolic acid) (PLGA) nanoparticles by loading with Aβ generation inhibitor S1 (PQVGHL peptide) and curcumin to target the detrimental factors in AD development and by conjugating with brain targeting peptide CRT (cyclic CRTIGPSVC peptide), an iron-mimic peptide that targets transferrin receptor (TfR), to improve BBB penetration. The average particle size of drug-loaded PLGA nanoparticles and CRT-conjugated PLGA nanoparticles were 128.6 nm and 139.8 nm, respectively. The results of Y-maze and new object recognition test demonstrated that our PLGA nanoparticles significantly improved the spatial memory and recognition in transgenic AD mice. Moreover, PLGA nanoparticles remarkably decreased the level of Aβ, reactive oxygen species (ROS), TNF-α and IL-6, and enhanced the activities of super oxide dismutase (SOD) and synapse numbers in the AD mouse brains. Compared with other PLGA nanoparticles, CRT peptide modified-PLGA nanoparticles co-delivering S1 and curcumin exhibited most beneficial effect on the treatment of AD mice, suggesting that conjugated CRT peptide, and encapsulated S1 and curcumin exerted their corresponding functions for the treatment.
研究领域:
神经科学
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药理学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
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2020
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IF 1.345
Min-Ye Huang,Gu-Ran Yu
This study aimed to evaluate the effect Cycloastragenol (CAG), a triterpenoid saponin isolated from the Radix astragali, on Aβ-induced BBB damage. An immortalized endothelial cell line (bEnd.3) was employed to mimic a BBB. The Western blot, TUNEL staining, Flow cytometric analysis and Enzyme-linked immunosorbent assay were performed. The present results showed that CAG (10, 50, 75 μM) can alleviate oligomer Aβ1–42 induced bEnd.3 cell apoptosis and increase tight junction scaffold proteins expression. The result also indicated that CAG increased soluble Aβ efflux across BBB via upregulation of the P-gp and downregulation of RAGE expression.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Brain Sciences
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2022
·Vol. 12
·期 5
·571
·
IF 3.333
Chao Song,Chao Gao,Zhenxin Wang
(1) Background: Chemotherapy-induced cognitive impairment (CICI) is often observed in cancer patients and impairs their life quality. Grape-seed-orientated procyanidin has been shown to have anti-inflammatory and neuroprotective effects, yet its effects in preventing CICI have not been investigated. (2) Method: Adult male mice received 2.3 mg/kg cisplatin or saline injections for three cycles consisting of five daily injections followed by 5 days of rest. Procyanidin or saline was administered 1 h prior to cisplatin treatment. Cognitive testing, gelatin zymography, and blood–brain-barrier (BBB) penetration tests were performed after treatment cessation. RAW264.7 cells were treated by stimulated supernatant of SHSY5Y cells. In addition, high-mobility group protein B1 (HMGB1) expression and MMP-9 activity were tested. (3) Results: Repeated cisplatin treatment increased BBB penetration, MMP-9 activity, impaired performance in contextual fear conditioning, and novel object recognition tasks. The knockout of MMP-9 rescues cognitive impairment and cisplatin-induced upregulation of HMGB1 in SHSY5Y cells. HMGB1/TLR4/IP3K/AKT signaling contributes to the increased MMP-9 activity in RAW264.7 cells. Procyanidin treatment attenuates MMP-9 activity, BBB damage, and CICI. (4) Conclusions: The results indicated that MMP-9 activation and BBB disruption is involved in CICI. Procyanidin may effectively alleviate the harmful effects of cisplatin.Keywords:cisplatin;chemotherapy;MMP-9;RAW264.7 cells;procyanidin;blood–brain barrier (BBB);chemotherapy-induced cognitive impairment (CICI)
研究领域:
肿瘤学
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Neurology
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2022
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IF 4.086
Ren Siying,Han Shanshan,Wang Likun,Huang Yuanxin,Wu Jing,Wu Guofeng
Objective: To investigate the role of minimally invasive surgery (MIS) in intracerebral hemorrhage (ICH) evacuation combined with deferoxamine (DFX) treatment on perihematomal tight junction protein (claudin-5 and ZO-1) expression levels and blood-brain barrier (BBB) permeability in rabbits.Methods: We randomly assigned 65 male rabbits (weight: 1.9–2.6 kg) to a normal control group (NC group, 13 rabbits), hemorrhage model group (HM group, 13), DFX treatment group (DFX group, 13 rabbits), MIS group (MIS group, 13 rabbits), or MIS combined with DFX treatment group (MIS + DFX group, 13 rabbits). ICH was established in all of the groups except the NC group. MIS was performed to evacuate the hematoma 6 h after the ICH model was created in the MIS and MIS + DFX groups. The DFX and MIS + DFX groups were treated with DFX (100 mg/kg, dissolved in 2 mL of 0.9% saline solution, administered intramuscularly) at 2 h, and then every 12 h for 7 d. The same dose of 0.9% saline solution was administered to the NC, HM, and MIS groups at the same time points. Sixty-five rabbits were divided into 5 groups, and 13 rabbits in each group. Neurological deficit (i.e., Purdy's score) was recorded in all rabbits before euthanasia (N total = 65). In each group, 2 rabbits were used for iron concentration measurement (N total = 10), 2 rabbits were used for brain water content measurement (N total = 10), 3 rabbits were used for BBB permeability measurement (N total = 15), 3 rabbits were used for claudin-5, ZO-1 expression detection by Western Blotting (N total = 15), and 3 rabbits were used for claudin-5, ZO-1 mRNA detection by real-time PCR (N total = 15). On day 7, the rabbits were sacrificed and the perihematomal brain tissue was harvested to test the iron concentration, brain water content (BWC), tight junction proteins (claudin-5 and ZO-1) expression, and BBB permeability.Results: Purdy's score, iron concentration, and BWC were lower in the MIS and MIS + DFX groups compared to the HM and DFX groups. The MIS + DFX group showed a significant decrease in these indicators. The use of MIS to evacuate the hematoma led to increased expression levels of claudin-5 and ZO-1, as well as decreased BBB permeability. The MIS + DFX group exhibited a remarkable increase in claudin-5 and ZO-1 expression levels and a significant decrease in BBB permeability.Conclusions: MIS combined with DFX treatment could increase the expression levels of perihematomal tight junction proteins (claudin-5 and ZO-1) expression, reduce BBB permeability, and improve the neurological function. MIS combined with DFX treatment may also prevent secondary brain damage following ICH.
研究领域:
神经科学
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医学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Li Lin,Jingchuan Yan,Jin Sun,Jianfeng Zhang,Bo Liao
Objective: The PRAS40 is an essential inhibitory subunit of the mTORC1 complex, which regulates autophagy. It has been suggested that Erxian Decoction (EXD) could treat spinal cord injury (SCI) via the autophagy pathway. However, the mechanism of whether EXD acts through PRAS40 remains unclear. Methods: With the help of immobilized PRAS40, isothermal titration calorimetry (ITC) and molecular docking, the bioactive metabolites in the EXD were screened. To establish in vitro SCI models, PC12 cells were exposed to hydrogen peroxide (H2O2) and then treated with the identified EXD substances. Furthermore, Western blot assay was carried out to identify potential molecular mechanisms involved. For assessing the effect of metabolites in vivo , the SCI model rats were first pretreated with or without the metabolite and then subjected to the immunohistochemistry (IHC) staining, Basso, Beattie & Bresnahan (BBB) locomotor rating scale, and H&E staining. Results: The immobilized PRAS40 isolated indole, 4-nitrophenol, terephthalic acid, palmatine, sinapinaldehyde, and 3-chloroaniline as the potential ligands binding to PRAS40. Furthermore, the association constants of palmatine and indole as 2.84 × 106 M-1 and 3.82 × 105 M-1 were elucidated via ITC due to the drug-like properties of these two metabolites. Molecular docking results also further demonstrated the mechanism of palmatine binding to PRAS40. Western blot analysis of PC12 cells demonstrated that palmatine inhibited the expression of p-mTOR by binding to PRAS40, activating the autophagic flux by markedly increasing LC3. The injection of palmatine (10μM and 20 μM) indicated notably increased BBB scores in the SCI rat model. Additionally, a dose-dependent increase in LC3 was observed by IHC staining. Conclusion: This research proved that EXD comprises PRAS40 antagonists, and the identified metabolite, palmatine, could potentially treat SCI by activating the autophagic flux.
研究领域:
药理学
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神经科学
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中医
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Yonghao Wang,Mingheng Su,Zi Ye,Ziqian Jia,Qi Zhang
Ethnopharmacological relevance Gastrodia elata Blume ( G. elata ) is a traditional Chinese medicinal herb documented in the Compendium of Materia Medica and has been widely used for dizziness, convulsive disorders, vertigo, and neurological symptoms. Gastrodin (GAS), the principal bioactive constituent of G. elata , is known to exhibit anti-inflammatory, antioxidant, and neuroprotective properties. Nevertheless, whether GAS is beneficial for vascular cognitive impairment associated with dietary risk factors remains unclear. Clarifying this issue may help explain the pharmacological basis of the traditional neurological use of G. elata . Aim of the study This study investigated whether GAS could alleviate cognitive dysfunction aggravated by a high-salt diet (HSD) in chronic cerebral hypoperfusion (CCH) mice, and explored its possible involvement in cerebral blood flow (CBF) regulation, blood-brain barrier (BBB)-related structural preservation, and amyloidogenic processing. Materials and methods A mouse model of CCH combined with dietary risk was generated using bilateral common carotid artery stenosis (BCAS) and HSD exposure. Cognitive performance was assessed by the novel object recognition test, Y-maze test, and open field test. CBF was monitored using laser speckle imaging. Hippocampal transcriptomic sequencing was conducted to identify GAS-regulated pathways. Nissl staining, immunohistochemistry, Western blotting, and transmission electron microscopy were used to examine neuronal injury, BBB structure, and related protein expression. Serum Aβ and inflammatory cytokines were quantified by ELISA. Results HSD exposure further worsened BCAS-induced cerebral hypoperfusion and cognitive deficits. GAS administration restored CBF, improved behavioral performance, and showed a tendency toward partial improvement of hippocampal morphology. Transcriptomic analysis indicated that GAS-responsive differentially expressed genes were enriched in pathways associated with extracellular matrix interaction, tight junctions, vascular function, and PI3K-Akt signaling. Further experiments showed that GAS increased ZO-1, Occludin, and eNOS expression, preserved BBB-related ultrastructural features, restored Akt/mTOR pathway-associated phosphorylation, and attenuated BACE1/APP-, sAPPβ-, Aβ-, and serum TNF-α-related changes. Conclusion GAS ameliorates cognitive impairment induced by HSD exposure combined with BCAS, and this effect is associated with improved CBF, restoration of Akt/mTOR pathway-associated phosphorylation, eNOS-related endothelial regulation, preservation of BBB-related structural integrity, and attenuation of amyloidogenic processing-related and serum inflammatory marker changes. These results provide experimental support for the potential role of GAS in treating vascular cognitive impairment associated with dietary risk factors.
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2022
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IF 10.383
Jingxin Mo,Xianjue Chen,Meiying Li,Wenxu Liu,Wei Zhao,Lee Yong Lim,Richard D. Tilley,J. Justin Gooding,Qinghua Li
Glioblastoma is hard to be eradicated partly because of the obstructive blood–brain barrier (BBB) and the dynamic autophagy activities of glioblastoma. Here, hydroxychloroquine (HDX)-loaded yolk–shell upconversion nanoparticle (UCNP)@Zn0.5Cd0.5S nanoparticle coating with the cyclic Arg-Gly-Asp (cRGD)-grafted glioblastoma cell membrane for near-infrared (NIR)-triggered treatment of glioblastoma is prepared for the first time. UCNPs@Zn0.5Cd0.5S (abbreviated as YSN, yolk–shell nanoparticle) under NIR radiation will generate reactive oxygen species for imposing cytotoxicity. HDX, the only available autophagy inhibitor in clinical studies, can enhance cytotoxicity by preventing damaged organelles from being recycled. The cRGD-decorated cell membrane allowed the HDX-loaded nanoparticles to efficiently bypass the BBB and specifically target glioblastoma cells. Exceptional treatment efficacy of the NIR-triggered chemotherapy and photodynamic therapy was achieved in U87 cells and in the mouse glioblastoma model as well. Our results provided proof-of-concept evidence that HDX@YSN@CCM@cRGD could overcome the delivery barriers and achieve targeted treatment of glioblastoma.
研究领域:
纳米医学
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癌症研究
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神经科学
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药剂学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2023
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IF 9.7
Lin Liu,Min Liu,Jingya Xiu,Bowen Zhang,Haiyang Hu,Mingxi Qiao,Dawei Chen,Jiulong Zhang,Xiuli Zhao
Depression is one of the most common mental diseases, which seriously affects patients’ physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H 2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. Statement of Significance ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.
研究领域:
药学
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神经科学
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纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Shangmin Yu,Xinying Wang,Linlin Lv,Tongyan Liu,Qingxiang Guan
Depression is a chronic mental disorder which threatens human health and lives. However, the treatment of depression remains challenging largely due to blood brain barrier (BBB), which restricts drugs from entering the brain, resulting in a poor distribution of antidepressants in the brain. In this work, a novel brain-targeted drug delivery system was developed based on borneol-modified PEGylated graphene oxide (GO-PEG-BO). GO-PEG-BO was characterized and proved to possess excellent biocompatibility . By incorporating borneol , GO-PEG-BO could penetrate BBB efficiently by opening tight junctions and inhibiting the efflux system of BBB. The targeted distribution of GO-PEG-BO in the brain was observed by an in vivo biodistribution study. Moreover, GO-PEG-BO exhibited a neuroprotective effect, which is beneficial to the treatment of depression. Ginsenoside Rg1 (GRg1), which can relieve depressive symptoms but difficult to cross BBB, was loaded to GO-PEG-BO for the therapy of depression. In depressive rats, GRg1/GO-PEG-BO improved stress-induced anhedonia, despair and anxiety, and comprehensively relieved the depressive symptoms. In conclusion, GO-PEG-BO could serve as a promising nanocarrier for brain-targeted drug delivery, and provide a new strategy for the therapy of depression.
研究领域:
药学
·
纳米技术
·
神经科学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2018
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IF 8.097
Jianming Liang,Caifang Gao,Ying Zhu,Chengli Ling,Qi Wang,Yongzhuo Huang,Jing Qin,Jue Wang,Weigen Lu,Jianxin Wang
The unsatisfactory therapeutic outcome for glioma is mainly due to the poor blood–brain barrier (BBB) permeability and inefficient accumulation in the glioma area of chemotherapeutic agents. The existing drug delivery strategies can increase drug transport to the brain but are restricted by side effects and/or poor delivery efficiency. In this study, potent brain penetration enhancers were screened from the active components of aromatic resuscitation drugs used in traditional Chinese medicine. A novel glioma-targeting system based on enhancer-modified albumin nanoparticles was developed to safely and efficiently deliver drugs to the glioma regions in the brain. The nanoparticles improved the transport of nanoparticles across brain capillary endothelial cell (BCEC) monolayer by increasing endocytosis in endothelial cells and causing BBB disruption. In vivo imaging studies demonstrated that the systems could enter the brain and subsequently accumulate in glioma cells with a much higher targeting efficiency than that of transferrin-modified albumin nanoparticles. Of note, the nanoparticles could be captured and penetrate through endothelial cells fenestrae in pineal gland, which is suggestive of an effective way to deliver a nanosystem to the brain by bypassing the BBB. The nanoparticles showed good biocompatibility and negligible cytotoxicity. The results reveal an efficient and safe strategy for brain drug delivery in glioma therapy.
研究领域:
神经科学
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药理学
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纳米技术
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中医药
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Exploration
·
2025
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IF 22.5
Xiaojing Shi,Shuya Wang,Tingli Xiong,Ruishi Li,Wenxuan Zheng,Wensheng Chen,Tianjiao Zhao,Yongqi Yang,Xiaohong Ying,Weimin Qi,Yingci Xia,Jue Wang,Yuqi Zhang,Qiong Huang,Yayun Nan,Kelong Ai
Protecting neuronal mitochondria by eliminating the mitochondrial ROS (mtROS) storm is crucial to abrogate the neuronal damage cascade of ischemic stroke ischemia reperfusion (ISIR), which is a long-standing challenge in the field of ischemic stroke (IS). Existing blood-brain barrier (BBB) penetration methods are usually unable to distinguish between healthy brain tissue and cerebral infarction tissue, and BBB targeting is not compatible with mitochondrial targeting, resulting in a huge barrier to the specific elimination of mtROS in neuronal mitochondria in ISIR. This study introduces an elegantly designed tannic acid, polydopamine, and Mo-based heteropolyacid ternary composite nanomedicine (TPM), which not only has a superb ability to eliminate multiple ROS thanks to the introduction of polydopamine, but also can actively recognize the injured BBB site, specifically enter the neurons in the cerebral infarction area, and then highly specifically target the mitochondria of neurons to efficiently eliminate mtROS. TPM could significantly inhibit neuronal apoptosis by protecting mitochondria and eliminate inflammation by inhibiting activation of the STING pathway, thereby significantly reducing the size of cerebral infarction. This sequential targeting of TPM from the injured BBB to neuronal mitochondria provides a promising strategy to treat ISIR in the clinical setting.
研究领域:
纳米医学
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神经病学
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脑卒中治疗
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活性氧清除
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药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）