JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
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IF 3.075
Xiaoyuan Guo,Guojian Wu,Hong Wang,Lukui Chen
Tumor-targeting and blood-brain barrier (BBB)-penetrating are highly desirable for the treatment of glioma. In this study, we developed Pep-1&borneol–bifunctionalized carmustine-loaded micelles (Pep-1/Bor/CMS-M) capable of targeting interleukin-13 receptor–overexpressed glioma and penetrating the brain microvascular endothelial cells–associated physiologic barriers. Pep-1/Bor/CMS-M were nearly spherical particles with a diameter of 32.6 ± 1.1 nm and zeta potential of −21.3 ± 3.1 mV. Carmustine (CMS) released from Pep-1/Bor/CMS-M in pH 7.4 was significantly faster than in acidic environments. In human glioma BT325 cellular studies, Pep-1/Bor/CMS-M remarkably increased the cytotoxicity, notably improved the internalization, and effectively induced the cell apoptosis . Likewise, in human brain microvascular endothelial cells, Pep-1/Bor/CMS-M obviously promoted the cellular uptake, rapidly decreased the transepithelial electrical resistance, and thereby enhanced the ability of penetration. In orthotopic Luc-BT325 glioma tumor-bearing nude mouse models, the stronger fluorescence signal and longer retention were observed in brain tissues compared with other controls, after single administration of DiD-labeled Pep-1/Bor/M (DiD/Pep-1/Bor/M). Importantly, Pep-1/Bor/CMS-M displayed the strongest inhibition of tumor growth, the longest survival period, and low systemic toxicity in treating orthotopic glioma tumor-bearing nude mice. Simultaneous functionalization of Pep-1 and borneol offers a novel strategy for designing CMS-based nanomedicine and precisely treating glioma.
研究领域:
药理学
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纳米技术
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肿瘤学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Tissue Barriers
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2024
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IF 3.6
Qi Cao,Wei Zeng,Jingmin Nie,Yongjun Ye,Yanchao Chen
Impairment of the blood – brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.
研究领域:
神经科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 17
·6449-6464
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IF 8.307
Ziwei Yuan,Bin Wang,Yilong Teng,William Ho,Bin Hu,Kofi Oti Boakye-Yiadom,Xiaoyang Xu,Xue-Qing Zhang
Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood–brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.
研究领域:
生物医学工程
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分子生物学
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神经科学
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药学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
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IF 8
Lu Lu,Hongyuan Chen,Longkun Wang,Lin Zhao,Yanna Cheng,Aijun Wang,Fengshan Wang,Xinke Zhang
Purpose Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma.Materials and Methods We first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice.Results The binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice.Conclusion Our study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.
研究领域:
癌症治疗
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药学
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分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2026
·Vol. 19
·期 8
·1319
·
IF 5.7
Ziying Xu,Wei Xia,Haiqiang Wu,Haiping Zhang
Background/Objectives:Blood–brain barrier (BBB) permeability is a major practical obstacle in central nervous system (CNS) drug discovery, because only a small fraction of drug-like molecules achieve sufficient brain exposure.Methods:We present DeepBBB, a graph-based, data-composition-aware screening workflow for predicting BBB permeability and for constructing BBB-focused screening libraries from commercial chemical space. Rather than introducing a new graph-learning architecture, the workflow combines standard graph convolutional and graph-transformer models with deliberate control of training-set composition, commercial-library filtering, chemical-space profiling, and prospective experimental evaluation. Three model variants were trained on the Blood–Brain Barrier Database (B3DB): a baseline classifier/regressor pair (DeepBBB_V1_BC/RG), a variant trained with a more strongly negative-enriched configuration (DeepBBB_V2_BC), and a graph-transformer counterpart (DeepBBB_trans_BC/RG). Because the sample-level split assignments and per-compound predictions from the original runs were not recoverable, the archived summary metrics are reported descriptively in the main text and are not used to support calibration, scaffold-level validity, or generalization. Applying the workflow to the ChemDiv collection (~1.5 million compounds) and the Enamine REAL lead-like space (~1.7 billion compounds) produced three progressively more stringently filtered BBB-focused libraries (21,991; 4,808,885; and 151,790 compounds).Results:Analysis of available processed data indicated that the predicted BBB-permeable set occupies a compact, BBB-compatible property region. Physicochemical, fragment, and scaffold summaries were interpreted descriptively at the constructed-library level. In a first prospective campaign, one of 12 tested candidate compounds was PAMPA-BBB-positive (all-tested molecular-level positive fraction 8.3%; exact 95% CI 0.2–38.5%). In a second campaign, five of 35 tested candidate compounds were PAMPA-BBB-positive (14.3%; exact 95% CI 4.8–30.3%); 13 compounds were not quantifiable and were not treated as ordinary CNS-negative measurements, and the two campaigns differed in compound source, selection strategy, and assay setting, so the numerical difference is reported descriptively rather than causally.Conclusions:Together, these results support the feasibility of BBB-focused computational filtering and a PAMPA-BBB evaluation workflow for CNS-oriented discovery.
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DOI
高影响因子
JOURNAL OF DRUG TARGETING
·
2025
·
IF 3.9
Jing Jiang,Yue Xing,Shumeng Liu,Yue Na,Xia Lei,Fang Geng,Yafeng Zhang,Lihong Yang,Ning Zhang
Naringin (4',5,7-trihydroxyflavanone-7-rhamnoglucoside, NG), a potential treatment for Alzheimer’s disease (AD), has strong neuroprotective effects but is limited by poor solubility, low bioavailability, and limited brain accumulation. To address these issues, we developed ANG-NG-NPs, a novel NG-loaded poly (ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) nanoparticle modified with the brain-targeting peptide Angiopep-2 (TFFYGGSRGKRNNFKTEEY, ANG). ANG-NG-NPs exhibited an average size of 126.1 ± 4.50 nm, a zeta potential of -2.97 ± 0.29 mV, 73.43% ± 0.80% encapsulation efficiency (EE), and 24.68% ± 0.45% drug loading capacity (LC). In vitro release studies confirmed its sustained-release properties. In vivo, ANG-NG-NPs extended NG’s circulation time and increased brain uptake. Notably, ANG-NG-NPs restored learning and memory in APP/PS1 mice, improved hippocampal cell health, and reduced hyperphosphorylated tau protein (p-Tau) expression. These findings suggest ANG-NG-NPs as a promising brain-targeting system for treating central nervous system disorders.
研究领域:
药剂学
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神经科学
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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
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Yue Wang,Xiangshu Cheng,Junchao Cai,Rui Peng,Lulu Wang,Jiarong Zhao,Tao Deng,Peng Xie
Carbon dots (CDs) are widely used in biomedical research because of their excellent optical properties and biocompatibility. However, current research often overlooks the physiological activities of CDs, such as their anti-inflammatory activity, in the nervous system, especially in the brain, resulting in few reports on the utilization of their various properties in disease diagnosis and treatment. Herein, a well-designed GABA-tryptophan CDs (GABA-Trp CDs) with excellent blood–brain barrier (BBB) permeability is prepared through the screening of functional precursors. Exploratory research on its therapeutic effect and corresponding mechanism for inflammatory depressive disorder is conducted based on the verification of its anti-inflammatory activity. During this process, GABA-Trp CDs also possess broad-spectrum emissions, distinguishing them from traditional CDs for deep brain imaging assisted by BBB penetration. The results indicate that GABA-Trp CDs can treat inflammatory depression through the anti-inflammatory pathway, including downregulating factors such as lipocalin 2 (Lcn2), and inhibiting the activity of local immune cells in the brain and microglia, further relieving lipid metabolism disorder and repairing myelin damage. The successful application and research of GABA-Trp CDs in the brain provide new insights into CDs in the field of neurological diagnosis and treatment.
研究领域:
纳米医学
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神经病学
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生物医学成像
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神经药理学
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炎症研究
✓ 已验证
产品关联
DOI
高影响因子
SHOCK
·
2023
·
IF 3.1
Luo S,Lyu Z,Ge L,Li Y,Liu Y,Yuan Y,Zhao R,Huang L,Zhao J,Huang H,Luo Y
Background Protein kinase ataxia telangiectasia mutated (ATM) regulates the function of endothelial cells and responds quickly to endotoxin. However, the function of ATM in lipopolysaccharide (LPS) -induced blood-brain barrier (BBB) disruption remains unknown. This study aimed to investigate the role and underlying mechanism of ATM in the regulation of the BBB function in sepsis. Methods We used lipopolysaccharide (LPS) to induce BBB disruption in vivo and to establish an in vitro model of cerebrovascular endothelial cells. BBB disruption was assessed by measuring Evans blue leakage and expression of vascular permeability regulators. To investigate the role of ATM, its inhibitor AZD1390 and clinically approved doxorubicin, an anthracycline that can activate ATM, were administered as scheduled. To explore the underlying mechanism, protein kinase B (AKT) inhibitor MK-2206 was administered to block the AKT/dynamin-related protein 1 (DRP1) pathway. Results LPS challenge induced significant BBB disruption, ATM activation and mitochondrial translocation. Inhibiting ATM with AZD1390 aggravated BBB permeability as well as the following neuroinflammation and neuronal injury, while activation of ATM by doxorubicin abrogated these defects. Further results obtained in brain microvascular endothelial cells showed that ATM inhibition reduced the phosphorylation of DRP1 at serine (S) 637, promoted excessive mitochondrial fission, and resulted in mitochondrial malfunction. By activating ATM, doxorubicin increased the protein binding between ATM and AKT and promoted the phosphorylated activation of AKT at S473, which could directly phosphorylate DRP1 at S637 to repress excessive mitochondrial fission. Consistently, the protective role of ATM was abolished by the AKT inhibitor MK-2206. Conclusions ATM protects against LPS-induced BBB disruption by regulating mitochondrial homeostasis, at least in part, through the AKT/DRP1 pathway.
研究领域:
神经科学
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免疫学
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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
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Chunfu Wei,Jing Zhang,Guanlin Wang,Zizhao Zhai,Chuangxin Chen,Zhengwei Huang,Xin Pan,Chuanbin Wu,Wenhao Wang,Xuejuan Zhang
Central nervous system (CNS) diseases remain a therapeutic challenge due to the blood-brain barrier (BBB). The nose-to-brain pathway offers a promising non-invasive route to bypass the BBB, yet the impact of nanocarrier size on this multi-stage delivery process is poorly understood. This study systematically investigated the role of particle size using solid lipid nanoparticles (SLNS) of 80, 120, 240, 360, and 480 nm, formulated into nasal sprays. In vivo imaging in mice revealed a non-monotonic relationship, with 240 nm SLNS (SLNS3) achieving peak brain accumulation via both olfactory and trigeminal pathways, approximately 1.7-fold higher than other sizes. In vitro models deconstructing the delivery cascade showed that while smaller particles (80 nm) penetrated mucus and nasal epithelium more efficiently, the 240 nm SLNS exhibited superior uptake by neuronal cells and unparalleled transcytosis efficiency to microglia and glioma cells. Mechanistic studies unveiled that SLNS3 uniquely exploited multiple endocytic pathways (clathrin, caveolae, and macropinocytosis) for entry and was preferentially trafficked to the endoplasmic reticulum and Golgi apparatus, facilitating transcellular transport. The superior nose-to-brain delivery efficiency of 240 nm SLNS3 was also validated by a glioma model. Together, our findings pinpoint 240 nm as an optimal size within the SLNS system, reveal the governing cellular mechanisms, and provide a valuable reference for the rational design of nose-to-brain nanomedicines.
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DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
·
IF 13.3
Ji Liu,Mengjuan Sun,Zhen Li,Hongguang Xiang,Qiyue Wang,Xiaofei Xin,Yan Shen
Glioblastoma, the most common malignant brain tumor with a poor prognosis, still needs to develop effective therapeutic strategies to prolong the patient’s survival. Inducing GBM tumor cell ferroptosis could be the specific assay to improve GBM therapeutic efficiency. In comparison, ferroptosis in GBM cells is limited by the low intracellular ferrous ion concentration and oxidation resistance. Herein, an MNP-based ferroptosis catalytic nanoreactor loading cisplatin (CMNP-Cis-Arg) was designed to evaluate their targeted delivery and therapeutic efficiency in GBM treatment. The ferroptosis catalytic nanoreactors achieved an effective GBM targeted transportation via chitosan oligosaccharide driven GLUT1-mediated BBB permeabilization and arginine-based tumor chemotactic. CMNP-Cis-Arg improves synergistically lipid oxidation in GBM cells by inducing ROS generation and depleting intracellular GSH. The MNPs elevate ROS levels in tumor cells by enhancing Fe 2+ -based Fenton reaction and the encapsulated cisplatin as a chemotherapy agent depleting GSH via inducing the DNA strand broken. Moreover, the CMNP-Cis-Arg further induces NO biosynthesis and generates ONOO – with high oxidability to increase lipid oxidation. The anti-GBM ability of the CMNP-Cis-Arg was evaluated both in vitro and in vivo, significantly inducing the GBM tumor cells’ apoptosis and reducing the tumor burden in an orthotopic mouse model. The investigation provided a novel ferroptosis catalytic nanoreactor and confirmed their anti-GBM efficiency in boosting tumor intracellular ferroptosis, suggesting a potential therapeutic strategy worth further investigating preclinically.
研究领域:
肿瘤学
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纳米技术
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药学
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神经科学
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产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
·
IF 10.5
Guowang Cheng,Zhiwen Liu,Zhao Yan,Jiaxin Wu,Zilin Li,Sijia Gao,Chunye Zheng,Shuanshuan Guo,Yue Pan,Xiaojia Chen,Guanghui Lin,Jianhua Zhou,Tongkai Chen
Parkinson's disease (PD)-induced motor dysfunction and cognitive impairment are becoming increasingly common due to global population aging. However, efficient treatment strategies for these conditions are still lacking. Recent studies indicated that neuroinflammation and neuronal apoptosis could greatly worsen the symptoms of PD. Therefore, anti-apoptotic and anti-inflammatory drugs could be useful in the management of PD. In the present study, minocycline (MIN)-loaded Fe 3 O 4 nanoparticles (Fe 3 O 4 -MIN NPs) were prepared for the targeted treatment of PD. Owing to their near-infrared (NIR) irradiation-induced photothermal effects, the Fe 3 O 4 -MIN NPs could cross the blood-brain barrier (BBB), thus enhancing the delivery of Fe 3 O 4 -MIN NPs to the brain parenchyma. Subsequently, the Fe 3 O 4 -MIN NPs exerted strong anti-inflammatory effects and alleviated neuroinflammation in the brain. Furthermore, they exerted anti-oxidative effects, scavenging excessive reactive oxygen species in the brain parenchyma and thus protecting both dopaminergic and hippocampal neurons from neuroinflammation and apoptosis. Consequently, Fe 3 O 4 -MIN NPs + NIR treatment attenuated the motor dysfunction and cognitive impairment observed in PD mice. Notably, the Fe 3 O 4 -MIN NPs also showed high biocompatibility. Hence, these BBB-penetrating MIN-loaded Fe 3 O 4 NPs demonstrate great therapeutic potential for PD accompanied by cognitive impairment.
研究领域:
神经科学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
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2023
·
IF 5
Ye Xiong,Yanqiong Fu,Zhuoli Li,Yu Zheng,Maiyin Cui,Chan Zhang,Xin Yi Huang,Yong Jian,Bai Hui Chen
Glial activation is involved in neuroinflammation and blood–brain barrier (BBB) damage, which plays a key role in ischemic stroke-induced neuronal damage; therefore, regulating glial activation is an important way to inhibit ischemic brain injury. Effects of laquinimod (LAQ) include inhibiting axonal damage and neuroinflammation in multiple neuronal injury diseases. However, whether laquinimod can exert neuroprotective effects after ischemic stroke remains unknown. In this study, we investigated the effect of LAQ on glial activation, BBB damage, and neuronal damage in an ischemic stroke model. Adult ICR mice were used to create a photothrombotic stroke (PT) model. LAQ was administered orally at 30 min after ischemic injury. Neurobehavioral tests, Evans Blue, immunofluorescence, TUNEL, Nissl staining, and western blot were performed to evaluate the neurofunctional outcome. Quantification of immunofluorescence was evaluated by unbiased stereology. LAQ post-treatment significantly reduced infarction and improved forepaw function at 5 days after PT. Interestingly, LAQ treatment significantly promoted anti-inflammatory microglial activation. Moreover, LAQ treatment reduced astrocyte activation, glial scar formation, and BBB breakdown in ischemic brains. Therefore, this study demonstrated that LAQ post-treatment restricted microglial polarization, astrogliosis, and glial scar and improved BBB damage and behavioral function. LAQ may serve as a novel target to develop new therapeutic agents for ischemic stroke.
研究领域:
神经科学
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药理学
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神经病学
·
炎症
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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）