AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma

Wen, Liang; Wang, Kai; Zhang, Fengtian; Tan, Yanan; Shang, Xuwei; Zhu, Yun; Zhou, Xueqing; Yuan, Hong; Hu, Fuqiang

doi:10.1016/j.biomaterials.2020.119793

Cited by 25 publications

(21 citation statements)

References 47 publications

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“…The physiological BBB model and pathological BBB model in vitro 9 and the orthotopic GBM‐bearing mice models were established according to previous methods. 8 , 9 The detailed methodology was provided in Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

“…We then used Evans Blue (EB) to study pathological BBB recovery caused by axitinib in orthotropic GBM models. 9 , 20 Axitinib (10 mg/kg) was I.V. administered to orthotropic GBM‐bearing mice; then, EB was intravenously injected, and normal animals served as the control.…”

Section: Methodsmentioning

confidence: 99%

“… 7 , 8 Our previous studies have found that the regulation of BBB function could promote more chemotherapeutics distributed or targeted at GBM, finally realizing effective and safe anti‐GBM effect of chemotherapy. 9 Therefore, the innovation of pharmaceutics research methods is especially needed for some clinically intractable or even drug‐free CNS diseases. And, the treatment strategy of BBB functional regulation may be more therapeutically valuable and can be put into clinical application more quickly.…”

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 Previous studies have indicated that a decreased permeability of the pathological BBB in the period of therapeutics treatment could predict a good prognosis. 9 , 15 Hence, we hypothesized that pathological BBB restoration might provide new opportunities for GBM safe and effective therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“… 4 Furthermore, claudin‐5 and occludin are key components of TJs and play an important role in maintaining the integrity and function of the BBB. 8 , 9 Our previous studies have indicated that the VEGF/VEGFR signaling pathway was involved in BBB permeability regulation in the occurrence of GBM, and the activation of the VEGF downstream signaling pathway PI3K‐AKT could obviously open the BBB for enhanced intracranial drug delivery with a visible improved anti‐GBM effect. 9 Herein, we further proposed to inhibit the interaction between VEGF and its receptor VEGFR to finally realize a functional restoration of the pathological BBB for anti‐GBM therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Effect of axitinib regulating the pathological blood–brain barrier functional recovery for glioblastoma therapeutics

et al. 2021

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of axitinib regulating the pathological blood–brain barrier functional recovery for glioblastoma therapeutics

et al. 2021

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Combining Multifunctional Delivery System with Blood–Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease

Ke,

Yu,

et al. 2023

Adv Healthcare Materials

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Alzheimer's disease (AD) is a neurodegenerative illness characterized by intracellular tau‐phosphorylation, β‐amyloid (Aβ) plaques accumulation, neuroinflammation, and impaired behavioral ability. Owing to the lack of effective brain delivery approaches and the presence of the blood–brain barrier (BBB), current AD therapeutic endeavors are severely limited. Herein, a multifunctional delivery system (RVG‐DDQ/PDP@siBACE1) is elaborately combined with a protein kinase B (AKT) agonist (SC79) for facilitating RVG‐DDQ/PDP@siBACE1 to target and penetrate BBB, enter brain parenchyma, and further accumulate in AD brain lesion. Moreover, compared with the unitary dose of RVG‐DDQ/PDP@siBACE1, this collaborative therapy strategy exhibits a distinctive synergistic function including scavenging reactive oxygen species (ROS), decreasing of Aβ production, alleviating neuroinflammation by promoting the polarized microglia into the anti‐inflammatory M2‐like phenotype and significantly enhancing the cognitive functions of AD mice. More strikingly, according to these results, an innovative signaling pathway “lncRNA MALAT1/miR‐181c/BCL2L11” is found that can mediate the neuronal apoptosis of AD. Taken together, combining the brain targeted delivery system with noninvasive BBB opening can provide a promising strategy and platform for targeting treatment of AD and other neurodegenerative diseases.

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Enhanced VEGF secretion and blood–brain barrier disruption: Radiation‐mediated inhibition of astrocyte autophagy via PI3K‐AKT pathway activation

Zhang,

Li,

Qiu

et al. 2023

Glia

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Radiation‐induced damage to the blood–brain barrier (BBB) is the recognized pathological basis of radiation‐induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation‐induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K‐AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K‐AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K‐AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K‐AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.

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AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma

Cited by 25 publications

References 47 publications

Effect of axitinib regulating the pathological blood–brain barrier functional recovery for glioblastoma therapeutics

Effect of axitinib regulating the pathological blood–brain barrier functional recovery for glioblastoma therapeutics

Combining Multifunctional Delivery System with Blood–Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease

Enhanced VEGF secretion and blood–brain barrier disruption: Radiation‐mediated inhibition of astrocyte autophagy via PI3K‐AKT pathway activation

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