JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-16
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IF 10.6
Qi Ji,Zhang Long,Ren Zhongyu,Yuan Yi,Yu Jiahao,Zhang Yining,Gu Linbo,Wang Xu,Wang Yan,Xu Haoyue,Yu Rutong,Zhou Xiuping
Background The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree. Results In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects. Conclusion Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
研究领域:
肿瘤学
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药学
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分子生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
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2024
·
IF 10.7
Kaili Liang,Li Yang,Jiawei Kang,Bo Liu,Ding Zhang,Liyan Wang,Wei Wang,Qing Wang
Parkinson's disease (PD) poses a significant therapeutic challenge, mainly due to the limited ability of drugs to cross the blood-brain barrier (BBB) without undergoing metabolic transformations. Levodopa, a key component of dopamine replacement therapy, effectively enhances dopaminergic activity. However, it encounters obstacles from peripheral decarboxylase, hindering its passage through the BBB. Furthermore, levodopa metabolism generates reactive oxygen species (ROS), exacerbating neuronal damage. Systemic pulsatile dosing further disrupts natural physiological buffering mechanisms. In this investigation, we devised a ROS-responsive levodopa prodrug system capable of releasing the drug and reducing ROS levels in the central nervous system. The prodrug was incorporated within second near-infrared region (NIR-II) gold nanorods (AuNRs) and utilized angiopep-2 (ANG) for targeted delivery across the BBB. The processes of tight junction opening and endocytosis facilitated improved levodopa transport. ROS scavenging helped alleviate neuronal oxidative stress, leading to enhanced behavioral outcomes and reduced oxidative stress levels in a mouse model of PD. Following treatment, the PD mouse model exhibited enhanced flexibility, balance, and spontaneous exploratory activity. This approach successfully alleviated the motor impairments associated with the disease model. Consequently, our strategy, utilizing NIR-Ⅱ AuNRs and ANG-mediated BBB penetration, coupled with the responsive release of levodopa, offers a promising approach for dopamine supplementation and microenvironmental regulation. This system holds substantial potential as an efficient platform for delivering neuroprotective drugs and advancing PD 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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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Applied Materials Today
·
2022
·
IF 8.663
Lukuan Xie,Honglei Lin,Lingrui Lv,Wenxin Zhang,Feng Feng,Fulei Liu,Wenyuan Liu,Lingfei Han
Parkinson's disease (PD), one of common neurodegenerative diseases, afflicts many elderly people lacking of effective treatment strategies. Rhynchophylline (RIN) is an anti-PD natural active compound. However, RIN can hardly cross the blood-brain barrier (BBB) and is easily excreted as a substrate of P-glycoprotein (P-gp), making it difficult to exert anti-PD efficacy in brain. Nanocarrier-based brain targeting strategies provide an attractive platform to address brain distribution problems of drugs. In this work, we designed a brain-targeting core-shell nanoparticle (RIN/TAR-A2-CSN) for the programmed co-delivery of RIN and P-gp inhibitor Tariquidar (TAR). It was composed of Angiopep-2 (A2) modified reduction-responsive PEG shell material and thiamine disulfide system (TDS) grafted polyglutamate core material. After entering the body, first RIN/TAR-A2-CSN crossed the BBB into the brain via A2-receptor-mediated transport. Subsequently, the shell material disintegrated under reducing conditions, and the TDS-grafted core material was reduced to become hydrophilic, thereby leading to the drugs "locked-in" the brain. Finally, the released TAR inhibits P-gp-mediated RIN efflux, increases the retention time of RIN in the brain, and fully exerts the anti-PD effect of RIN. The brain targeting efficiency of RIN/TAR-A2-CSN was improved to 5.8 times that of free RIN. In addition, the therapeutic effect on the MPTP-induced PD mice model was significantly improved. This work develops a novel brain targeting strategy for drugs to overcome BBB and inhibit efflux. RIN/TAR-A2-CSN nanoparticles show the potential to become PD therapeutics.
研究领域:
神经药理学
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纳米技术
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药学
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神经退行性疾病
✓ 已验证
产品关联
DOI
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 13
·5054-5067
·
IF 8.307
Beibei Zhang,Rui Xue,Chunyang Sun
Glioblastoma (GBM) is the most lethal primary intracranial tumor because of its high invasiveness and recurrence. Therefore, nanocarriers with blood–brain barrier (BBB) penetration and transcranial-controlled drug release and activation are rather attractive options for glioblastoma treatment. Herein, we designed a multifunctional nanocarrier (T-TKNPVP) that combined targeted X-ray-induced photodynamic therapy (X-PDT) and cascaded reactive oxygen species (ROS)-boosted chemotherapy. The T-TKNPVP loaded with verteporfin (VP) and paclitaxel (PTX) was self-assembled from an angiopep-2 (Ang) peptide, functionalized Ang-PEG-DSPE and ROS-sensitive PEG-TK-PTX conjugate. After systemic injection, the T-TKNPVP efficiently crossed the BBB and targeted the GBM cells via receptor-mediated transcytosis. Upon X-ray irradiation, they can generate a certain amount of ROS, which not only induces X-PDT but also locoregionally activates PTX release and action by cleaving the TK bridged bonds. As evidenced by 9.4 T MRI and other experiments, such nanocarriers offer significant growth inhibition of GBM in situ and prolong the survival times of U87-MG tumor-bearing mice. Taken together, the designed T-TKNPVP provided an alternative avenue for realizing transcranial X-PDT and X-ray-activated chemotherapy for targeted and locoregional GBM treatment in vivo.
研究领域:
癌症治疗
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纳米技术
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神经科学
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药学
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放射学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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