ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Xuefang Ding,Yujie Su,Cheng Wang,Fangrong Zhang,Kerong Chen,Yu Wang,Min Li,Wei Wang
Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug and gene carriers. In this study, polyethylenimine (PEI)-modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF)-targeted siRNA (siVEGF) for the synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT–PEI–CD conjugates were successfully synthesized and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that SWNT–PEI–CD/siVEGF complexes could achieve high cellular uptake and specific intracellular distribution of siRNA in AT1R overexpressed PANC-1 cells. Strong down-regulation of VEGF was also verified by qualitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot in complex-treated PANC-1 cells. The in vitro angiogenesis assay showed that SWNT–PEI–CD/siVEGF complexes highly inhibited tube formation of human umbilical vein endothelial cells. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT–PEI–CD/siVEGF complexes exhibited significant distribution at tumor sites and caused obvious inhibition of tumor growth and tumor-associated angiogenesis repression induced by the drug combination of CD and siVEGF. Finally, a WST-1 assay indicated that SWNT–PEI–CD possessed low cytotoxicity, and a hemolysis test showed good biocompatibility of SWNT–PEI–CD. Hematological and histological analyses confirmed that SWNT–PEI–CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT–PEI–CD/siVEGF co-delivery system with tumor-targeting specificity, improved endosomal escaping properties, and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor antiangiogenic therapy.
研究领域:
癌症生物学
·
纳米医学
·
药学
·
分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Yuzhe Huang,Jian Guo,Shuangying Gui
The current treatments used in inflammatory bowel disease (IBD) therapy have significant side effects. Thus, it is very necessary to position and release TNF-α siRNA in inflamed tissues. Here, we demonstrate that poly(lactic- co -glycolic acid) can pack TNF-α siRNA efficiently into nanoparticles (NPs), and galactosylated chitosan (GC) can be grafted onto the NP surface, improving the RAW 264.7 macrophage-targeting kinetics of the NPs in vitro. Next, we orally administered GC-modified NPs loaded with TNF-α siRNA to C57BL/6 mice treated with 3% dextran sodium sulfate (DSS) to investigate their use in the treatment of colitis . When TNF-α siRNA loaded NPs were released into the colitis tissues of mice, GC-modified NPs (GPNs) alleviated the inflammation more efficiently than unmodified PGLA NPs (PNs). A series of colitis parameters (e.g., weight loss, myeloperoxidase (MPO) activity) demonstrated that GPNs have better anti-inflammatory effects than PNs. As indicated by flow cytometry, grafting GC onto NPs increased the macrophage uptake capacity and improved the kinetics of endocytosis. Collectively, our findings indicate that GC- modified TNF-α siRNA loaded NPs are powerful and efficient nanoscale materials for the delivery of therapeutic molecules to colitis tissues.
研究领域:
药学
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生物技术
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纳米医学
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炎症研究
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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
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Lan Wu,Lin-Ping Wu,Jingya Wu,Jin Sun,Zhonggui He,Cristina Rodríguez-Rodríguez,Katayoun Saatchi,Lea Ann Dailey,Urs O. Häfeli,Dongmei Cun,Mingshi Yang
Pulmonary delivery of small interfering RNA (siRNA)-based drugs is promising in treating severe lung disorders characterized by the upregulated expression of disease-causing genes. Previous studies have shown that the sustained siRNA release in vitro can be achieved from polymeric matrix nanoparticles based on poly(lactide-co-glycolide) (PLGA) loaded with lipoplexes (LPXs) composed of cationic lipid and anionic siRNA (lipid–polymer hybrid nanoparticles, LPNs). Yet, the in vivo efficacy, potential for prolonging the pharmacological effect, disposition, and safety of LPNs after pulmonary administration have not been investigated. In this study, siRNA against enhanced green fluorescent protein (EGFP-siRNA) was either assembled with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) to form LPX or co-entrapped with DOTAP in PLGA nanoparticles to form LPNs. The disposition and clearance of LPXs and LPNs in mouse lungs were studied after intratracheal administration by using single-photon emission computed tomography/computed tomography (SPECT/CT) and gamma counting. Fluorescence spectroscopy, Western blot, and confocal laser scanning microscopy were used to evaluate the silencing of the EGFP expression mediated by the LPXs and LPNs after intratracheal administration to transgenic mice expressing the EGFP gene. The in vivo biocompatibility of LPXs and LPNs was investigated by measuring the cytokine level, total cell counts in bronchoalveolar lavage fluid, and observing the lung tissue histology section. The results showed that the silencing of the EGFP expression mediated by LPNs after pulmonary administration was both prolonged and enhanced as compared to LPXs. This may be attributed to the sustained release characteristics of PLGA, and the prolonged retention in the lung tissue of the colloidally more stable LPNs in comparison to LPXs, as indicated by SPECT/CT. The presence of PLGA effectively alleviated the acute inflammatory effect of cationic lipids to the lungs. This study suggests that PLGA-based LPNs may present an effective formulation strategy to mediate sustained gene silencing effects in the lung via pulmonary administration.
研究领域:
药剂学
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纳米技术
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分子生物学
·
肺科学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2014
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IF 5.684
Junmin Qian,Minghui Xu,Aili Suo,Weijun Xu,Ting Liu,Xuefeng Liu,Yu Yao,Hongjie Wang
To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer , [poly( l -glutamic acid γ-hydrazide)- b -poly(N,N-dimethylaminopropyl methacrylamide)] 3 - g -poly(ethylene glycol) ((PGAH- b -PDMAPMA) 3 - g -PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition–fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by 1 H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form “two-in-one” nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione : 10 mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy.
研究领域:
药学
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纳米技术
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癌症治疗
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高分子化学
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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
Journal of Biomedical Nanotechnology
·
2015
·Vol. 11
·期 4
·668-679
·
IF 5.338
Yuan Yuanyuan,Gong Faming,Cao Yang,Chen Weicai,Cheng Du,Shuai Xintao
The gene silencing activity of small interfering RNA (siRNA) has led to their use as tools for target validation and as potential therapeutics for a variety of diseases. A major challenge is the development of vectors with high delivery efficiency and low toxicity. Although poly(ethylenimine)
(PEI) has been regarded as the most promising polymeric vector for nucleic acid delivery, the nonbiodegradable structure greatly hinders its clinical application. In the present study, a diblock copolymer, PEG-PAsp(DIP-DETA), of poly(ethylene glycol) (PEG) and poly(L-aspartic acid) (PAsp)
randomly grafted with pH-sensitive 2-(diisopropylamino)ethylamine (DIP) and diethylenetriamine (DETA) groups was synthesized via ring-opening polymerization and aminolysis reaction. Similar to polyethylenimine (PEI), the copolymer possesses a multiamine structure that not only allows effective
siRNA complexation at neutral pH but also facilitates lysosomal release of siRNA via a proton buffering effect. Moreover, the poly(L-aspartic acid) backbone renders the vector biodegradability, which is not achievable with PEI. This novel polymeric vector can mediate effective intracellular
siRNA delivery in various cancer cells. Consequently, the delivery of BCL-2 siRNA resulted in target gene silencing, inducing apoptosis and inhibiting the growth of cancer cells. These results show the potential of this non-PEI based polymeric vector with proton buffering capacity and biodegradability
for siRNA delivery in cancer therapy.
研究领域:
药学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
Biomaterials Research
·
2025
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IF 9.6
Yunsheng Lu,Yibin Huang,Chenchen Mao,Pengfei Shan,Chenkang Wu,Jiongzhou Zhu,Yujie Lin,Zhongyu Li,Mingdong Lu
Silencing NOP2/Sun RNA methyltransferase family member 2 (NSUN2) effectively inhibits gastric cancer (GC) progression but is limited by RNase degradation, rapid renal clearance, and low uptake. Based on the characteristic high levels of reactive oxygen species (ROS) in the tumor microenvironment, this study designed and synthesized a novel ROS-responsive ferrocene nanoparticle loaded with siNSUN2 (PRPFc@siNSUN2). Under ROS conditions, the nanoparticle disintegrates to release siNSUN2. Characterization by proton nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, and ultraviolet–visible spectrophotometry revealed that PRPFc@siNSUN2 is spherical, with an average diameter of 88.79 ± 1.14 nm, an encapsulation efficiency of 83.10%, and a drug loading capacity of 13.85%. Moreover, these nanoparticles demonstrated excellent stability and, under hydrogen peroxide conditions, exhibited structural disruption leading to the release of siNSUN2, thereby confirming their high ROS responsiveness. In vitro, PRPFc@siNSUN2 markedly enhanced the inhibition of GC cell proliferation, migration, and invasion, and promoted apoptosis, accompanied by increased intracellular ROS and improved siNSUN2 uptake. In vivo studies further confirmed that PRPFc@siNSUN2 markedly enhanced the therapeutic efficacy of siNSUN2 against GC, while exhibiting low cytotoxicity and good biocompatibility. Overall, our findings indicate that PRPFc@siNSUN2, with its favorable morphology, stability, and ROS-triggered release, substantially improves the anti-GC effects of siNSUN2 by inhibiting GC cell proliferation, migration, and invasion, as well as by promoting apoptosis. These results support NSUN2 as a promising therapeutic target and underscore the potential of PRPFc@siNSUN2 nanoparticles in drug delivery, offering a novel strategy to improve clinical outcomes for GC patients.
研究领域:
肿瘤学
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分子生物学
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药剂学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2019
·Vol. 24
·期 18
·3413
·
IF 3.06
Ehexige Ehexige,Tsogzolmaa Ganbold,Xiang Yu,Shuqin Han,Huricha Baigude
Lipid nanoparticles (LNP) are the most potent carriers for the delivery of nucleic acid-based therapeutics. The first FDA approved a short interfering RNA (siRNA) drug that uses a cationic LNP system for the delivery of siRNA against human transthyretin (hTTR). However, preparation of such LNP involves tedious multi-step synthesis with relatively low yields. In the present study, we synthesized cationic peptidomimetic functionalized cholesterol (denote Chorn) in straightforward chemical approaches with high yield. When formulated with helper lipids, Chorn LNPs complexed with siRNA to form nanoparticles with an average diameter of 150 nm to 200 nm. Chorn LNP mediated transfection of a green fluorescence protein (GFP) expressing plasmid resulted in 60% GFP positive cells. Moreover, Chorn LNP delivered siRNA against polo-like kinase 1 (Plk1), a disease related gene in cancer cells and efficiently suppressed the expression of the gene, resulting in significant morphological changes in the cell nuclei. Our data suggested that cholesterol based cationic LNP, prepared through a robust chemical strategy, may provide a promising siRNA delivery system.Keywords:siRNA;lipid nanoparticle;peptidomimetic;cholesterol;Plk1
研究领域:
药学
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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
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Yue Hu,Qing Nie,Xianling Cong,Wen Wu,Qiong Wu,Qihui Liu,Yuanyuan Li,Haiyan Liu,Jingyan Ge,Fangfang Chen
Cancer represents a significant global public health challenge, and conventional cancer therapies such as surgery and chemoradiotherapy are not enough due to the increased complexity of cancer. Nanotechnology has the potential to revolutionize tumor treatments by integrating gene therapy, tumor targeting, and drug delivery. In this study, we demonstrated that Snail2 plays a crucial role in the migration and invasion of lung and liver carcinoma. We proposed a novel approach to synergize the aminated crosslinking dextran coat of superparamagnetic iron oxide nano worms (CLIO-NH 2 , CN) with small interfering Snail2 RNA (siSnail2). The efficiency of siSnail2 delivery was significantly improved by coating CN with N-Isopropylacrylamide-modified polyethylenimine (CNP). In vitro, experiments revealed that CNP@siSnail2 effectively inhibited cancer cell EMT, migration, and invasion. Moreover, CNP@ siSnail2 promoted cancer cell death through various mechanisms, including apoptosis and ferroptosis . The combination of CNP@ siSnail2 and cisplatin significantly improved the anti-tumor effect of the treatment. Animal models demonstrated that the combined treatment of CNP@ siSnail2 and cisplatin resulted in excellent tumor inhibition effects. Our findings provide a potential combined treatment strategy for cancer therapy.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Yan Fang,Qian Shen,Yao Lin,Jing Zhu,Xiaolan Zhu,Rui Huang,Yijia Wu,Feiyang Shen,Qian Li,Guopei Zheng,Zhe Zhang,Qian Chu,Junhao Hu,Jianfeng Shen
Malignant serous effusion (MSE), including malignant pleural effusion (MPE) and malignant ascites (MA), is a common and severe complication in advanced malignancies, associated with poor prognosis and high recurrence rates. Currently, no standardized treatments are available for MSE management, posing significant clinical challenges. Here, we identify elevated LIN28B expression and dysregulation of DNA repair pathways as two major features associated with MSE from patient and preclinical samples. We develop a targeted siRNA nanoparticle delivery system (siLin28B/DSSP@lip-PEG-FA) in combination with the PARP inhibitor BMN673, providing a synergistic therapeutic strategy against MSE. This combination significantly alleviated MA accumulation and prolonged survival in a preclinical ovarian cancer (OC) model without causing systemic cytotoxicity. Mechanistically, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy markedly remodeled the immune microenvironment by decreasing M2 macrophages and neutrophil populations with altered subtypes. Notably, Arg1-positive neutrophils, producing pro-inflammatory cytokines to increase vascular permeability, were diminished after the combination treatment. Furthermore, in vitro and in vivo experiments demonstrated that suppression of PARP and LIN28B inhibited vascular leakage and reinforced tight junction integrity. Collectively, our findings highlight dual targeting of PARP and LIN28B as a promising MA management approach in patients with advanced cancers, with the potential to improve patient quality of life.
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DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Shuya Liu,Dongliang Wang,Sishi Ye,Junjie Zhang,Beiyan Du,Zhijie Lian,Wen Yang,Jie Zhou,Qi Chen,Juan Li,Jingying Li,Huanghao Yang
Given the significant advantages the eye presents as a target organ for gene therapy, it has remained at the forefront of translational research in this field. However, gene delivery to the desired tissue, particularly the retina, via a noninvasive route of administration poses a substantial physical challenge due to the presence of multiple ocular barriers. Here, we develop disulfide-appended small interfering RNA (DS-siRNA) Nanoeyedrops that target pathological retinal angiogenesis. These Nanoeyedrops enable noninvasive and effective gene delivery into the retina through the thiol-mediated uptake route. We have demonstrated that the thiol-mediated uptake route represents a powerful approach capable of overcoming ocular barriers. Ultimately, we have applied these Nanoeyedrops to deliver VEGF siRNA, which has exhibited substantial effects in both choroidal neovascularization and retinoblastoma mouse models. It serves as a highly efficient delivery system that enables noninvasive ocular gene delivery with high bioavailability, thereby offering a promising strategy for treating retinal diseases.
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产品关联
DOI
PubMed
高影响因子
Translational Neurodegeneration
·
2025
·Vol. 14
·期 1
·1-20
·
IF 15.2
Li Zhaohan,Yang Jun,Li Jianan,Zhao Shuxuan,Jiang Shaoping,Liu Weimin,Li Xinjian,Zhang Simeng,Du Haiyan,Ni Junjun,Huang Yuanyu,Qing Hong,Ruan Shaobo
Background The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions This study provides a reliable delivery platform for gene therapies for AD.
研究领域:
神经科学
·
分子生物学
·
药剂学
·
基因治疗
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Tseyenkhorloo Erdene-Ochir,Tsogzolmaa Ganbold,Jargalmaa Zandan,Shuqin Han,Gereltu Borjihan,Huricha Baigude
Cationic curdlan derivatives are a class of promising carriers for nucleic acid delivery including short interfering RNA (siRNA). While our previous studies demonstrated the siRNA delivery efficiency of aminated curdlan derivatives, the associated cytotoxicity issue remained unsolved. To investigate the effects of alkylation on the toxicity as well as the transfection efficiency, we conjugated short alkyl chains to 6-amino-6-deoxy-curdlan (6AC-100). The cytotoxicity of alkylated 6AC-100 derivatives (denote CuVa polymers) decreased with the increase of the degree of substitution (DS). CuVa3, with the highest DS, showed a 50% decreased cytotoxicity compared to 6AC-100 to 6AC-100 at a concentration of 140 μg/mL. The CuVa polymers readily complexed with siRNA to form nanoparticles, and induced significant knockdown of a disease related gene (STAT3) in mouse melanoma cell line B16. However, B16 cells transfected with siSTAT3 complexed to CuVa3 showed the highest phenotypic changes. These findings suggest that CuVa polymers have significantly enhanced biocompatibility and may be a promising delivery system for delivery of therapeutic siRNAs.
研究领域:
药学
·
生物技术
·
纳米技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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