MACROMOLECULAR BIOSCIENCE
·
2023
·Vol. 23
·期 4
·2200529
·
IF 4.6
Yuanyuan Yuan,Yiyao Wang,Huiling Huang,Shuiliang Tao,Jinsheng Huang
Successful clinical application of siRNA to liver-associated diseases reinvigorates the RNAi therapeutics and delivery vectors, especially for anticancer combination therapy. Fine tuning of copolymer-based assembly configuration is highly important for a desirable synergistic cancer cell-killing effect via the codelivery of chemotherapeutic drug and siRNA. Herein, an amphiphilic triblock copolymer methoxyl poly(ethylene glycol)- block -poly( L -lysine)- block -poly(2-(diisopropyl amino)ethyl methacrylate) (abbreviated as mPEG-PLys-PDPA or PLD) consisting of a hydrophilic diblock mPEG-PLys and a hydrophobic block PDPA is synthesized. Three distinct assemblies (i.e., nanosized micelle, nanosized polymersome, and microparticle) are acquired, along with the increase in PDPA block length. Furthermore, the as-obtained polymersome can efficiently codeliver doxorubicin hydrochloride (DOX) as a hydrophilic chemotherapeutic model and siRNA against ADP-ribosylation factor 6 (siArf6) as an siRNA model into cancer cell via lysosomal pH-triggered payload release. PC-3 prostate cell is synergistically killed by the DOX- and siArf6-coloading polymersome (namely PLD@DOX/siArf6). PLD@DOX/siArf6 may serve as a robust nanomedicine for anticancer therapy.
研究领域:
药学
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生物医学工程
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癌症研究
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纳米技术
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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
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Yu Zou,Quan Zhou,Yinan Zhao,Defu Zhi,Huiying Chen,Rui Wang,Benzhi Ju,Shubiao Zhang
Ionizable lipids are the leading vectors for gene therapy. Understanding the effects of molecular structure on efficient gene delivery is one of the most important challenges for maximizing the utility of such lipid vectors. We synthesized an array of pH-responsive and ionizable lipids to investigate the relationship between lipid structure and activity. The optimized lipid (EDM) has double tertiary amines in the headgroup and an ester linker. EDM exhibited efficient DNA and siRNA delivery to, and gene silencing of, A549 cells. EDM has a p K a value of 6.67, which enabled it to quickly escape from the endosome after entering the cell; the ester linkages rapidly degraded and enabled gene release into the cytoplasm. EDM also delivered IGF-1R siRNA to inhibit tumor growth and induce cancer cell apoptosis by efficient inhibition of IGF-1R expression in mice. Our study on the structure–activity relationships of ionizable lipids will facilitate clinical applications.
研究领域:
药学
·
基因治疗
·
分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
Nanomaterials
·
2022
·Vol. 12
·期 10
·1692
·
IF 5.719
Yixiang Cao,Shiyin Zhang,Ming Ma,Yu Zhang
CXC chemokine receptor 4 (CXCR4) is a promising therapeutic target. Previous studies have shown that intracellular delivery of siRNA to knockdown CXCR4 expression in cancer cells is an effective therapeutic strategy. To prepare efficient magnetic nucleic acid carriers, it is now necessary to improve the endocytosis efficiency of PEGylated magnetic nanoparticles. In our work, Heptafluorobutyryl-polyethylene glycol-polyethyleneimine (FPP) was first prepared and then used to coat magnetic nanoparticles (MNPs) to obtain magnetic nanocarriers[email protected]The materials were characterized by19F-Nuclear Magnetic Resonance (NMR), transmission electron microscope (TEM), energy dispersive spectroscopy (EDS), and dynamic light scattering (DLS). The biosecurity of[email protected]was confirmed by cell viability and apoptosis experiments. Cellular uptake of[email protected]and siRNA transfection enhanced by external magnetic fields were detected by fluorescence microscopy, confocal laser microscopy, and flow cytometry. The results show that the cellular uptake efficiency of[email protected]was significantly improved, and transfection efficiency reached more than 90%. The knockdown of CXCR4 on the 4 T1 cell membrane was confirmed by real-time polymerase chain reaction (RT-PCR) and flow cytometry. In conclusion, the fluorinated cationic polymer-coated magnetic nanoparticles[email protected]can be loaded with siRNA to reduce CXCR4 expression as well as be expected to be efficient universal siRNA carriers.Keywords:magnetic nanoparticles;fluorination;polyethyleneimine;polyethylene glycol;RNA interference;CXC chemokine receptor 4
研究领域:
纳米技术
·
分子生物学
·
药学
·
癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Sijia Jiang,Yang Zhou,Chenglong Ge,Renxiang Zhou,Mengyao Ren,Lichen Yin,Jiang Zhu
During the progression of severe sepsis, the oxidized mitochondrial DNA (mtDNA) in macrophages is cleaved by flap-structure-specific endonuclease 1 (FEN1) into small fragments, which are subsequently released into the cytosol and extracellular space to activate multiple pro-inflammatory signaling pathways such as NLRP3 inflammasome, cGAS-STING, and TLR9-NF-κB. Herein, biomimetic nanocomplexes (NCs) partially cloaked with macrophage membrane (MM) are developed to efficiently deliver FEN1 siRNA (siFEN1) into macrophages for sepsis management. To construct the NCs, membrane-penetrating, helical polypeptide (PG) first condenses siFEN1 and forms the cationic inner core, which is further coated with MM. By optimizing the membrane protein/siFEN1 weight ratios, partial membrane coating can be achieved, which enables the formation of NCs with both enhanced serum stability and efficient macrophage uptake efficiency. After systemic administration in cecal ligation and puncture-induced sepsis mice, the NCs exhibit prolonged blood circulation time and effective accumulation to the inflamed tissues, facilitated by MM-mediated charge neutralization of the cationic nanocore and inflammation homing. Subsequently, the NCs are efficiently internalized by macrophages through the interaction between the partially exposed polycationic core and the target cell membranes, provoking robust FEN1 silencing to suppress mtDNA fragmentation and leakage. Consequently, the NCs effectively restore immune homeostasis in sepsis mice, thereby mitigating cytokine storm and alleviating multiple organ failure.
研究领域:
纳米医学
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免疫学
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分子生物学
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基因治疗
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炎症性疾病
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2019
·
IF 3.829
Jiu Wang,Yajing Wang,Ziqiang Wang,Fan Wang,Jie He,Xiaoyun Yang,Weidong Xie,Ying Liu,Yaou Zhang
The present study aims at designing a thermosensitive gel prepared from w1/o/w2 multiple microemulsions (MMEs) for the vaginal delivery of siRNA. The w1/o/w2 MMEs were prepared by two-step emulsifications: the first step was to prepare primary emulsions (w1/o) by low energy emulsification (LEE); the second step was to obtain stable w1/o/w2 MMEs by self-emulsifying. An extensive formulation optimization process was undertaken. The final w1/o/w2 MMEs could be formed in ddH2O, phosphate buffer solution (PBS, pH 7.4) and 1640 culture media with diameter size about 166.5 ± 13.1, 271.0 ± 11.1 and 278.7 ± 12.1 nm respectively. The release rates of siRNA from solutions, MMEs and MMEs-gels were completed within 2 h, 6 h and13 h respectively. The transfection efficiency of MMEs was confirmed both in vitro and in vivo. The relative target gene expressions of MMEs were 0.07 ± 0.05% vs. 0.37 ± 0.06% in Hela cells against Lipofectamine2000® and 1.88% ± 0.00% vs. 9.65% ± 0.02% in mouse vaginal mucosa against PEI. Good biocompatibility of MMEs was verified by cytotoxicity and pathological studies. Overall, our results indicated the potential of the MMEs-gel system for the vaginal delivery of siRNA.
研究领域:
药剂学
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生物医学工程
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Guirong Zheng,Ruirui Zhao,Aixiao Xu,Zhichun Shen,Xian Chen,Jingwei Shao
Combination with chemotherapeutic drug and gene therapy has been proven highly effective in suppressing tumor progression. Hence, an asialoglycoprotein receptor (ASGPR)-targeting nanodrug delivery system based on mesoporous silica (MSN) nanocarrier for co-delivery of sorafenib (SO) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) to hepatocellular carcinoma (HCC) was successfully designed and synthesized. The structure of nanoparticles was characterized by IR, particle size, zeta potential and N2 adsorption-desorption. The nanoparticles were further evaluated for drug release, cellular uptake, transfection, cell cytotoxicity and cell cycle against HepG2 and Huh7 cells. In vitro testing demonstrated that MSN-LA delivery system could not only induce S cell cycle arrest, enhance the cytotoxicity and improve the tumor target of SO and siVEGF, but also enhance the siVEGF transfection efficiency in ASGPR-overexpressing Huh7 cells. Overall, the MSN-LA delivery system can be a promising drug carrier which could further enhance the anti-cancer efficacy of SO and siVEGF via the active targeting property of LA .
研究领域:
药剂学
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肿瘤学
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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 BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Tsogzolmaa Ganbold,Shuqin Han,Agula Hasi,Huricha Baigude
Natural carbohydrate polymer-based nanoparticles have great biocompatibility that is required for the safe delivery of various drugs including nucleic acid therapeutics. Herein, we designed curdlan-based nanoparticles for cancer cell targeted delivery of short interfering RNA (siRNA). iRGD peptide conjugated 6-amino-6-deoxy curdlan specifically delivered siRNA to integrin expressing cancer cells. Incubation of cancer cells with free iRGD peptide competitively blocked cellular uptake of the iRGD functionalized curdlan nanoparticles. Chloroquine but not nystatin inhibited cellular uptake of iRGD functionalized curdlan nanoparticles, indicating that the iRGD peptide conjugated curdlan nanoparticles were internalized through the receptor (clathrin)-mediated endocytosis. Moreover, a disease related gene Plk1 was substantially knocked down by siRNA carried by 6AC-iRGD nanoparticles in HepG2 cells. Our data suggested that iRGD functionalized curdlan may provide a biocompatible carrier for siRNA delivery.
研究领域:
生物医学工程
·
分子生物学
·
药剂学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-17
·
IF 10.435
Lan Biyun,Zhang Liming,Yang Liqun,Wu Junfeng,Li Na,Pan Chenglin,Wang Xiaoyi,Zeng Lexiang,Yan Li,Yang Chuan,Ren Meng
AbstractExcessive expression of matrix metalloproteinase 9 (MMP-9) impedes healing of diabetic chronic wounds, thus wound dressing that could effectively inhibit the expression of MMP-9 offers significant clinical translation for diabetic wound healing. Herein, a hybrid hydrogel dressing was developed for localized and sustained delivery of MMP-9 siRNA (siMMP-9). siMMP-9 was complexed with Gly-TETA (GT), the GT/siMMP9 complex was then loaded into a thermosensitive hydrogel based on Pluronic F-127 (PF) and methylcellulose (MC). In vitro, this hybrid hydrogel dressing exhibited negligible cytotoxicity, prolonged the release of GT/siMMP-9 for up to 7 days, and significantly reduced MMP-9 expression. In vivo assessment in diabetic rats demonstrated that hydrogel provided localized and sustained delivery via the thermosensitive controlled release of entrapped GT/siMMP-9 into wound tissues for 7 days, resulting in dramatic MMP-9 silencing which significantly improved diabetic wound closure. This hybrid hydrogel dressing exhibited excellent biocompatibility, with no observed systemic toxicity in rats. Taken together, the hybrid hydrogel dressing may constitute an effective and biocompatible means of enhancing diabetic wound healing through effective silencing of the MMP-9 gene, and this hydrogel delivery system also offers a platform for in vivo delivery of siRNA for the treatment of other diseases.
研究领域:
药学
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生物医学工程
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伤口愈合
·
糖尿病
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DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 7
·2777-2792
·
IF 5.251
Ziming Lin,Moxyel Bao,Zexuan Yu,Lingjing Xue,Caoyun Ju,Can Zhang
Cationic liposomes have shown great potential in efficient siRNA delivery, and their positive charge is crucial for tight extracellular siRNA binding, effective intracellular siRNA disassembly and physiological toxicity. Thus, the development of novel cationic lipids with a suitable positive charge is desirable for safe and efficient siRNA delivery. Herein, we fabricated a library of 21 tertiary amine-derived cationic lipids (TA) to achieve a balance between effectiveness and safe siRNA delivery. The screened TA13 liposomes, which consisted of TA13 and helper lipid DOPE at a mole ratio of 1 : 1, readily condensed siRNA to form lipoplexes (TA13 LPs), achieving stronger gene silencing in diverse cells than the commercially available vector Lipo2000. Moreover, the TA13 LPs demonstrated effective in vivo gene silencing and good safety in normal mice. The improved gene silencing efficiency of the TA13 LPs is ascribed to their capability of sequentially conquering the barriers met by in vivo siRNA delivery. Notably, the TA13 LPs delivered ApoB-siRNA and obviously decreased ApoB mRNA expression in the liver and the total cholesterol and low-density lipoprotein in the serum of hypercholesterolemia mice, indicating a potential siRNA therapeutic for hypercholesterolemia treatment. It is anticipated that these novel tertiary amine-based liposomes can provide a simple and widely-used platform for the safe and effective delivery of siRNA, and their structure–activity relationships can aid in the further development of effective cationic lipids.
研究领域:
药学
·
分子生物学
·
治疗学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 7
·期 3
·901-913
·
IF 5.831
Daping Xie,Junjie Du,Moxyel Bao,Anwei Zhou,Chunli Tian,Lingjing Xue,Caoyun Ju,Jian Shen,Can Zhang
Robust efficiency for cytosolic small interfering RNA (siRNA) delivery is of great importance for effective gene therapy. To significantly improve the cytosolic siRNA delivery, a “one-pot modular assembly” strategy is developed to assemble a triple-play enhanced cytosolic siRNA delivery system via a facile and innocuous copper-free click reaction. Specifically, three modules are prepared including octreotide for receptor-mediated endocytosis, a cell-penetrating peptide (CPP) for cell penetration, and glutamic acid for the charge-reversal property. All three modules with distinct facilitating endocytosis effects are expediently assembled on the surface of the siRNA/liposome complex to fabricate a multifunctional integrated siRNA delivery system (OCA-CC). OCA-CC has been demonstrated to have enhanced cytosolic delivery and superior gene-silencing efficiency in multiple tumor cells due to the combined effects of all the three modules. High levels of survivin-silencing are also achieved by OCA-CC on orthotopic human breast cancer (MCF-7)-bearing mice accompanied by significant tumor inhibition. This research provides a facile strategy to produce safe and tunable siRNA delivery systems for effective gene therapy and to facilitate the development of multifunctional siRNA vectors.
研究领域:
药剂学
·
分子生物学
·
基因治疗
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
Theranostics
·
2018
·
IF 8.537
Zhanwei Zhou,Qingyan Zhang,Minghua Zhang,Huipeng Li,Gang Chen,Chenggen Qian,David Oupicky,Minjie Sun
Stimuli-responsive polycations have been developed for improved nucleic acid transfection and enhanced therapeutic efficacy. The most reported mechanisms for controlled release of siRNA are based on polyelectrolyte exchange reactions in the cytoplasm and the degradation of polycations initiated by specific triggers. However, the degradation strategy has not always been sufficient due to unsatisfactory kinetics and binding of cationic fragments to siRNA, which limits the gene silencing effect. In this study, a new strategy that combines degradation and charge reversal is proposed. Methods: We prepared a polycation (CrossPPA) by crosslinking of phenylboronic acid (PBA)-grafted 1.8k PEI with alginate. It was compared with 25k PEI, 1.8k PEI and 1.8k PEI-PBA on siRNA encapsulation, ATP-responsive behavior and mechanism, cytotoxicity, cell uptake, siRNA transfection, in vivo biodistribution and in vivo anti-tumor efficacy. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model separately. Results: The crosslinking strategy obviously improve the siRNA loading ability of 1.8k PEI. We validated that intracellular levels of ATP could trigger CrossPPA disassembly and charge reversal, which resulted in efficient and rapid siRNA release due to electrostatic repulsion. Besides, CrossPPA/siRNA showed strong cell uptake in 4T1 cells compared with 1.8k PEI/siRNA. Notably, the cytotoxicity of CrossPPA was pretty low, which was owing to its biodegradability. Furthermore, the crosslinked polyplexes significantly enhanced siRNA transfection and improved tumor accumulation. The high gene silencing ability of CrossPPA polyplex led to strong anti-tumor efficacy when using Bcl2-targeted siRNA. Conclusion: These results indicated that the ATP-triggered disassembly and charge reversal strategy provided a new way for developing stimuli-responsive siRNA carriers and showed potential for nucleic acid delivery in the treatment of cancer.
研究领域:
生物医学工程
·
药学
·
癌症研究
·
纳米技术
·
基因治疗
✓ 已验证
DOI
PubMed
高影响因子
BMEMat
·
2026
·
IF 17.2
Jingwen Xie,Jingxing Si,Xiaobei Deng,Jing Tan,Ruijie Zhu,Jizhou Qi,Gaoxia Ma,Bin Wang,Yi Wang,Yunzhou Guo,Yuping Chen,Shiqun Shao,Youqing Shen
Intranasal administration presents a direct, non-invasive pathway for delivering small interfering RNA (siRNA) to glioblastoma (GBM), but its efficiency is hampered by intranasal and intratumoral barriers. To overcome these barriers, here, we develop a multipotent nanocage system featuring a crosslinked yet reactive oxygen species (ROS)-cleavable, zwitterionic poly (tertiary amine oxide) (PTAO) shell for efficient intranasal siRNA delivery. This design ensures ultrastable siRNA encapsulation under physiological conditions while enabling traceless siRNA release selectively in tumor cells with elevated ROS levels. Notably, the gene silencing efficacy of the nanocages remains unaffected after 1 month of room-temperature storage in solution. By leveraging the zwitterionic property of PTAO, the nanocages exhibit prolonged intranasal residence and enhanced mucus penetration. Furthermore, they induce lipid raft-dependent macropinocytosis and subsequent transcytosis that promotes brain accumulation via the trigeminal nerve pathway and enables deep tumor penetration. This endocytosis mechanism directs nanocages into the non-degradative endoplasmic reticulum-Golgi pathway for intracellular trafficking, bypassing lysosomal trapping. In an orthotopic GBM mouse model, intranasal administration of nanocages loading PLK1 siRNA significantly suppressed glioma growth and extended survival without obvious safety issues. Our study demonstrates the potential of the nanocage platform as an intranasal delivery vehicle, promising broad therapeutic applications in GBM and other neurological disorders.
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产品关联
DOI
高影响因子
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