Nanoscale
·
2020
·Vol. 12
·期 19
·10623-10638
·
IF 6.895
Fabiao Hu,Ting Yan,Wei Guo,Qiuli Liu,Myong Hun Han,Chang Liu,Yuping Liu,Wenyun Zheng,Fang You,Yi Yang,Wenliang Zhang,Xingyuan Ma
Therapeutic recombinant proteins have numerous advantages and benefits over chemical drugs, particularly high specificity and good biocompatibility. However, the therapeutic potential and clinical application of current anticancer protein drugs are limited as most biomarkers are located within cells, and multiple physiological barriers exist between the point of administration and the intracellular biomarker. Herein, we report a novel strategy to accurately deliver a cell-permeable dominant-negative TATm-Survivin (TmSm) protein (T34A) to intracellular survivin in cancer cells by overcoming multiple barriers in vivo. A poly(D,L-lactide-co-glycolide) (PLGA) inner core, a polyethylene glycol (PEG) modification, and a TATm peptide were simultaneously introduced to mediate tumor tissue targeting and response to pH-triggered TmSm release. Compared to free TmSm, the PEGylated-PLGA nanoparticle platform achieved a significantly higher cellular uptake efficiency (1.79-fold for A549 and 1.77-fold for Capan-2), effectively decreased IC50 (1.22-fold for A549 and 1.17-fold for Capan-2), and largely elevated apoptosis in different cancer cells (1.17-fold for A549 and 1.15-fold for Capan-2). Besides, this newly developed nanoplatform showed increased protein drug accumulation in the tumor site in A549-bearing nude mice and reached a tumor inhibition rate of 55.81% (1.35-fold versus free TmSm) by reducing the expression of intracellular survivin. All these results confirmed that our newly developed delivery strategy is a very promising tool, which helps protein drugs to cross multiple barriers in vivo and achieves precise targeting to intracellular biomarkers. This strategy could also be applied to other types of protein drugs to further improve their clinical anticancer therapeutic efficacy.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Wenqiang Xue,Jinglei Du,Yingying Wei,Shizhao Zhou,Shicai Wang,Yongzhen Yang,Lin Chen,Shiping Yu
Background Small interfering RNA (siRNA) provides a new method for anti-tumor therapy by targeting Survivin gene in liver cancer. However, free Survivin siRNA is easily degraded and cleared by endonucleases or macrophages in the blood circulation. Therefore, it is urgent to construct a safe and efficient delivery system to achieve effective transfection of Survivin siRNA.Methods In this study, cationic carbon dots (CCDs) with active targeting ability (FA-PEI-CDs) were designed and prepared using carbon dots (CDs), polyethyleneimine (PEI), and folic acid (FA). Then, Survivin siRNA was loaded by electrostatic adsorption to design a gene-loaded complex with gene silencing effect (FA-PEI-CDs@Survivin siRNA).Results As FA-PEI-CDs had good dispersibility, an average diameter of about 21.71 nm and a zeta potential of 5.11 mV. They had good proton buffering capacity and excellent biocompatibility and could not cause erythrocyte hemolysis and thrombosis. When FA-PEI-CDs were mixed with Survivin siRNA at a mass ratio of 2:1, they can completely load siRNA without being interfered by polyanion in vivo and avoid the degradation of siRNA by serum or intracellular nuclease, which significantly increased the circulation time of siRNA in blood. Meantime, when the mass ratio of FA-PEI-CDs to Survivin siRNA was 3:1, the maximum transfection efficiency was 22.8% and 28.5% in HL-7702 cells and HepG2 cells, respectively. In vitro cell experiments confirmed that the gene complex can specifically kill tumor cells without damaging normal liver cells. In vivo tumor inhibition experiments further confirmed that FA-PEI-CDs@Survivin siRNA can cause tumor cell necrosis and reduce the expression of Survivin protein.Conclusion In summary, FA-PEI-CDs can carry Survivin siRNA to achieve tumor gene silencing therapy, which will expand the treatment of liver cancer and provide a new idea for carbon nanomaterials in biological genetic engineering.
研究领域:
医学
·
遗传学
·
纳米材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Zhongjuan Wang,Haijuan Zou,Zirui Wang,Jiamin Wu,Zhongsheng Xia,Min Feng
RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150 mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin . Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.
研究领域:
药学
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2021
·Vol. 21
·期 9
·795-805
·
IF 2.222
Yang Feng,Chun Liu-Fu,Chen Zhi-Yi
Background: Non-viral delivery systems is a promising method for gene or drug delivery. Polyethyleneimine (PEI) is a double-edged sword. It internalizes itself into the cell through endocytosis and promotes gene transfer efficiency. However, the strong positive charge also makes PEI
highly toxic to cells. Ultrasound-targeted microbubble destruction (UTMD) is a promising non-viral method for gene and drug delivery, but its efficiency still needs to be improved. Objective: The aim of this study was to explore a system that combines ultrasound with non-viral gene delivery
for the treatment of cervical cancer HeLa cells. Methods: In this study, we synthesized a kind of cationic ultrasound contrast agent(CUCA) that the physical and chemical properties, gene carrying capacity and cytotoxicity were verified. On the basis of previous studies, we further optimized
the following transfusion parameters including ultrasound parameters, microbubble concentration, plasmid concentration, cell density and other parameters. The experiment was designed to compare the following six groups: (1) Plasmid group (P group), plasmid 15 μg; (2) PEI + plasmid group
(PEI + P group),1 μl of PEI containing 10 nmol nitrogen and 1 μg of DNA containing 3 nmol phosphate for a PEI/DNA ratio equal to a nitrogen/phosphate ratio of 7 for transfection; (3) Ultrasound + plasmid group (US + P), plasmid 15 μg; (4) Ultrasound + cationic liposomal ultrasound
contrast agent + plasmid group (UTMD + P group), plasmid 15 μg and cationic liposomal ultrasound contrast agent 5%; (5) Ultrasound + cationic liposomal ultrasound contrast agent + PEI + plasmid group (UTMD + PEI + P group), PEI/DNA ratio equal to a nitrogen/phosphate ratio of 7 for transfection
and cationic liposomal ultrasound contrast agent 5%; and (6) Blank group, no treatment), The influence on Hela cells was observed under microscope, the efficiency of apoptosis was measured by flow cytometry, and cell viability was tested in CCK 8. Results: The optimized transfection parameters
can improve the transfection efficiency of ultrasound combined with C-UCA to a certain extent, but its transfection efficiency is still lower than that of branched polyethyleneimine (bPEI) 25 kDa. By investigating the effect of HeLa cells apoptosis induced by UTMD in combination with PEI mediated
survivin miRNA, we found that both PEI alone and ultrasound in combination with CUCA were able to transfect cells with survivin miRNA to effectively induce HeLa cell apoptosis. However, the synergistic effect between the two methods was not significant. Conclusion: In contrast, the combined
use of ultrasound, C-UCA and PEI may significantly reduce the transfection efficiency of UTMD and PEI, and the specific mechanism remains to be further studied.
研究领域:
肿瘤学
·
医学超声
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Jing Zhang,Min Zha,Shanghua Xiao,Nina Filipczak,Satya Siva Kishan Yalamarty,Xiangping Wu,Chenkai Gong,Xiang Li
Objective Nanoparticles constructed with silver/manganese dioxide (Ag@MnO2) as the core, in conjunction with survivin siRNA (sis) and cyclo(RGD-DPhe-K) (Ag@MnO2-sis-c-L), were prepared for integrated tumor diagnosis and therapy.Methods Ag@MnO2-sis-c-L particles were prepared and characterized. The silver and manganese content were determined by inductively coupled plasma optical emission spectroscopy (ICP-OES). The stability of sis in the system was evaluated by incubation with 50% FBS before the agarose gel electrophoresis experiment. The in vitro photothermal conversion ability, cytotoxicity to 4T1 cells, and cellular uptake of preparations were evaluated. The dialysis technique was employed to determine the in vitro release profile of Ag and Mn from Ag@MnO2-sis-c-L under various pH conditions. The pharmacokinetic behavior and tissue distribution of silver in vivo were detected by ICP-OES. Animal model experiments were conducted to further evaluate the anti-tumor efficacy of Ag@MnO2-sis-c-L against breast cancer in combination with infrared irradiation.Results Our newly synthesized Ag@MnO2-sis-c-L nanoparticles displayed superior physicochemical properties. The combined application of these nanoparticles with photothermal therapy (PTT) exerted the strongest synergistic inhibitory effects on tumor growth. Survivin protein expression in tumor tissues were markedly suppressed following delivery of nanoparticles loaded with sis. Additionally, magnetic resonance imaging revealed the high imaging capability of hybrid nanoparticles.Conclusion This study supports the potential utility of Ag@MnO2-sis-c-L coupled with PTT in therapeutic and diagnostic imaging applications.
研究领域:
纳米医学
·
肿瘤学
·
生物材料
·
分子影像学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2017
·
IF 4.811
Suhui Ni,Yun Liu,Yue Tang,Jing Chen,Shuhan Li,Ji Pu,Lidong Han
The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABA B receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABA B receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABA B receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39 ± 2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment.
研究领域:
药学科学
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纳米技术
·
分子生物学
·
药物递送系统
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Guo Wei,Ma Xingyuan,Fu Yunhui,Liu Chang,Liu Qiuli,Hu Fabiao,Miao Hui,Zhang Tong,Liu Yuping,Han Myong Hun,You Fang,Yang Yi,Zheng Wenyun
Survivin as a member of the inhibitor of apoptosis proteins (IAPs) family is undetectable in normal cells, but highly expressed in cancer cells and cancer stem cells (CSCs) which makes it an attractive target in cancer therapy. Survivin dominant negative mutants have been reported as competitive inhibitors of endogenous survivin protein in cancer cells. However, there is a lack of systematic comparative studies on which mutants have stronger effect on promoting apoptosis in cancer cells, which will hinder the development of novel anti-cancer drugs. Here, based on the previous study of survivin and its analysis of the relationship between structure and function, we designed and constructed a series of different amino acid mutants from survivin (TmSm34, TmSm48, TmSm84, TmSm34/48, TmSm34/84, and TmSm34/48/84) fused cell-permeable peptide TATm at the N-terminus, and a dominant negative mutant TmSm34/84 with stronger pro-apoptotic activity was selected and evaluated systematically in vitro. The double-site mutant of survivin (TmSm34/84) showed more robust pro-apoptotic activity against A549 cells than others, and could reverse the resistance of A549 CSCs to adriamycin (ADM) (reversal index up to 7.01) by decreasing the expression levels of survivin, P-gp, and Bcl-2 while increasing cleaved caspase-3 in CSCs. This study indicated the selected survivin dominant negative mutant TmSm34/84 is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells and sensitizing chemotherapeutic drugs.
研究领域:
肿瘤学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL RESEARCH
·
2017
·Vol. 34
·期 12
·2829-2841
·
IF 3.002
Li Zhengxiong,Zhang Linlin,Tang Cui,Yin Chunhua
Purpose The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. Methods Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes. The nanoparticles were assessed by structural characterization, drug loading and release, cellular uptake, intracellular distribution, gene transfection, in vitro anti-proliferation of hepatoma cells, and in vivo tumor growth inhibition in H-22 tumor bearing mice. Results SL-IDMSN showed high loading capacity for both DOX and iSur-pDNA due to their hierarchical mesostructures. The cleavage of Schiff-base linkage on SL-IDMSN in the weakly acidic endosomes/lysosomes led to microenvironment-specific release of both DOX and iSur-pDNA. Meanwhile, the imidazole modification could trigger the efficient endosomal escape via proton sponge effect, thereby enhancing nuclear accumulation of iSur-pDNA and gene silencing efficiency. More importantly, these superior performances of SL-IDMSN resulted in their improved inhibitory effects on in vitro cancer cell proliferation and in vivo tumor growth. Conclusions SL-IDMSN is a microenvironment-sensitive and biocompatible nanocarrier for the co-delivery of DOX and iSur-pDNA, which might be a promising carrier for co-delivery of chemotherapeutic drugs and gene drugs for synergistic cancer therapy.
研究领域:
纳米技术
·
药学
·
癌症研究
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Huiying Chen,Xuefeng Fan,Yinan Zhao,Defu Zhi,Shaohui Cui,Enxia Zhang,Haoming Lan,Jianjun Du,Zhen Zhang,Shubiao Zhang,Yuhong Zhen
Silencing the inhibitor of apoptosis (IAP) by RNAi is a promising method for tumor therapy. One of the major challenges lies in how to sequentially overcome the system barriers in the course of the tumor targeting delivery, especially in the tumor accumulation and penetration. Herein we developed a novel stimuli-responsive polysaccharide enveloped liposome carrier, which was constructed by layer-by-layer depositing redox-sensitive amphiphilic chitosan (CS) and hyaluronic acid (HA) onto the liposome and then loading IAP inhibitor survivin-shRNA gene and permeation promoter hyaluronidase (HAase) sequentially. The as-prepared HA/HAase/CS/liposome/shRNA (HCLR) nanocarrier was verified to be stable in blood circulation due to the negative charged HA shield. The tumor targeting recognition and the enhanced tumor accumulation of HCLR were visualized by fluorescence resonance energy transfer (FRET) and in vivo fluorescence biodistribution. The deshielding of HA and the protonizing of CS in slightly acidic tumor extracellular pH environment (pHe, 6.8–6.5) were demonstrated by ζ potential change from −23.1 to 29.9 mV. The pHe-responsive HAase release was confirmed in the tumor extracellular mimicking environments, and the intratumoral biodistribution showed that the tumor penetration of HCLR was improved. The cell uptake of HCLR in pHe environment was significantly enhanced compared with that in physiological pH environment. The increased shRNA release of HCLR was approved in 10 mM glutathione (GSH) and tumor cells. Surprisingly, HCLR suppressed the tumor growth markedly through survivin silencing and meanwhile maintained low toxicity to mice. This study indicates that the novel polysaccharide enveloped HCLR is promising in clinical translation, thanks to the stimuli-triggered tumor accumulation, tumor penetration, cell uptake, and intracellular gene release.
研究领域:
药学
·
生物技术
·
癌症研究
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2025
·
IF 7.7
Zhiren Zhou,Lina Zou,Ping Zhang,Chunmei Li,Ye Zhu,Huanyu Ren,Zheng Li,Huiru Niu,Hao Liao,Xiaojing Zhang,Shanshan An,Fei Ren,Xiuhong Ge,Lang Cheng,Feiyan Yang,Hongzhi Pan,Shengzhong Rong,Dong Chang,Hongkun Ma
Survivin serves as a crucial biomarker for bladder cancer, so exploring the detection method is essential. Therefore, a sensitive ratiometric electrochemical immunosensor was developed. In brief, a double-layered amino graphene oxide (NH 2 -GO) sandwich enhanced by Fe-Ni@Ti 3 C 2 T x (NH 2 -GO/Fe-Ni@Ti 3 C 2 T x /NH 2 -GO) significantly amplified the detection signal. ferrocene@Au nanoparticles (Fc@AuNPs) provided a reference signal, and Ab 1 was anchored via an Au-N bond. Moreover, AuPt-methylene blue (AuPt-MB) served not only as a secondary signal but also anchored Ab 2 through Au-NH 2 and Pt-NH 2 bonds. Black phosphorus nanoplates (BPNPs) improved conductivity and provided additional binding sites for AuPt-MB. The immunosensor exhibited a broad detection range (0.001~1000 ng/mL) and a low detection limit (0.00065 ng/mL), facilitating successful survivin detection in human urine samples with promising clinical analysis applications.
研究领域:
生物医学工程
·
分析化学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Cell and Developmental Biology
·
2022
·
IF 6.081
Deng Changping,Hu Fabiao,Zhao Zhangting,Zhou Yiwen,Liu Yuping,Zhang Tong,Li Shihui,Zheng Wenyun,Zhang Wenliang,Wang Tianwen,Ma Xingyuan
Quantitative analysis and regulating gene expression in cancer cells is an innovative method to study key genes in tumors, which conduces to analyze the biological function of the specific gene. In this study, we found the expression levels of Survivin protein (BIRC5) and P-glycoprotein (MDR1) in MCF-7/doxorubicin (DOX) cells (drug-resistant cells) were significantly higher than MCF-7 cells (wild-type cells). In order to explore the specific functions of BIRC5 gene in multi-drug resistance (MDR), a CRISPR/Cas9-mediated knocking-in tetracycline (Tet)-off regulatory system cell line was established, which enabled us to regulate the expression levels of Survivin quantitatively (clone 8 named MCF-7/Survivin was selected for further studies). Subsequently, the determination results of doxycycline-induced DOX efflux in MCF-7/Survivin cells implied that Survivin expression level was opposite to DOX accumulation in the cells. For example, when Survivin expression was down-regulated, DOX accumulation inside the MCF-7/Survivin cells was up-regulated, inducing strong apoptosis of cells (reversal index 118.07) by weakening the release of intracellular drug from MCF-7/Survivin cells. Also, down-regulation of Survivin resulted in reduced phosphorylation of PI3K, Akt, and mTOR in MCF-7/Survivin cells and significantly decreased P-gp expression. Previous studies had shown that PI3K/Akt/mTOR could regulate P-gp expression. Therefore, we speculated that Survivin might affect the expression of P-gp through PI3K/Akt/mTOR pathway. In summary, this quantitative method is not only valuable for studying the gene itself, but also can better analyze the biological phenomena related to it.
研究领域:
癌症生物学
·
分子生物学
·
基因工程
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2014
·Vol. 2
·期 44
·7756-7764
·
IF 0
Jiang Wu,Ying Liu,Wei Li,Chunyan Wang,Yanjun Li,Ying Tian,Jing Sun,Shouju Wang,Xin Wang,Yuxia Tang,Hong Zhu,Zhaogang Teng,Guangming Lu
Small interfering RNA (siRNA) has great potential for gene therapy of breast cancer. The development of multifunctional nanocarriers possessing the targeted ability and multimodal imaging function is important to increase siRNA transfection efficiency and to visualize the delivery events. Herein, we demonstrate flavin mononucleotide (FMN) and polyethylenimine (PEI) modified Fe3O4@mTiO2 nanoparticles (Fe3O4@mTiO2/FMN-PEI) as novel magnetic fluorescent siRNA delivery systems. The system has magnetic targeting, magnetic resonance imaging (MRI), optical imaging, and high siRNA binding ability. Survivin-siRNA delivered by this system can effectively enter into MCF-7 cells, which can be further enhanced by exerting an external magnetic field. More importantly, the siRNA delivery events including the location, trafficking, distribution, and release, can be visualized by MRI and optical imaging. Gene silencing by survivin-siRNA can cause significant protein knockdown (96%) and considerable cell apoptosis (30%), indicating the usefulness of Fe3O4@mTiO2/FMN-PEI as a siRNA delivery system.
研究领域:
癌症研究
·
基因治疗
·
纳米技术
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
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