Oncotarget
·
2016
·
IF 5.008
Tao Liu,Xidong Wu,Yigang Wang,Tao Zhang,Ting Wu,Fang Liu,Wansong Wang,Gang Jiang,Minqiang Xie
The co-delivery of drug and gene has become the primary strategy in cancer therapy. Based on our previous work, to co-deliver docetaxel (DOC) and MMP-9 siRNA more efficiently for HNE-1 nasopharyngeal carcinoma therapy, a folate-modified star-shaped copolymer (FA-CD-PLLD) consisting of β-cyclodextrin (CD) and poly(L-lysine) dendron (PLLD) was synthesized, and then used for DOC and MMP-9 co-delivery. Different from commonly used amphiphilic copolymers micelles, the obtained CD derivative could be used directly for the combinatorial delivery of nucleic acid and hydrophobic DOC without a complicated micellization process. In vitro and in vivo assays are carried out to confirm the effectiveness of the target strategy and combined treatment. It was found that the conjugation of CD-PLLD with FA could enhance the DOC/MMP-9 delivery effect obviously, inducing a more significant apoptosis and decreasing invasive capacity of HEN-1 cells. In vivo assays showed that FA-CD-PLLD/DOC/MMP-9 could inhibit HNE-1 tumor growth and decrease PCNA expression effectively, indicating a promising strategy for nasopharyngeal carcinoma therapy. Moreover, the in vivo distribution of DOC and MMP-9, blood compatibility and toxicity are also explored.
研究领域:
药剂学
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2018
·
IF 4.485
Zheru Long,Yan-Ping Wu,Hua-Ying Gao,Yi-Fang Li,Rong-Rong He,Mingxian Liu
Here, polyamidoamine grafted halloysite nanotubes (PAMAM-g-HNTs) were synthesized for loading of siRNA in order to intracellular delivery of siRNA and treat of breast cancer via gene therapy. The successful grafting of PAMAM on HNTs was confirmed by various analytical methods. The size, zeta potential, and grafting ratio of PAMAM-g-HNTs is ∼206.2 nm, +19.8 mV, and 3.04%, respectively. PAMAM-g-HNTs showed good cytocompatibility toward HUVECs (84.7%) and MCF-7 cells (82.3%) even at high concentration of 100 μg/mL. PAMAM-g-HNTs/siRNA exhibited enhanced cellular uptake efficiency of 94.3% compared with Lipofectamine 2000 (Lipo2000)/siRNA (83.6%). PAMAM-g-HNTs/small interfering RNA-vascular endothelial growth factor (siVEGF) led to 78.0% knockdown of cellular VEGF mRNA and induced 33.6% apoptosis in the MCF-7 cells, which is also much higher than that of Lipo2000/siVEGF. In vivo anti-cancer results demonstrated that PAMAM-g-HNTs/siVEGF treated 4T1-bearing mice showed enhanced anti-cancer efficacy than Lipo2000/siVEGF group. Also, the nanocarrier system showed negligible toxic effects toward the major organs of mice. In vivo fluorescence imaging studies showed that there is a slight decrease in the fluorescence signal of PAMAM-g-HNTs/cy5-siVEGF after 72 h post-injection. Therefore, PAMAM-g-HNTs show promising application as novel nanovectors for siRNA delivery and gene therapy of cancer.
研究领域:
纳米医学
·
肿瘤学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 6
·期 7
·1986-1993
·
IF 5.831
Wenxin Zhang,Yang Zhou,Xudong Li,Xin Xu,Yongbing Chen,Rongying Zhu,Lichen Yin
As one of the intractable challenges in the clinic, the treatment of acute liver failure (ALF) is limited due to high mortality and resource cost. RNA interference (RNAi) provides a new modality for the anti-inflammatory therapy of ALF, while its therapeutic efficacy is greatly hampered by the lack of effective carriers to cooperatively overcome the various systemic barriers. Herein, we developed macrophage-targeting and reactive oxygen species (ROS)-responsive polyplexes to enable efficient systemic delivery of TNF-α siRNA (siTNF-α) to attenuate hepatic inflammation in mice bearing ALF. Se-PEI, obtained from the cross-linking of 600 Da polyethylenimine (PEI) via the ROS-responsive diselenide bond, was developed to condense siTNF-α, and the obtained polyplexes were further coated with carboxylated mannan (Man-COOH). Man-COOH coating allowed active targeting of polyplexes to macrophages with over-expressed mannose receptors (MRs), and it shielded the surface positive charges to enhance the serum stability of polyplexes. Se-PEI could be degraded by ROS in inflammatory macrophages to promote intracellular siRNA release to potentiate the gene knockdown efficiency, and in the meantime reduce the material cytotoxicity associated with high molecular weight. As such, i.v. injected Man-COOH/Se-PEI/siTNF-α polyplexes afforded notable TNF-α silencing by ∼80% in inflamed liver tissues at 500 μg siRNA per kg, and notably reduced serum TNF-α levels to achieve potent anti-inflammatory performance against ALF.
研究领域:
药理学
·
纳米技术
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 23
·6791-6803
·
IF 7.59
Yandong Xie,Xueying Lu,Zhen Wang,Mingxi Liu,Liang Liu,Ran Wang,Kun Yang,Hong Xiao,Jianyong Li,Xianglong Tang,Hongyi Liu
Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood–brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.
研究领域:
肿瘤学
·
纳米技术
·
药理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2013
·
IF 5.371
Yuefang Zhao,Yuting Qin,Yang Liang,Haijuan Zou,Xiao Peng,Huan Huang,Ming Lu,Min Feng
Short interfering RNAs (siRNAs) as chemotherapeutic RNAi agents hold great promise for a significant improvement in cancer therapy. Despite the promise, effective transport of siRNA with minimal side effects remains a challenge. The common problem associated with the low delivery efficiencies of current polycation-based gene delivery systems is their low stability in the presence of salt and serum. In the present study we developed the polyglutamate derivatives (PGS) polyelectrolyte brushes for NF-κB p65 siRNA delivery. The PGS polyelectrolyte brushes/siRNA polyplex was colloidally stable (150 nm diameter) in physiological saline (150 mM NaCl), likely due to the osmotic brushes of PGS. The size-controlled siRNA/PGS polyplex also showed the serum resistance resulting in their efficient cellular uptake was not negatively influenced by the presence of serum. The endothermic profile of ITC, their low values of Gibbs free energy and binding constants Kb under salt conditions provided the direct evidence that PGS polyelectrolyte brushes had a much lower binding affinity for serum proteins, compared with PEI 25KDa. PGS polyelectrolyte brushes delivering NF-κB p65 siRNA achieved efficient down-regulation of NF-κB p65 protein in HeLa cells. The NF-κB p65 down-regulation mediated by PGS polyelectrolyte brushes was more significant than PEI 25KDa and comparable to Lipofectamine 2000. Furthermore, the combination treatment with PGS polyelectrolyte brushes/NF-κB p65 siRNA polyplex and doxorubicin demonstrated synergistic apoptotic and cytotoxic effects on HeLa cancer cells. The high stability in physiological saline and salt-induced serum resistance of PGS polyelectrolyte brushes/siRNA polyplex has potential applications together with standard chemotherapies such as doxorubicin to be a viable method to improve the clinical outcomes in cancer therapies.
研究领域:
生物医学工程
·
药剂学
·
癌症研究
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-11
·
IF 5.228
Liu Hongmei,Chang Hong,Lv Jia,Jiang Cong,Li Zhenxi,Wang Fei,Wang Hui,Wang Mingming,Liu Chongyi,Wang Xinyu,Shao Naimin,He Bingwei,Shen Wanwan,Zhang Qiang,Cheng Yiyun
Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers.
研究领域:
药学
·
分子生物学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Tongyi Shang,Xinying Yu,Yuan Gu,Rong Du,Yanjun Cai,Yuwei Li,Guodong Zheng,Chaoqun Wang,Jian Zhang,Jifang Liu,Shisong Han,Bin Yang
Cancer immunotherapy is the most promising method for tumor therapy in recent years, among which the macrophages play a critical role in the antitumor immune response. However, tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumor-killing M1 phenotype. Moreover, the over-expressed CD47 on tumor cells severely hinders the function of macrophages by blocking the CD47/SIRPα pathway. Herein, a nano-assembly system of CHTR/siRNA was constructed through the host-guest interaction of a hyperbranched amino-functionalized β-cyclodextrin and immune agonist imiquimod (R848), while CD47 siRNA was loaded inside through electrostatic interaction. The Toll-like receptor (TLR) 7/8 agonist R848 can “re-educate” macrophages from the protumoral M2 phenotype to antitumoral M1 phenotype, while CD47 siRNA can down-regulate the “don't eat me” CD47 signal on the surface of cancer cells and enhance the phagocytosis of cancer cells by macrophages. Through the dual regulation of TAMs, the immunosuppressive tumor microenvironment was relieved, and the host-guest drug-carrying system resulted in synergistic immunotherapy effect on tumors and inhibited tumor growth. The facile self-assembly of nanodrug offers a new strategy in co-delivery of multiple therapeutic agents for cascade cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Yan Zhang,Qin LiMiao,Feng MengFan,Xianghui Yu,Yuqing Wu
Small interfering RNA (siRNA), comprising 21-23 nucleotides, functions by complementary binding to specific mRNA sequences, thereby suppressing target protein expression. Despite their vast potential in disease therapy, siRNAs face challenges due to their susceptibility to degradation and high electronegativity, rendering them unstable in the bloodstream and impeding their passage across endothelial barriers. Moreover, successful intracellular delivery necessitates overcoming endosomal entrapment, posing a significant hurdle for carrier material development. In this study, leveraging the strong affinity of histidine oligomers (His6) for metal ions, we engineered nanoparticles (HmA) by gentle assembly with divalent zinc ions under pH=8 conditions. We designed the RNA-binding functional peptide L2-NTD to enhance siRNA stability and delivery efficiency when complexed with HmA. The resulting siRNA+L2-NTD@HmA nanoparticles were formed via in situ encapsulation, ensuring efficient siRNA delivery into cells with minimal cytotoxicity and degradation. This approach presents a novel strategy for the design and artificial fabrication of carriers for effective RNA delivery.
研究领域:
分子生物学
·
药物递送
·
纳米医学
✓ 已验证
产品关联
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
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2020
·
IF 4.389
Yuxuan Qi,Yiwen Pan,Feng Gu,Shuai Wei,Chenglong Fei,Jingfen Han
RNA interference technology is a powerful tool with substantially clinical prospects for carcinoma therapy, in which efficiency and specificity of delivery of dsRNA remains a critical issue. Herein, aiming at delivery of dsRNA in efficient and safe way, we constructed targeting delivery platform (CTL-PEG-FA) by grafting curdlan with trilysine through click reaction, then modifying with PEG linked folic acid. The CTL-PEG-FA vector exhibited excellent gene binding capacity to condense siRNA and dramatically reduced cytotoxicity. Increased cell uptake of CTL-PEG-FA/Bcl-2 siRNA was achieved by the synergism of folate mediated endocytosis and charge interaction, and further causing severe HepG2 cells injury through apoptosis mechanism after down-regulation of Bcl-2 protein. In vivo experiments, CTL-PEG-FA/Bcl-2 siRNA complex distinctly accumulated in tumor site and significantly inhibited the growth of tumor, while no obvious toxicity was observed. Therefore, well-performed CTL-PEG-FA with excellent biocompatibility, has the potential to be the candidate of gene therapy for clinical applications.
研究领域:
生物技术
·
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Ruiying Zhang,Hanfeng Li,Tong Zhang,Bing Zhang,Yihu Wang,Yanchuan Guo
Addressing the underappreciated critical role of angiogenesis and immune dysregulation in keloid formation, we developed a novel nanocarrier (PCS) based on a dual network of physical cross-linking for the efficient release of siTGF-β1 and chlorogenic acid. PCS was self-assembled from polyethylenimine/siTGF-β1 and chlorogenic acid-embedded polylysine/sodium alginate. The results demonstrated that PCS could inhibit the proliferation, induce apoptosis of human umbilical vein endothelial cells and human keloid fibroblasts by regulating their cell cycle, and improve the immune microenvironment at the lesion. By transcriptomics and network pharmacology analysis, PCS inhibited keloid development mainly through the TGF-β1/EGR1 signaling pathway. The final results of animal experiments also proved that the material exerted a favorable effect in keloid treatment. Overall, PCS, as a novel nanocarrier combining siRNA-based gene therapy with chlorogenic acid, was a promising approach for the treatment of keloids.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Yongzhi Cui,Yuanyuan Guo,Li Kong,Jingyu Shi,Ping Liu,Rui Li,Yongtao Geng,Weihang Gao,Zhiping Zhang,Dehao Fu
The complex pathogenesis of osteoporosis includes excessive bone resorption, insufficient bone formation and inadequate vascularization, a combination which is difficult to completely address with conventional therapies. Engineered exosomes carrying curative molecules show promise as alternative osteoporosis therapies, but depend on specifically-functionalized vesicles and appropriate engineering strategies. Here, we developed an exosome delivery system based on exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs). The engineered exosomes BT-Exo-si Shn3 , took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the Shn3 gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-si Shn3 an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic Shn3 gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, Shn3 gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-si Shn3 could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.
研究领域:
生物技术
·
药学
·
干细胞研究
·
分子生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）