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Harnessing the RNA interference pathway to advance treatment and prevention of hepatocellular carcinoma 被引量:14
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作者 Patrick Arbuthnot Liam Jed Thompson 《World Journal of Gastroenterology》 SCIE CAS CSCD 2008年第11期1670-1681,共12页
Primary liver cancer is the fifth most common malignan- cy in the world and is a leading cause of cancer-related mortality.Available treatment for hepatocellular carcino- ma(HCC),the commonest primary liver cancer,is ... Primary liver cancer is the fifth most common malignan- cy in the world and is a leading cause of cancer-related mortality.Available treatment for hepatocellular carcino- ma(HCC),the commonest primary liver cancer,is rarely curative and there is a need to develop therapy that is more effective.Specific and powerful gene silencing that can be achieved by activating RNA interference(RNAi) has generated enthusiasm for exploiting this pathway for HCC therapy.Many studies have been carried out with the aim of silencing HCC-related cellular oncogenes or the hepatocarcinogenic hepatitis B virus(HBV)and hepatitis C virus(HCV).Proof of principle studies have demonstrated promising results,and an early clinical trial assessing RNAi-based HBV therapy is currently in progress.Although the data augur well,there are several significant hurdles that need to be overcome before the goal of RNAi-based therapy for HCC is realized.Particu- larly important are the efficient and safe delivery of RNAi effecters to target malignant tissue and the limitation of unintended harmful non-specific effects. 展开更多
关键词 RNA interference Hepatocellular carcinoma Hepatitis B virus Hepatitis C virus Molecular pathogenesis delivery vectors
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Improving gene transfection efficiency of highly branched poly(β-amino ester)s through the in-situ conversion of inactive terminal groups
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作者 Zhili Li Qijun Wo +3 位作者 Dongdong Huang Dezhong Zhou Lei Guo Yeqing Mao 《Chinese Chemical Letters》 SCIE CAS CSCD 2024年第8期304-308,共5页
Highly branched poly(β-amino ester)s(HPAEs)have emerged as a safe and efficient type of non-viral gene delivery vectors.However,the presence of inactive terminal secondary amine groups compromises their gene transfec... Highly branched poly(β-amino ester)s(HPAEs)have emerged as a safe and efficient type of non-viral gene delivery vectors.However,the presence of inactive terminal secondary amine groups compromises their gene transfection capability.In this study,HPAEs with similar topological structures and chemical compositions but varying numbers of terminal secondary 4-amino-1-butanol(S4)and secondary/tertiary 3-morpholinopropylamine(MPA)groups were synthesized.The results demonstrate that an increased number of secondary/tertiary MPA groups in-situ significantly enhances the DNA binding capability of HPAEs,leading to the formation of smaller HPAE/DNA polyplexes with higher zeta potential,ultimately resulting in superior gene transfection efficiency in bladder epithelial cells.This study establishes a sim-ple yet effective strategy to maximize the gene transfection potency of HPAEs by converting the inactive terminal groups in-situ without the need for complex modifications to their topological structure and chemical composition. 展开更多
关键词 Gene therapy Gene delivery vector Highly branched poly(β-amino ester)s Terminal groups Epithelial cells
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Recent advances in polymeric biomaterials-based gene delivery for cartilage repair 被引量:5
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作者 Ran Yang Fei Chen +2 位作者 Jinshan Guo Dongfang Zhou Shifang Luan 《Bioactive Materials》 SCIE 2020年第4期990-1003,共14页
Untreated articular cartilage damage normally results in osteoarthritis and even disability that affects millions of people.However,both the existing surgical treatment and tissue engineering approaches are unable to ... Untreated articular cartilage damage normally results in osteoarthritis and even disability that affects millions of people.However,both the existing surgical treatment and tissue engineering approaches are unable to regenerate the original structures of articular cartilage durably,and new strategies for integrative cartilage repair are needed.Gene therapy provides local production of therapeutic factors,especially guided by biomaterials can minimize the diffusion and loss of the genes or gene complexes,achieve accurate spatiotemporally release of gene products,thus provideing long-term treatment for cartilage repair.The widespread application of gene therapy requires the development of safe and effective gene delivery vectors and supportive gene-activated matrices.Among them,polymeric biomaterials are particularly attractive due to their tunable physiochemical properties,as well as excellent adaptive performance.This paper reviews the recent advances in polymeric biomaterial-guided gene delivery for cartilage repair,with an emphasis on the important role of polymeric biomaterials in delivery systems. 展开更多
关键词 Cartilage repair Gene therapy Polymeric biomaterials delivery vectors Gene-activated matrices
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mRNA cancer vaccines:Advances,trends and challenges 被引量:14
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作者 Qing He Hua Gao +2 位作者 Dejiang Tan Heng Zhang Jun-zhi Wang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2022年第7期2969-2989,共21页
Patients exhibit good tolerance to messenger ribonucleic acid(m RNA)vaccines,and the choice of encoded molecules is flexible and diverse.These vaccines can be engineered to express full-length antigens containing mult... Patients exhibit good tolerance to messenger ribonucleic acid(m RNA)vaccines,and the choice of encoded molecules is flexible and diverse.These vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex(MHC)restriction,are relatively easy to control and can be rapidly mass produced.In 2021,the U.S.Food and Drug Administration(FDA)approved the first m RNA-based coronavirus disease 2019(COVID-19)vaccine produced by Pfizer and Bio NTech,which has generated enthusiasm for m RNA vaccine research and development.Based on the above characteristics and the development of m RNA vaccines,m RNA cancer vaccines have become a research hotspot and have undergone rapid development,especially in the last five years.This review analyzes the advances in m RNA cancer vaccines from various perspectives,including the selection and expression of antigens/targets,the application of vectors and adjuvants,different administration routes,and preclinical evaluation,to reflect the trends and challenges associated with these vaccines. 展开更多
关键词 MRNA Cancer vaccine Tumor-associated antigens Neoantigens mRNA delivery vectors ADJUVANTS Administration routes
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Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model
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作者 Jian Guan Mingyang Liu +9 位作者 Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo 《Journal of Bio-X Research》 2022年第4期181-196,共16页
Objective: To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugatedlet-7a mimics(Chol-let-7a) and control mimics(Chol-miRCtrl) on hepatocellular carcinomain vivo.Metho... Objective: To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugatedlet-7a mimics(Chol-let-7a) and control mimics(Chol-miRCtrl) on hepatocellular carcinomain vivo.Methods: The antitumor effects of two intravenous dosing regimens ofChol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in theChol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then,let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution ofChol-let-7a andChol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital.Results: Continuous treatment withChol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in theChol-miRCtrl and blank xenograft group (P < 0.01 andP < 0.01, respectively), while intermittent dosing withChol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in theChol-miRCtrl and the blank control group, respectively (P < 0.05 andP < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosingChol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues;mild hypercellularity with dilated capillary lumens in the renal tissue;and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed thatChol-let-7a andChol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration ofChol-let-7a andChol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in theChol-miRCtrl group. Finally, RT-PCR analysis showed thatlet-7a levels were significantly increased in Chol-let-7a-treated xenografts compared withChol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001);however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively.Conclusions: Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy.Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future. 展开更多
关键词 drug-induced renal injury hepatic toxicity in vivo off target effects let-7 mimics nonviral delivery vector
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Lung gene therapydHow to capture illumination from the light already present in the tunnel 被引量:2
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作者 Emily Xia Manjunatha Ankathatti Munegowda +1 位作者 Huibi Cao Jim Hu 《Genes & Diseases》 SCIE 2014年第1期40-52,共13页
Gene therapy has been considered as the most ideal medical intervention for genetic diseases because it is intended to target the cause of diseases instead of disease symptoms.Availability of techniques for identifica... Gene therapy has been considered as the most ideal medical intervention for genetic diseases because it is intended to target the cause of diseases instead of disease symptoms.Availability of techniques for identification of genetic mutations and for in vitro manipulation of genes makes it practical and attractive.After the initial hype in 1990s and later disappointments in clinical trials formore than a decade,light has finally come into the tunnel in recent years,especially in the field of eye gene therapy where it has taken big strides.Clinical trials in gene therapy for retinal degenerative diseases such as Leber’s congenital amaurosis(LCA)and choroideremia demonstrated clear therapeutic efficacies without apparent side effects.Although these successful examples are still rare and sporadic in the field,they provide the proof of concept for harnessing the power of gene therapy to treat genetic diseases and to modernize our medication.In addition,those success stories illuminate the path for the development of gene therapy treating other genetic diseases.Because of the differences in target organs and cells,distinct barriers to gene delivery exist in gene therapy for each genetic disease.It is not feasible for authors to review the current development in the entire field.Thus,in this article,we will focus onwhatwe can learn from the current success in gene therapy for retinal degenerative diseases to speed up the gene therapy development for lung diseases,such as cystic fibrosis. 展开更多
关键词 Cystic fibrosis Gene therapy Lung diseases vector delivery Animal model
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