Co-reporter:Lingdong Li;Chuanjiang Yu;Jiang Ren;Sujuan Ye;Wenjing Ou;Yu Wang;Weihan Yang;Guoxing Zhong;Xiang Chen;Xiaolan Su;Huashan Shi;Wen Zhu;Lijuan Chen
Journal of Cancer Research and Clinical Oncology 2014 Volume 140( Issue 6) pp:895-907
Publication Date(Web):2014/06/01
DOI:10.1007/s00432-014-1607-5
LKB1 and FUS1 are two kinds of new tumor suppressor genes as well as early-stage genes in lung cancer. Recent studies showed that LKB1 and FUS1 play important roles in lung carcinogenesis process. We hypothesized that combined gene therapy with LKB1 and FUS1 could inhibit lung cancer growth and development synergistically.In this study, two kinds of tumor suppressor genes, LKB1 and FUS1, were constructed in an eukaryotic coexpression plasmid pVITRO2, and then, we evaluated the synergistic effects of the two genes on anticancer activity and explored the relevant molecular mechanisms.We defined coexpression of LKB1 and FUS1 could synergistically inhibited lung cancer cells growth, invasion and migration and induced the cell apoptosis and arrested cell cycle in vitro. Intratumoral administration of liposomes: pVITRO2–LKB1–FUS1 complex (LPs–pVITRO2–LKB1–FUS1) into subcutaneous lung tumor xenograft resulted in more significant inhibition of tumor growth. Furthermore, intravenous injection of LPs–pVITRO2–LKB1–FUS1 into mice bearing experimental A549 lung metastasis demonstrated synergistic decrease in the number of metastatic tumor nodules. Finally, combined treatment with LKB1 and FUS1 prolonged overall survival in lung tumor-bearing mice. Further study showed that the synergistic anti-lung cancer effects of coexpression of LKB1 and FUS1 might be related to upregulation of p-p53, p-AMPK and downregulation of p-mTOR, p-FAK, MMPs, NEDD9, VEGF/R and PDGF/R.Our results suggest that combined therapy with eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes may be a novel and efficient treatment strategy for human lung cancer.
Co-reporter:Miao-Miao Xun, Xue-Chao Zhang, Ji Zhang, Qian-Qian Jiang, Wen-Jing Yi, Wen Zhu and Xiao-Qi Yu
Organic & Biomolecular Chemistry 2013 vol. 11(Issue 7) pp:1242-1250
Publication Date(Web):12 Dec 2012
DOI:10.1039/C2OB27211C
Non-viral gene vectors play an important role in the development of gene therapy. In this report, different hydrophobic chains were introduced into low molecular weight (LMW) PEI-based biodegradable oligomers to form a series of lipopolymers (LPs), and their structure–activity relationships were studied. Results revealed that the nine polymers can condense plasmid DNA well to form nanoparticles with appropriate sizes (120–250 nm) and positive zeta-potentials (+25–40 V). In vitro experiments were carried out and it was found that LP2 showed much higher transfection efficiency both in the presence and in the absence of serum under the polymer/DNA weight ratio of 0.8 in A549 cells.
Co-reporter:Qiang Liu, Qian-Qian Jiang, Wen-Jing Yi, Ji Zhang, Xue-Chao Zhang, Ming-Bo Wu, Yi-Mei Zhang, Wen Zhu, Xiao-Qi Yu
Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 11) pp:3105-3113
Publication Date(Web):1 June 2013
DOI:10.1016/j.bmc.2013.03.048
A series of novel 1,4,7,10-tetraazacyclododecanes (cyclen)-based cationic lipids bearing histidine imidazole group 10a–10e were synthesized. These amphiphilic molecules have different hydrophobic tails (long chain, cholesterol or α-tocopherol) and various type of linking groups (ether, carbamate or ester). These molecules were used as non-viral gene delivery vectors, and their structure–activity relationships were investigated. As expected, the imidazole group could largely improve the buffering capabilities comparing to cyclen. The liposomes formed from 10 and dioleoylphosphatidyl ethanolamine (DOPE) could bind and condense plasmid DNA into nanoparticles with proper size and zeta-potentials. Comparing with Lipofectamine 2000, the formed lipoplexes gave lower transfected cells proportion, but higher fluorescence intensity, indicating their good intracellular delivering ability. Furthermore, results indicate that transfection efficiency of the cationic lipids is influenced by not only the hydrophobic tails but also the linking group. The cyclen-based cationic lipid with α-tocopherol hydrophobic tail and an ester linkage could give the highest transfection efficiency in the presence of serum.
Co-reporter:Shuo Li, Yu Wang, Shan Wang, Ji Zhang, Shi-Fei Wu, Bo-Lin Wang, Wen Zhu, Xiao-Qi Yu
Bioorganic & Medicinal Chemistry 2012 Volume 20(Issue 4) pp:1380-1387
Publication Date(Web):15 February 2012
DOI:10.1016/j.bmc.2012.01.016
Several 1,4,7,10-tetraazacyclododecane (cyclen)-based linear (3a–c) and cross-linked (8a–d) polymers containing biodegradable ester or disulfide bonds were described. These polymeric compounds were prepared by ring-opening polymerization from various diol glycidyl ethers. The molecular weights of the title polymers were measured by GPC. Agarose gel retardation assays showed that these compounds have good DNA-binding ability and can completely retard plasmid DNA (pDNA) at weight ratio of 20 for linear polymers and 1.2 for cross-linked polymers. The degradation of these polymers was confirmed by GPC. The formed polyplexes have appropriate sizes around 400 nm and zeta-potential values about 15–40 mV. The cytotoxicities of 8 assayed by MTT are much lower than that of 25 KDa PEI. In vitro transfection toward A549 and 293 cells showed that the transfection efficiency (TE) of 8c-DNA polyplex is close to that of 25 kDa PEI at 8c/DNA weight ratio of 4. Structure–activity relationships (SAR) of these linear and cross-linked polymers were discussed in their DNA-binding, cytotoxicity, and transfection studies. In addition, in the presence of serum, the TE of 8/DNA polyplexes could be improved by introducing chloroquine or Ca2+ to pretreated cells.
Co-reporter:Qing-Dong Huang;Jiang Ren;Wen-Jing Ou;Yun Fu;Mao-Qiang Cai;Ji Zhang;Xiao-Qi Yu
Chemical Biology & Drug Design 2012 Volume 79( Issue 6) pp:879-887
Publication Date(Web):
DOI:10.1111/j.1747-0285.2012.01355.x
In this study, two novel cationic lipids containing protonated cyclen and quaternary ammonium moieties were designed and synthesized as non-viral gene delivery vectors. The structures of the two lipids differ in their hydrophobic region (cholesterol or diosgenin). Cationic liposomes were easily prepared from the lipids individually or from the mixtures of each cationic lipid and dioleoylphosphatidylethanolamine. Several studies including DLS, gel retardation assay, and ethidium bromide intercalation assay suggest that these amphiphilic molecules are able to bind and compact DNA into nanometer particles which can be used as non-viral gene delivery agents. Our results from in vitro transfection show that in association with dioleoylphosphatidylethanolamine, two cationic lipids can induce effective gene transfection in human embryonic kidney 293 cells, although the gene transfection efficiencies of two cationic lipids were found to be lower than that of lipofectamine 2000TM. Besides, different cytotoxicity was found for two lipoplexes. This study demonstrates that the title cationic lipids have large potential to be efficient non-viral gene vectors.
Co-reporter:W Ou, S Ye, W Yang, Y Wang, Q Ma, C Yu, H Shi, Z Yuan, G Zhong, J Ren, W Zhu and Y Wei
Cancer Gene Therapy 2012 19(7) pp:489-498
Publication Date(Web):May 11, 2012
DOI:10.1038/cgt.2012.18
LKB1 is a novel candidate tumor suppressor gene in lung cancer. In this study, we evaluated the effect of cationic liposomes (LPs)-mediated LKB1 gene (LPs-pVAX-LKB1) on low-dose cisplatin (cis-diamminedichloroplatinum)-mediated antitumor activity in lung cancer, both in vitro and in vivo. Our study demonstrated that cationic LPs-mediated LKB1 gene therapy could sensitize the response of lung cancer cells to cisplatin, and significantly induce apoptosis and inhibit proliferation, invasion and metastasis, compared with control groups. Combined treatment with intratumoral administration of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into subcutaneous A549 lung tumor xenograft resulted in significant (P<0.01) inhibition of tumor growth. Furthermore, combined treatment with intravenous injections of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into mice bearing experimental A549 lung metastasis demonstrated significant (P<0.01) decrease in the number of lung metastatic tumor nodules. Mice life spans of combination treatment group were also dramatically prolonged, compared with controls. Further studies indicated that LKB1-enhancing cisplatin-mediated antitumor effects might be associated with the upregulation of p-p53 and p-JNK, and downregulation of p-mammalian target of rapamycin, matrix metalloproteinase (MMP)-2 and MMP-9. This study suggests that the combination of LKB1 gene therapy with low-dose cisplatin-based chemotherapy may be a potent therapeutic strategy for lung cancer.
Co-reporter:Dr. Qing-Dong Huang;Jiang Ren;Hong Chen;Wen-Jing Ou;Dr. Ji Zhang;Yun Fu;Dr. Wen Zhu;Dr. Xiao-Qi Yu
ChemPlusChem 2012 Volume 77( Issue 7) pp:584-591
Publication Date(Web):
DOI:10.1002/cplu.201200060
Abstract
Two novel cationic lipids based on protonated cyclen and steroid (cholesterol or diosgenin) moieties with carbamate linkage have been designed and synthesized for gene delivery. Cationic liposomes were easily prepared from each of these lipids individually or from the mixtures of each cationic lipid and dioleoylphosphatidyl ethanolamine (DOPE). Several studies including dynamic light scattering, gel retardation assay, ethidium bromide intercalation assay, and transmission electron microscopy (TEM) imaging demonstrate that these amphiphilic molecules are able to bind and compact DNA into nanoparticles which may act as nonviral gene delivery agents. Results from in vitro transfection show that in association with (DOPE), two cationic lipids can induce effective gene transfection in HEK 293, A549, and H460 cells. Especially, in tumor cells (A549 and H460), the gene transfection efficiency of two cationic lipids were found to be higher than that of commercially available Lipofectamine 2000. The lipoplexes formed from both cationic lipids were found to have low cytotoxicity in three cell lines even at high N/P ratios.
Co-reporter:Qin-Fang Zhang, Wei-Han Yang, Wen-Jing Yi, Ji Zhang, Jiang Ren, Tian-Yi Luo, Wen Zhu, Xiao-Qi Yu
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 23) pp:7045-7049
Publication Date(Web):1 December 2011
DOI:10.1016/j.bmcl.2011.09.098
A series of novel cationic lipids based on 1,4,7-triazacyclononane (TACN) with different hydrophobic chains were synthesized via the formation of a biodegradable ester bond. These lipids were found to have good buffering capacity at the pH range of 5.0–6.5, which is similar to that of the acidic endosomal compartments. The liposomes formed from these lipids and DOPE could condense DNA into nanoparticles with proper sizes. In vitro experiments showed moderate to good gene transfection efficiency of the formed lipoplexes. The structure–activity relationships of this type of lipids were discussed.
Co-reporter:Miao-Miao Xun, Xue-Chao Zhang, Ji Zhang, Qian-Qian Jiang, Wen-Jing Yi, Wen Zhu and Xiao-Qi Yu
Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 7) pp:NaN1250-1250
Publication Date(Web):2012/12/12
DOI:10.1039/C2OB27211C
Non-viral gene vectors play an important role in the development of gene therapy. In this report, different hydrophobic chains were introduced into low molecular weight (LMW) PEI-based biodegradable oligomers to form a series of lipopolymers (LPs), and their structure–activity relationships were studied. Results revealed that the nine polymers can condense plasmid DNA well to form nanoparticles with appropriate sizes (120–250 nm) and positive zeta-potentials (+25–40 V). In vitro experiments were carried out and it was found that LP2 showed much higher transfection efficiency both in the presence and in the absence of serum under the polymer/DNA weight ratio of 0.8 in A549 cells.
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