Inhibition of Intracerebral Gliomas with DNAzymes
DNAzyme 抑制脑内胶质瘤
基本信息
- 批准号:6736432
- 负责人:
- 金额:$ 10万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-06-01 至 2005-11-30
- 项目状态:已结题
- 来源:
- 关键词:angiogenesis inhibitorsathymic mousecell linechemical synthesisconfocal scanning microscopydrug delivery systemsfluorescent dye /probegliomagrowth factor receptorshistidineimmunocytochemistryin situ hybridizationlaboratory mouseliposomeslysineneoplasm /cancer blood supplyneoplastic cellnorthern blottingsoligonucleotidespolymersvascular endothelial growth factors
项目摘要
DESCRIPTION (provided by applicant): Angiogenesis of solid tumors is an important target of cancer therapy. It has been well recognized that growth and metastasis of solid tumors require persistent angiogenesis and that induction of angiogenesis is a discrete component of the tumor phenotype. Vascular endothelial growth factor and its cognate receptors (VEGFR1 and 2) are critical factors in promoting tumor angiogenesis. Our laboratory has recently identified a catalytic oligodeoxynucleotide (DNAzyme) that targets the VEGFR2 mRNA transcript. With intratumoral injections of subcutaneous implanted breast cancer, the VEGFR2 DNAzyme was found to inhibit tumor growth markedly in vivo. One objective of this proposal is to extend this therapy to a clinically relevant model, C6 gliomas. Our laboratory has also synthesized a polymer composed of histidine and lysine (HK polymer) that significantly increases transfection and oligonucleotide delivery. The linear and branched HK polymers offer the potential for effective delivery of therapeutic oligonucleotides including DNAzymes. Our overall aim and long term goal is to develop an effective antiangiogenic oligonucleotide approach to reduce tumor growth in vivo. Aim 1 is designed to improve the bioactivity efficiency of the DNAzyme targeting the mRNA of the VEGF 2 receptor. Although the DNAzyme targeting VEGFR2 developed by our laboratory effectively reduced tumor growth, modification of the annealing arms by the addition ofphosphorothioate linkages is expected to augment the potency of the DNAzyme. Therefore, the current VEGFR2 DNAzyme will be modified to augment its resistance to enzymatic degradation and thus increase its bioactivity. To transport the DNAzyme more effectively to tumor endothelial cells, Aim 2 will determine a more effective branched HK cartier of the DNAzyme. Several HK polymers that vary in the degree of branching and the histidine/lysine ratio will be tested for their ability to increase the efficacy of the DNAzyme. The most effective HK carrier will then be modified with a ligand to further augment the uptake of the complex into tumor endothelial cells. With improved design of HK-containing complexes, it is anticipated that this cartier in complex with the VEGFR DNAzyme will have more anfitumor efficacy toward an orthotopically implanted glioma.
描述(申请人提供):实体肿瘤的血管生成是癌症治疗的重要靶点。众所周知,实体肿瘤的生长和转移需要持续的血管生成,而血管生成的诱导是肿瘤表型的一个独立组成部分。血管内皮生长因子及其同源受体(VEGFR1和VEGF2)是促进肿瘤血管生成的关键因子。我们的实验室最近发现了一种针对VEGFR2 mRNA转录本的催化寡核苷酸(DNAzyme)。皮下注射VEGFR2 DNAzyme可显著抑制体内肿瘤生长。这项建议的一个目标是将这种治疗方法扩展到临床相关的C6胶质瘤模型。我们实验室还合成了一种由组氨酸和赖氨酸组成的聚合物(HK聚合物),显著增加了转染率和寡核苷酸递送。线状和支化的香港聚合物提供了有效传递包括DNAzyme在内的治疗性寡核苷酸的潜力。我们的总体目标和长期目标是开发一种有效的抗血管生成寡核苷酸方法来减少体内肿瘤的生长。目的1旨在提高靶向血管内皮生长因子2受体基因的脱氧核酶的生物活性。虽然我们实验室开发的靶向VEGFR2的DNAzyme有效地减少了肿瘤的生长,但通过添加硫代硫键来修饰退火臂有望增强DNAzyme的效力。因此,将对现有的VEGFR2 DNAzyme进行修饰,以增强其对酶降解的抵抗力,从而提高其生物活性。为了更有效地将DNAzyme运送到肿瘤内皮细胞,Aim 2将确定DNAzyme的一个更有效的分支HK Cartier。几种支化度和组氨酸/赖氨酸比率不同的香港聚合物将接受测试,以确定它们是否有能力提高DNAzyme的功效。然后,最有效的HK载体将被配体修饰,以进一步增强该复合体对肿瘤内皮细胞的摄取。随着含有HK的复合体设计的改进,预计这种与VEGFR DNAzyme形成的复合体将对原位种植的胶质瘤具有更好的抗肿瘤效果。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ARCHIBALD JAMES MIXSON其他文献
ARCHIBALD JAMES MIXSON的其他文献
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{{ truncateString('ARCHIBALD JAMES MIXSON', 18)}}的其他基金
Developing nanoplexes for RNAi-expressing plasmids
开发 RNAi 表达质粒的纳米复合物
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- 资助金额:
$ 10万 - 项目类别:
Developing nanoplexes for RNAi-expressing plasmids
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- 批准号:
10017994 - 财政年份:2019
- 资助金额:
$ 10万 - 项目类别:
Ident. of Structural Features of HK Polyplexes for Imprv. siRNA Deliv. to Tumors
识别。
- 批准号:
8272681 - 财政年份:2009
- 资助金额:
$ 10万 - 项目类别:
Ident. of Structural Features of HK Polyplexes for Imprv. siRNA Deliv. to Tumors
识别。
- 批准号:
8071231 - 财政年份:2009
- 资助金额:
$ 10万 - 项目类别:
Ident. of Structural Features of HK Polyplexes for Imprv. siRNA Deliv. to Tumors
识别。
- 批准号:
7735866 - 财政年份:2009
- 资助金额:
$ 10万 - 项目类别:
Gene Delivery of P53 in a Tumor-bearing Mouse Model
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- 批准号:
7026946 - 财政年份:2004
- 资助金额:
$ 10万 - 项目类别:
Gene Delivery of P53 in a Tumor-bearing Mouse Model
P53 在荷瘤小鼠模型中的基因传递
- 批准号:
6881550 - 财政年份:2004
- 资助金额:
$ 10万 - 项目类别:
Gene Delivery of P53 in a Tumor-bearing Mouse Model
P53 在荷瘤小鼠模型中的基因传递
- 批准号:
7214631 - 财政年份:2004
- 资助金额:
$ 10万 - 项目类别:
Gene Delivery of P53 in a Tumor-bearing Mouse Model
P53 在荷瘤小鼠模型中的基因传递
- 批准号:
6773406 - 财政年份:2004
- 资助金额:
$ 10万 - 项目类别:
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