Nuclear-targeted nanoparticles for gene delivery

用于基因传递的核靶向纳米粒子

基本信息

批准号：
7454388
负责人：
VINOD D LABHASETWAR
金额：
$ 25.84万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7454388
关键词：
Affect Angiogenic Factor Antibodies Apoptosis Appendix Biochemical Biocompatible Biodistribution Cancer Model Cell Cycle Cell Cycle Arrest Cell Nucleus Cell Proliferation Cell division Cell membrane Cells Characteristics Complex Condition Cytoplasm Cytosol DDAB DNA DNA delivery Data Development Diffusion Disease regression Dose Drug Delivery Systems Drug Formulations Drug Kinetics Dynein ATPase Early Endosome Encapsulated Endocytosis Endosomes Exocytosis Figs - dietary Gene Delivery Gene Expression Gene Transfer Genes Genetic Transcription Glutamate Carboxypeptidase II Goals Intravenous Lead Lipids Liposomes Liver Lysine Lysosomes Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Mediating Methods Microtubules Modeling Molecular Movement Mus Mutation Nature Nuclear Nuclear Envelope Nuclear Pore Complex Outcome PC3 cell line Pathologic Pathway interactions Phosphoproteins Physiological Polymers Principal Investigator Process Property Prostatic Neoplasms Proteins Purpose Rate Reporting Research Personnel Serum Sorting - Cell Movement Surface System TP53 gene Testing Therapeutic Therapeutic Effect Time Transfection Treatment Efficacy Tumor Angiogenesis Tumor Suppressor Genes Tumor Tissue Viral base biodegradable polymer cell growth expression vector gene therapy intravenous administration nanoparticle neoplastic cell nucleocytoplasmic transport particle physical property plasmid DNA polylactic acid-polyglycolic acid copolymer programs success therapeutic gene trafficking tumor tumor growth tumor-specific gene delivery uptake

项目摘要

DESCRIPTION (provided by applicant): The movement of DNA from the cytoplasm to the nucleus remains one of the major barriers to efficient gene transfer and expression. Without localization of DNA to the nucleus, no transcription or "gene therapy" can take place. Based on our studies on intracellular trafficking of nanoparticles, we have recently discovered surface modified NPs that are taken up by cells via non-endocytic pathway, have significantly greater intracellular uptake and retention than unmodified NPs, and more importantly, these nanoparticles target to the nucleus. Our objective is to test the hypothesis that the direct nuclear delivery of modified nanoparticles would deliver the encapsulated DNA directly to the nucleus that would also enhance the level of gene expression. Our goal is to investigate the molecular mechanism of nuclear localization of modified nanoparticles and determine their efficacy as a non-viral gene expression vector. To test our hypothesis, we will use wild-type (wf)-p53 gene, a tumor suppressor gene as a model therapeutic gene, and cancer as a model pathologic condition. We propose that the nanoparticle-mediated sustained expression of wf-p53 gene in the tumor tissue would lead effective regression of tumor via induction of cell apoptosis and/or over expression of anti-angiogenic factors. The specific aims of the proposal are: i) To investigate the formulation determinants that are critical to enhancing and sustaining the level of gene expression; ii) To investigate the molecular mechanism of nuclear-localization of modified nanoparticles; iii) To determine the therapeutic efficacy of wf-p53 gene encapsulated in modified nanoparticles in prostate cancer cell line; iv) To study the pharmacokinetics of biodistribution of modified nanoparticles via intravenous administration to achieve tumor-specific gene delivery; and v) To evaluate the efficacy of modified nanoparticles using wf-p53 gene in a murine model of prostate cancer. We anticipate that these nanoparticles can be used as an effective non-viral sustained gene expression system. Efficient nuclear delivery of nanoparticles could have far reaching implications, especially for delivery of drugs and proteins directly to the nucleus, both for therapeutic purposes and as well as to study their cellular and biochemical functions.

描述（由申请人提供）： DNA 从细胞质到细胞核的运动仍然是有效基因转移和表达的主要障碍之一。如果 DNA 不定位到细胞核，就不可能发生转录或“基因治疗”。基于我们对纳米颗粒细胞内运输的研究，我们最近发现表面修饰的纳米颗粒通过非内吞途径被细胞摄取，比未修饰的纳米颗粒具有显着更高的细胞内摄取和保留，更重要的是，这些纳米颗粒靶向细胞核。我们的目标是测试这样的假设：修饰纳米颗粒的直接核递送会将封装的 DNA 直接递送至细胞核，这也将增强基因表达水平。我们的目标是研究修饰纳米颗粒核定位的分子机制，并确定它们作为非病毒基因表达载体的功效。为了检验我们的假设，我们将使用野生型 (wf)-p53 基因（一种肿瘤抑制基因）作为模型治疗基因，并使用癌症作为模型病理状况。我们提出，纳米颗粒介导的wf-p53基因在肿瘤组织中的持续表达将通过诱导细胞凋亡和/或抗血管生成因子的过度表达而导致肿瘤的有效消退。该提案的具体目标是： i) 研究对于增强和维持基因表达水平至关重要的配方决定因素； ii) 研究修饰纳米粒子核定位的分子机制； iii) 确定封装在修饰纳米粒子中的wf-p53基因对前列腺癌细胞系的治疗功效； iv) 研究修饰纳米粒子通过静脉注射生物分布的药代动力学，以实现肿瘤特异性基因递送； v) 评估使用 wf-p53 基因修饰的纳米颗粒在前列腺癌小鼠模型中的功效。我们预计这些纳米颗粒可以用作有效的非病毒持续基因表达系统。纳米粒子的有效核递送可能具有深远的影响，特别是对于将药物和蛋白质直接递送至细胞核，既用于治疗目的，又用于研究其细胞和生化功能。