Design and Characterization of Multi-Targeted Gene Delivery Nanoparticles for Specific Cancer Therapy

用于特定癌症治疗的多靶点基因递送纳米颗粒的设计和表征

基本信息

  • 批准号:
    1403564
  • 负责人:
  • 金额:
    $ 30.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2017-08-31
  • 项目状态:
    已结题

项目摘要

Proposal Number: CBET-1403564 Principal Investigator: Efrosini KokkoliInstitution: University of Minnesota - Twin CitiesTitle: Design and Characterization of Multi-Targeted Gene Delivery Nanoparticles for Specific Cancer Therapy By 2030 there could be 27 million incident cases of cancer worldwide, 17 million cancer deaths annually and 75 million persons alive with cancer within five years of diagnosis. Active targeting of an adhesion molecule that is expressed on the surface of the tumor cells, is a promising area of research and targeted nanoparticle delivery to cancer is an area of interest that may offer hope in improving the treatment of therapy-resistant cancers. Unfortunately, cancer-specificity by selective recognition of individual cellular receptors has rarely been achieved adequately to date, suffering from unintended delivery to healthy organs as some target disease markers are also expressed in areas other than tumors. The focus of this work is on the problem of specific delivery of non-viral gene delivery vehicles to cancer cells versus healthy cells. Proposed is the development of a multi-targeted therapeutic system, that will make the recognition of cancer cells more specific. The hypothesis of this work is that a higher degree of specificity for cancer cells could be achieved by designing a modular multi-targeted non-viral system that: i) introduces simultaneous targeting of the overexpressed cancer surface receptors alpha(5)beta(1) and alpha(6)beta(4) integrins as the first level of targeting at the extracellular level, and ii) targets the upregulated transcriptional activity of NF-kB that is inactive in healthy cells while it is highly upregulated in a variety of diseases including cancer, thereby introducing a new form of transcriptional targeting as the second level of specific targeting. To test this hypothesis the following tasks have been set: Research Task 1: Evaluate the effect of peptide concentration on the miscibility of peptide-amphiphiles and polyethylene glycol (PEG) molecules. Langmuir-Blodgett membranes will be designed that will mimic the interfaces of the dual-ligand stealth liposomes by mixing lipids, lipidated PEG and the peptide-amphiphiles that bind specifically to the alpha(5)beta(1) and alpha(6)beta(4) integrins. The effect of peptide concentration on the mixing behavior between the peptides and PEG will be investigated by atomic force microscopy. Research Task 2: To engineer multi-targeted stealth liposomes, functionalized with peptide-amphiphiles that bind specifically to the alpha(5)beta(1) and alpha(6)beta(4) integrins, and deliver them to cells with different integrin expression levels. Peptide-functionalized stealth liposomes will be prepared with different concentrations of the two peptides. The liposomes will be delivered to different cancer cells with varying levels of integrin expression. Fluorescent dyes will be encapsulated initially, and the binding and internalization of the liposomes will be evaluated with plate assays and confocal microscopy studies. The liposomes will be evaluated further with respect to promoting specific transcriptional targeting as they will deliver the diphtheria toxin fragment A (DTA) gene under the control of the NF-kB promoter. The toxicity of different cells with varying levels of integrin expression will be evaluated with plate assays. Research Task 3: To evaluate the multi-targeted stealth liposomes in vivo. Dual-ligand formulations from Research Task 2 that will be shown to bind best to DLD-1 colon cancer cells will be evaluated in this task for their ability to reach the colon tumor site in vivo, with microPET/CT imaging and biodistribution studies. Non-targeted and single-ligand stealth liposomes will be used as controls. The single- and dual-ligand optimal formulations will further be evaluated for their efficacy and toxicity. For these studies the DTA gene under the control of the NF-kB promoter will be employed.​
建议编号:CBET-1403564首席研究员:埃弗罗西尼·科科利研究所:明尼苏达大学双子城分校标题:用于特定癌症治疗的多靶点基因传递纳米颗粒的设计和特性到2030年,全球可能有2,700万癌症病例,每年有1,700万癌症死亡,5年内有7,500万癌症患者存活。主动靶向肿瘤细胞表面表达的黏附分子是一个很有前途的研究领域,而将纳米颗粒定向输送到癌症是一个有兴趣的领域,可能会为改善耐药癌症的治疗带来希望。不幸的是,到目前为止,通过选择性识别单个细胞受体来实现癌症特异性的方法还很少,因为一些靶向疾病标记物也在肿瘤以外的区域表达,因此意外地将其传递到健康器官。这项工作的重点是将非病毒基因递送载体特定地输送到癌细胞和健康细胞的问题上。建议开发一种多靶点治疗系统,使对癌细胞的识别更加特异。这项工作的假设是,通过设计一种模块化的多靶点非病毒系统,可以实现对癌细胞的更高程度的特异性:i)引入同时靶向过表达的癌症表面受体α(5)β(1)和α(6)β(4)整合素的靶向作为细胞外水平的第一靶向,以及ii)靶向在健康细胞中不活跃的核因子-kB的转录活性,而它在包括癌症在内的各种疾病中高度上调,从而引入一种新的转录靶向形式作为第二水平的特异性靶向。为了验证这一假设,已经设置了以下任务:研究任务1:评估多肽浓度对多肽-两亲性和聚乙二醇(PEG)分子相容性的影响。设计的Langmuir-Blodgett膜将通过混合脂类、脂化的聚乙二醇酯和与α(5)β(1)和α(6)β(4)整合素特异结合的两亲肽来模拟双配体隐形脂质体的界面。用原子力显微镜研究多肽浓度对多肽与聚乙二醇混合行为的影响。研究任务2:设计多靶点隐形脂质体,用与α(5)β(1)和α(6)β(4)整合素特异结合的两亲肽功能化,并将它们输送到具有不同整合素表达水平的细胞。用不同浓度的两种多肽制备多肽功能化隐形脂质体。脂质体将被输送到不同整合素表达水平的不同癌细胞。荧光染料最初将被包裹,脂质体的结合和内化将通过平板分析和共聚焦显微镜研究进行评估。脂质体将在核因子-kB启动子的控制下传递白喉毒素片段A(DTA)基因,因此将进一步评估其促进特异性转录靶向的作用。整合素表达水平不同的不同细胞的毒性将通过平板法进行评估。研究任务3:体内评价多靶点隐形脂质体。研究任务2中将被证明与DLD-1结肠癌细胞结合最好的双配体配方将在这项任务中通过微型PET/CT成像和生物分布研究来评估它们在体内到达结肠癌部位的能力。非靶向和单配体隐形脂质体将作为对照。单配体和双配体的最优处方将进一步评估其有效性和毒性。在这些研究中,将使用受核因子-kB启动子控制的DTA基因。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Efrosini Kokkoli其他文献

Efrosini Kokkoli的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Efrosini Kokkoli', 18)}}的其他基金

Bioengineering & Translational Medicine Conference
生物工程
  • 批准号:
    1745949
  • 财政年份:
    2017
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Standard Grant
EAGER: Interfacial Design of Modular, Multifunction Peptide Amphiphile Hydrogels for Tissue Engineering
EAGER:用于组织工程的模块化多功能肽两亲水凝胶的界面设计
  • 批准号:
    1253913
  • 财政年份:
    2012
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Standard Grant
Engineering and characterizing nanoparticles for cancer targeting
用于癌症靶向的纳米粒子的工程和表征
  • 批准号:
    1159967
  • 财政年份:
    2012
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Standard Grant
CAREER: Design and Characterization of Aptamer-Amphiphiles for Selective Binding
职业:用于选择性结合的适体双亲物的设计和表征
  • 批准号:
    0846274
  • 财政年份:
    2009
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Continuing Grant
Nanostructured Interfaces for Targeted Drug Delivery
用于靶向药物输送的纳米结构界面
  • 批准号:
    0553682
  • 财政年份:
    2006
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Standard Grant

相似海外基金

Design and characterization of multi-use organic molecules for photoelectric conversion
用于光电转换的多用途有机分子的设计和表征
  • 批准号:
    18F18035
  • 财政年份:
    2018
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Design, fabrication, and characterization of multi-scale micro-electromagnets for extraction of nucleic acids (DNA and RNA) from cells
用于从细胞中提取核酸(DNA 和 RNA)的多尺度微电磁体的设计、制造和表征
  • 批准号:
    475617-2015
  • 财政年份:
    2017
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Design, fabrication, and characterization of multi-scale micro-electromagnets for extraction of nucleic acids (DNA and RNA) from cells
用于从细胞中提取核酸(DNA 和 RNA)的多尺度微电磁体的设计、制造和表征
  • 批准号:
    475617-2015
  • 财政年份:
    2015
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Postgraduate Scholarships - Doctoral
Design, synthesis and characterization of multi-ferroic materials - from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    203773-2007
  • 财政年份:
    2011
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Individual
Design, synthesis and characterization of multi-ferroic materials - from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    203773-2007
  • 财政年份:
    2010
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Individual
Design, synthesis and characterization of multi-ferroic materials- from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    349693-2007
  • 财政年份:
    2010
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Accelerator Supplements
Design, synthesis and characterization of multi-ferroic materials- from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    349693-2007
  • 财政年份:
    2009
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Accelerator Supplements
Parameterized Architecture-Level Thermal Modeling and Characterization for Multi-Core Microprocessor Design
多核微处理器设计的参数化架构级热建模和表征
  • 批准号:
    0902885
  • 财政年份:
    2009
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Standard Grant
Design, synthesis and characterization of multi-ferroic materials - from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    203773-2007
  • 财政年份:
    2009
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Individual
Design, synthesis and characterization of multi-ferroic materials- from inhomogeneous nanostructure to functional macroscopic properties
多铁性材料的设计、合成和表征——从不均匀纳米结构到功能宏观特性
  • 批准号:
    349693-2007
  • 财政年份:
    2008
  • 资助金额:
    $ 30.53万
  • 项目类别:
    Discovery Grants Program - Accelerator Supplements
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了