In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy

原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗

基本信息

  • 批准号:
    10596246
  • 负责人:
  • 金额:
    $ 11.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-05 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10% of the genome. RNAi molecules can, in theory, be designed against any gene of interest, but siRNA use in clinical oncology faces delivery barriers such as nuclease degradation, rapid renal clearance, poor distribution into tumor tissues, and poor cell membrane penetration. To overcome these challenges, most RNAi therapies focus on synthetic lipo- and poly-plex nano-formulations. Unfortunately, while these technologies typically achieve very high delivery into the liver, high-penetrance siRNA tumor delivery remains elusive. The overarching goal of this project is to develop siRNA chemical modifications that provide potent, safe, tumor-penetrating, and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. The approach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45 linker with a diacyl lipid (siRNA-EG45<L2), which forms a nano-complex with albumin (alb-NC) in situ following intravenous injection. This albumin “hitchhiking” siRNA-EG45<L2 enhances siRNA pharmacokinetic properties, is very safe, provides natural tumor tropism, and increases tumor delivery level, homogeneity of tumor delivery, and tumor:liver delivery ratio compared to conventional nano-polyplexes formed with in vivo-jetPEI (PEI-NPs). The alb-NCs especially outperformed PEI-NPs for accumulating within challenging patient derived xenograft (PDX) tumors that have reduced access to delivery by the enhanced permeability and retention (EPR) effect. The specific goal of this proposal is to further explore and optimize siRNA chemical modifications for in situ formation of effective alb-NCs. We will benchmark new candidates against conventional nano-formulations in simple (xenograft), immune-competent (allograft) and rigorous (PDX and spontaneous) tumor models. This platform will be validated for silencing of the oncogene myeloid cell leukemia 1 (Mcl-1) to treat triple negative breast cancer (TNBC). Mcl-1 is a vetted target with relevance in a broad range of cancers, supporting its use for proof-of-concept. Furthermore, TNBC is a highly aggressive clinical breast cancer subtype with few treatment options. TNBC patients are currently relegated to chemotherapies, and do not typically benefit from molecularly- targeted therapies. This project is uniquely accessible by our multi-PI interdisciplinary team with bioengineering expertise in intracellular biologic drug delivery nanotechnologies (Duvall), chemical synthesis (Uddin), analysis of noncoding RNA transport on serum components (Vickers), Mcl-1 pathway modulation and analysis (Cook), and cutting edge preclinical models, including PDX, for testing experimental therapies (Brantley-Sieders). Our basic science expertise will be supplemented by consultation with Dr. Ingrid Mayer, a medical oncologist involved in breast cancer clinical trials at Vanderbilt. This group will enable previously inaccessible investigations toward development of more effective, tumor-penetrating, and molecularly-targeted TNBC therapeutics.
用于递送小分子药物的癌症纳米制剂受限于仅能靶向约10%

项目成果

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科研奖励数量(0)
会议论文数量(0)
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Rebecca Sara Cook其他文献

Rebecca Sara Cook的其他文献

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{{ truncateString('Rebecca Sara Cook', 18)}}的其他基金

In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10737831
  • 财政年份:
    2021
  • 资助金额:
    $ 11.76万
  • 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10445055
  • 财政年份:
    2021
  • 资助金额:
    $ 11.76万
  • 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10661771
  • 财政年份:
    2021
  • 资助金额:
    $ 11.76万
  • 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
  • 批准号:
    8764759
  • 财政年份:
    2014
  • 资助金额:
    $ 11.76万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8196980
  • 财政年份:
    2009
  • 资助金额:
    $ 11.76万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8591383
  • 财政年份:
    2009
  • 资助金额:
    $ 11.76万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    7768523
  • 财政年份:
    2009
  • 资助金额:
    $ 11.76万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    7998156
  • 财政年份:
    2009
  • 资助金额:
    $ 11.76万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8390510
  • 财政年份:
    2009
  • 资助金额:
    $ 11.76万
  • 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
  • 批准号:
    8593797
  • 财政年份:
    2003
  • 资助金额:
    $ 11.76万
  • 项目类别:

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新型同种异体骨软骨移植联合生长因子-胶原蛋白结合域融合技术的建立
  • 批准号:
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  • 财政年份:
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  • 财政年份:
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    $ 11.76万
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复合同种异体移植促进角膜移植的存活
  • 批准号:
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  • 财政年份:
    2009
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    $ 11.76万
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
  • 批准号:
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  • 财政年份:
    2009
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增强同种异体移植后的抗肿瘤免疫力
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  • 财政年份:
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    $ 11.76万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    8010394
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    2008
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    $ 11.76万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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增强同种异体移植后的抗肿瘤免疫力
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