Targeted polymeric nanocarriers for combination therapy of metastatic prostate ca

用于转移性前列腺癌联合治疗的靶向聚合物纳米载体

基本信息

  • 批准号:
    7558242
  • 负责人:
  • 金额:
    $ 20.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-02-01 至 2011-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer mortality in American men. Whereas localized prostate cancer is highly treatable, metastasized prostate cancer has a 5-year survival rate of 33%. The long term goal of our research is to develop targeted, combination gene and drug delivery nanocarriers for treatment of metastatic prostate cancers. The objectives of this study are to 1) design and synthesize polymeric nanocarriers for simultaneous delivery of a small-molecule anti-cancer prodrug of geldanamycin and a gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 2) develop a HER2-targeted PEG- based shield that will localize carriers in tumor cells and release from the nanocarrier intracellularly to allow DNA delivery to the nucleus, and 3) determine the pharmacokinetics and disposition of these nanocarriers in rodent models of prostate cancer. Our rational is combination of drug and DNA delivery in a single carrier will maximize therapeutic benefit by utilizing the known synergy of TRAIL and geldanamycin, and by ensuring delivery of both to a tumor cells. The addition of an endosome pH triggered-release shield and HER2/neu targeting/internalization peptide will maximize tumor delivery and internalization, while minimizing toxicity to non- target tissues. Finally, these agents have little or no toxicity to normal tissues, limiting the possible side-effects and maximizing the therapeutic window. Project Narrative: This study is an innovative approach to improving human health by developing a HER2 targeted therapy for treating metastatic prostate cancer with a combination of gene and drug therapy. We will use a nanoscopic drug/gene carrier that targets only metastatic prostate cancer cells. If successful, this will provide a new platform for building treatments for HER2+ prostate cancers, an aggressive phenotype present in >80% of highly metastatic hormone refractory prostate tumors.
描述(由申请人提供):前列腺癌是美国男性癌症死亡的第二大原因。虽然局限性前列腺癌是高度可治疗的,但转移性前列腺癌的5年生存率为33%。我们研究的长期目标是开发靶向的、基因和药物联合递送纳米载体用于治疗转移性前列腺癌。本研究的目的是1)设计和合成用于同时递送格尔德霉素的小分子抗癌前药和编码肿瘤坏死因子相关凋亡诱导配体(TRAIL)的基因的聚合物纳米载体,2)开发HER 2靶向的基于PEG的屏蔽物,其将载体定位在肿瘤细胞中并在细胞内从纳米载体释放以允许DNA递送到细胞核,和3)确定这些纳米载体在前列腺癌啮齿动物模型中的药代动力学和处置。我们的理由是在单一载体中药物和DNA递送的组合将通过利用TRAIL和格尔德霉素的已知协同作用并通过确保两者递送至肿瘤细胞而使治疗益处最大化。内体pH触发释放屏蔽物和HER 2/neu靶向/内化肽的添加将使肿瘤递送和内化最大化,同时使对非靶组织的毒性最小化。最后,这些药物对正常组织几乎没有毒性,限制了可能的副作用,并最大限度地提高了治疗窗口。 项目叙述:这项研究是一种创新的方法,通过开发一种HER 2靶向治疗方法来改善人类健康,该方法结合基因和药物治疗来治疗转移性前列腺癌。我们将使用纳米级药物/基因载体,仅针对转移性前列腺癌细胞。如果成功,这将为建立HER 2+前列腺癌的治疗提供一个新的平台,HER 2+前列腺癌是一种侵袭性表型,存在于>80%的高转移性激素难治性前列腺肿瘤中。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development.
  • DOI:
    10.4155/tde.11.19
  • 发表时间:
    2011-05
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Yáñez JA;Remsberg CM;Sayre CL;Forrest ML;Davies NM
  • 通讯作者:
    Davies NM
A sensitive near-infrared fluorescent probe for caspase-mediated apoptosis: Synthesis and application in cell imaging.
  • DOI:
    10.5582/ddt.2011.v5.5.220
  • 发表时间:
    2011-01-01
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Luan Y;Yang Q;Xie Y;Duan S;Cai S;Forrest ML
  • 通讯作者:
    Forrest ML
Impact of molecular weight on lymphatic drainage of a biopolymer-based imaging agent.
  • DOI:
    10.3390/pharmaceutics4020276
  • 发表时间:
    2012-05-23
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Bagby, Taryn R;Cai, Shuang;Forrest, Laird
  • 通讯作者:
    Forrest, Laird
Subcutaneous delivery of nanoconjugated doxorubicin and cisplatin for locally advanced breast cancer demonstrates improved efficacy and decreased toxicity at lower doses than standard systemic combination therapy in vivo.
  • DOI:
    10.1016/j.amjsurg.2011.06.027
  • 发表时间:
    2011-12
  • 期刊:
  • 影响因子:
    3
  • 作者:
    Cohen, Stephanie M.;Mukerji, Ridhwi;Cai, Shuang;Damjanov, Ivan;Forrest, M. Laird;Cohen, Mark S.
  • 通讯作者:
    Cohen, Mark S.
Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles.
  • DOI:
    10.1016/j.addr.2011.05.017
  • 发表时间:
    2011-09-10
  • 期刊:
  • 影响因子:
    16.1
  • 作者:
    Cai, Shuang;Yang, Qiuhong;Bagby, Taryn R.;Forrest, M. Laird
  • 通讯作者:
    Forrest, M. Laird
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Marcus Laird Forrest其他文献

Intralesional injection of CpG ODNs complexed with glatiramer acetate mitigates systemic cytokine toxicities and synergistically advances checkpoint blockade efficacy
  • DOI:
    10.1007/s13346-025-01798-9
  • 发表时间:
    2025-01-29
  • 期刊:
  • 影响因子:
    5.500
  • 作者:
    Huan Gong;J. Daniel Griffin;Chad E. Groer;Xiaoqing Wu;Mengyue Li;Moustafa M. Abdelaziz;Liang Xu;Marcus Laird Forrest;Cory J. Berkland
  • 通讯作者:
    Cory J. Berkland

Marcus Laird Forrest的其他文献

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{{ truncateString('Marcus Laird Forrest', 18)}}的其他基金

Development of a tumor-retentive immunostimulant as adjunct therapy for solid tumor cancers
开发肿瘤保留免疫刺激剂作为实体瘤癌症的辅助治疗
  • 批准号:
    10602219
  • 财政年份:
    2022
  • 资助金额:
    $ 20.84万
  • 项目类别:
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
  • 批准号:
    10363259
  • 财政年份:
    2021
  • 资助金额:
    $ 20.84万
  • 项目类别:
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
  • 批准号:
    10523358
  • 财政年份:
    2021
  • 资助金额:
    $ 20.84万
  • 项目类别:
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
  • 批准号:
    10335201
  • 财政年份:
    2021
  • 资助金额:
    $ 20.84万
  • 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
  • 批准号:
    8882897
  • 财政年份:
    2014
  • 资助金额:
    $ 20.84万
  • 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
  • 批准号:
    9124601
  • 财政年份:
    2014
  • 资助金额:
    $ 20.84万
  • 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
  • 批准号:
    8925802
  • 财政年份:
    2014
  • 资助金额:
    $ 20.84万
  • 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
  • 批准号:
    8422252
  • 财政年份:
    2013
  • 资助金额:
    $ 20.84万
  • 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
  • 批准号:
    8821486
  • 财政年份:
    2013
  • 资助金额:
    $ 20.84万
  • 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
  • 批准号:
    9022438
  • 财政年份:
    2013
  • 资助金额:
    $ 20.84万
  • 项目类别:

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