Antifungal Liposomes Targeted to Cell Wall Mannans

针对细胞壁甘露聚糖的抗真菌脂质体

基本信息

  • 批准号:
    9979038
  • 负责人:
  • 金额:
    $ 22.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-20 至 2022-01-31
  • 项目状态:
    已结题

项目摘要

Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. For instance, Candida albicans and Cryptococcus neoformans cause life-threatening invasive candidiasis and cryptococcosis, respectively. Patients at the greatest risk of developing these IFDs have weakened immune systems such as HIV positive individuals. The vulnerable population is increasing due to increasing numbers of immunosuppressed individuals receiving stem cell or organ transplants. Patients with candidiasis or cryptococcosis are treated with various antifungal drugs, but all antifungals have serious limitations due to human cell and organ toxicity, the emergence of resistant fungi, and the lack of sufficient fungicidal effect at safe doses. Even with the current antifungal therapies, these two IFDs are associated with dramatically increased medical costs, increased length of hospital stay, and one-year survival is only 12 to 90%, depending upon the patient population. Our proposal meets the critical need for improved antifungal therapeutics. A thick outer cell wall and secreted extracellular matrix rich in mannans, galactomannans, and mannoproteins help some pathogenic fungi including C. albicans and C. neoformans evade host defense. The C-type lectin receptor Dectin-2 on the surface of mammalian lymphocytes bind strongly to mannans in the fungal cell wall, matrix, and solubilized into tissue to signal an innate immune response to infection. We have strong preliminary data showing that truncated Dectin-2 functions in a liposomal membrane. Dectin-2-coated antifungal drug-loaded liposomes bind mannans in the cell-associated exopolysaccharide matrix of C. albicans and C. neoformans two orders of magnitude more efficiently than uncoated liposomes and kills both species an order of magnitude more efficiently. The overarching goal of this exploratory proposal is to demonstrate Dectin- 2-targeted antifungal loaded liposomes increase antifungal drug efficacy as compared to current antifungal drugs. In particular, we will show that Dectin-2-coated drug-loaded liposomes have enhanced antifungal activity toward C. albicans and C. neoformans in vitro and efficiently treat disseminated candidiasis in an in vivo mouse model. We have an established team of scientists already combining their expertise in diverse areas of science necessary to carry out these experiments including fungal biology and pathology, immunology and liposome biochemistry, genetics, and protein chemistry. Successful completion of this study will establish the feasibility of antifungal drug delivery specifically to fungal mannans that will ultimately improve outcomes of patients with candidiasis, aspergillosis, and cryptococcosis. We will have developed an experimental platform to rapidly innovate and optimize fungal mannan and biofilm targeted therapies that may be used to treat diverse life- threatening fungal infections and milder fungal infections of eyes, skin, toenails, and biomedical devices.
侵袭性真菌病(IFDs)每年造成数百万人死亡,并且难以治疗。

项目成果

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Richard Brian Meagher其他文献

Richard Brian Meagher的其他文献

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{{ truncateString('Richard Brian Meagher', 18)}}的其他基金

Targeted pan-antibacterial liposomes to control pathogenic mycobacteria
靶向泛抗菌脂质体控制致病性分枝杆菌
  • 批准号:
    10569282
  • 财政年份:
    2023
  • 资助金额:
    $ 22.65万
  • 项目类别:
Targeted delivery of antifungal drug loaded liposomes to control mucormycosis
靶向递送抗真菌药物脂质体来控制毛霉菌病
  • 批准号:
    10668509
  • 财政年份:
    2022
  • 资助金额:
    $ 22.65万
  • 项目类别:
Targeted delivery of antifungal drug loaded liposomes to control mucormycosis
靶向递送抗真菌药物脂质体来控制毛霉菌病
  • 批准号:
    10509943
  • 财政年份:
    2022
  • 资助金额:
    $ 22.65万
  • 项目类别:
Antifungal Imunoliposomes
抗真菌免疫脂质体
  • 批准号:
    9926213
  • 财政年份:
    2019
  • 资助金额:
    $ 22.65万
  • 项目类别:
NUCLEAR CAPTURE FOR CELL-TYPE SPECIFIC EPIGENETIC ANALYSIS OF ADIPOCYTES
用于脂肪细胞细胞类型特异性表观遗传分析的核捕获
  • 批准号:
    8760476
  • 财政年份:
    2014
  • 资助金额:
    $ 22.65万
  • 项目类别:
NUCLEAR CAPTURE FOR CELL-TYPE SPECIFIC EPIGENETIC ANALYSIS OF ADIPOCYTES
用于脂肪细胞细胞类型特异性表观遗传分析的核捕获
  • 批准号:
    8917210
  • 财政年份:
    2014
  • 资助金额:
    $ 22.65万
  • 项目类别:
Differential Expression of the Diverse Plant Actins
多种植物肌动蛋白的差异表达
  • 批准号:
    7931495
  • 财政年份:
    2009
  • 资助金额:
    $ 22.65万
  • 项目类别:
PLANT MOLECULAR BIOLOGY GORDON CONFERENCE
植物分子生物学戈登会议
  • 批准号:
    3435014
  • 财政年份:
    1988
  • 资助金额:
    $ 22.65万
  • 项目类别:
DIFFERENTIAL EXPRESSION OF DIVERSE PLANT ACTIN GENES
多种植物肌动蛋白基因的差异表达
  • 批准号:
    6039284
  • 财政年份:
    1986
  • 资助金额:
    $ 22.65万
  • 项目类别:
DIFFERENTIAL EXPRESSION OF DIVERSE PLANT ACTIN GENES
多种植物肌动蛋白基因的差异表达
  • 批准号:
    2684820
  • 财政年份:
    1986
  • 资助金额:
    $ 22.65万
  • 项目类别:

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