课题基金 / 基金详情

Artificial Polymeric Lipoproteins as Drug Carriers

Artificial Polymeric Lipoproteins as Drug Carriers
作为药物载体的人工聚合脂蛋白
批准号:
7251626
负责人:
Glen S. Kwon
金额:
$14.32万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-07-01 至 2011-03-31

项目摘要

项目成果

Glen S. Kwon的其他基金

相关文献

中文摘要
翻译
描述(由申请人提供):危及生命的全身性真菌疾病的发病率上升,例如侵袭性念珠菌病(1C),主要发生在免疫功能低下的患者中,高可归因于死亡率(约38%至49%)和高治疗失败率(约20%至50%)突出了抗真菌治疗进展的未满足需求。两性霉素B (AmB)是一种独特的广谱抗生素,尽管其水溶性差,在配方和给药方面存在挑战,特别是在其标准配方真菌素(r)中,以及不良毒性(剂量限制性肾毒性),但仍然是首选药物。我们的研究表明,DSPE-PEG胶束很容易溶解AmB并使这种膜作用药物解聚,从而大大降低了体外毒性,并轻微降低了体内毒性。值得注意的是,与Fungizone(r)相比,AmB/DSPE-PEG在NaCI存在的情况下可溶于水,并且与水溶性抗真菌药物5-FC和低水溶性抗真菌药物雷帕霉素兼容,后者也可被DSPE-PEG胶束溶解。因此,本研究的目的是探索这种新型AmB的潜力,首次利用其独特的物理稳定性通过单静脉输注线进行联合药物治疗,提高安全性,降低成本,提高治疗效果。假设AmB/DSPE -PEG比Fungizone(r)毒性更小,这是由于药物解聚、持续输注和钠补充(0.9% NaCI)一起输注在同一水溶液中。我们还假设AmB/DSPE-PEG可以与5-FC或雷帕霉素/DSPE-PEG在0.9% NaCI中通过相同的静脉给药线安全给药,从而提高抗真菌效果(加性或协同效应)。目的:采用微量肉汤稀释棋盘法评价AmB/DSPE-PEG、5-FC、雷帕霉素/DSPE-PEG联合对白色念珠菌的体外抑菌效果;定义AmB/DSPE -PEG的体内毒性,在含或不含5-FC或雷帕霉素/DSPE-PEG的无菌NaCI载体中施用,以真菌区(r)作为对照;确定AmB/DSPE-PEG、AmB/DSPE-PEG + 5-FC和AmB/DSPE-PEG +雷帕霉素/DSPE-PEG在啮齿动物体内的药动学;在1C小鼠模型中建立AmB/DSPE-PEG、5-FC或雷帕霉素/DSPE-PEG的抗真菌活性;并建立抗真菌药物AmB/DSPE-PEG + 5-FC或雷帕霉素/DSPE-PEG组合在1C小鼠模型中的抗真菌活性。
英文摘要
DESCRIPTION (provided by applicant): A rising incidence of life-threatening systemic fungal diseases, e.g. invasive candidiasis (1C), chiefly among immunocompromised patients, a high attributable mortality (ca. 38% to 49%), and a high rate of therapeutic failure (ca. 20% to 50%) highlight the unmet need for progress in antifungal therapy. Amphotericin B (AmB), a unique broad spectrum antibiotic, remains the drug of choice despite its poor water solubility, challenges in formulation and administration, particularly in its standard formulation, Fungizone(r), and untoward toxicity (dose-limiting nephrotoxicity). Our efforts have demonstrated that DSPE-PEG micelles easily solubilize AmB and deaggregate this membrane-acting drug, resulting in a major reduction of toxicity in vitro and a minor reduction of toxicity in vivo. Significantly, it has been demonstrated that AmB/DSPE-PEG is soluble in water in the presence of NaCI, in contrast to Fungizone(r), and is compatible with 5-FC, a water-soluble antifungal drug, and rapamycin, a poorly water-soluble antifungal drug, which has also been solubilized by DSPE-PEG micelles. Thus, the objective of the proposed research is to explore the potential of this novel form of AmB, utilizing its unique physical stability for combined drug therapy through a single IV access line for the first time, increasing safety, lowering cost, and increasing therapeutic efficacy. It is hypothesized that AmB/DSPE -PEG will be less toxic than Fungizone(r), owing to deaggregation of drug, continuous infusion, and sodium supplementation (0.9% NaCI), infused together in the same aqueous vehicle. It is also hypothesized that AmB/DSPE-PEG can be administered safely with 5-FC or rapamycin/DSPE-PEG in 0.9% NaCI via the same IV access line, increasing antifungal efficacy (additive or synergistic effects). The Specific Aims are to estimate in vitro efficacy of AmB/DSPE-PEG, 5-FC, rapamycin/DSPE-PEG combinations against Candida albicans isolates using the broth microdilution checkerboard method; define the in vivo toxicity of AmB/DSPE -PEG, administered in a sterile NaCI vehicle with and without 5-FC or rapamycin/DSPE-PEG, using Fungizone(r), as a control; define the pharmacokinetics of AmB/DSPE-PEG, AmB/DSPE-PEG + 5-FC, and AmB/ DSPE-PEG + rapamycin/DSPE-PEG in rodents; establish antifungal activity of AmB/DSPE-PEG, 5-FC, or rapamycin/DSPE-PEG in a validated murine model of 1C; and establish antifungal activity of combinations of antifungal agents: AmB/DSPE-PEG + 5-FC or rapamycin/DSPE-PEG in a validated murine model of 1C.
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Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
  • 批准号:
    10409814
  • 项目类别:
  • 资助金额:
    $20.92万
  • 财政年份:
    2021
  • 负责人:
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  • 依托单位:
Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
  • 批准号:
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  • 项目类别:
  • 资助金额:
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  • 财政年份:
    2021
  • 负责人:
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  • 依托单位:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
  • 批准号:
    10371257
  • 项目类别:
  • 资助金额:
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  • 财政年份:
    2021
  • 负责人:
    Glen S. Kwon
  • 依托单位:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
  • 批准号:
    10597075
  • 项目类别:
  • 资助金额:
    $34.12万
  • 财政年份:
    2021
  • 负责人:
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  • 依托单位: