Artificial Polymeric Lipoproteins as Drug Carriers

作为药物载体的人工聚合脂蛋白

基本信息

  • 批准号:
    7393256
  • 负责人:
  • 金额:
    $ 14.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-07-01 至 2011-03-31
  • 项目状态:
    已结题

项目摘要

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.
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。

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 }}

Glen S. Kwon其他文献

Polymeric micelle nanocarriers in cancer research
Polymeric Micelles for Multi-Drug Delivery in Cancer
  • DOI:
    10.1208/s12249-014-0251-3
  • 发表时间:
    2014-12-11
  • 期刊:
  • 影响因子:
    4.000
  • 作者:
    Hyunah Cho;Tsz Chung Lai;Keishiro Tomoda;Glen S. Kwon
  • 通讯作者:
    Glen S. Kwon
Soluble Self-Assembled Block Copolymers for Drug Delivery
  • DOI:
    10.1023/a:1011991617857
  • 发表时间:
    1999-01-01
  • 期刊:
  • 影响因子:
    4.300
  • 作者:
    Glen S. Kwon;Teruo Okano
  • 通讯作者:
    Teruo Okano
Production of paclitaxel-loaded PEG-emb/em-PLA micelles using PEG for drug loading and freeze-drying
使用聚乙二醇进行药物负载和冷冻干燥来生产紫杉醇负载的聚乙二醇-乳化/包埋-聚乳酸微球
  • DOI:
    10.1016/j.jconrel.2022.08.032
  • 发表时间:
    2022-10-01
  • 期刊:
  • 影响因子:
    11.500
  • 作者:
    Morteza Rasoulianboroujeni;Lauren Repp;Hye Jin Lee;Glen S. Kwon
  • 通讯作者:
    Glen S. Kwon
Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity
  • DOI:
    10.1007/s11095-007-9451-9
  • 发表时间:
    2007-10-03
  • 期刊:
  • 影响因子:
    4.300
  • 作者:
    M. Laird Forrest;Jaime A. Yáñez;Connie M. Remsberg;Yusuke Ohgami;Glen S. Kwon;Neal M. Davies
  • 通讯作者:
    Neal M. Davies

Glen S. Kwon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('Glen S. Kwon', 18)}}的其他基金

Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
  • 批准号:
    10409814
  • 财政年份:
    2021
  • 资助金额:
    $ 14.05万
  • 项目类别:
Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
  • 批准号:
    10199263
  • 财政年份:
    2021
  • 资助金额:
    $ 14.05万
  • 项目类别:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
用于联合治疗的寡(乳酸)n-前药纳米药物
  • 批准号:
    10371257
  • 财政年份:
    2021
  • 资助金额:
    $ 14.05万
  • 项目类别:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
用于联合治疗的寡聚(乳酸)n-前药纳米药物
  • 批准号:
    10597075
  • 财政年份:
    2021
  • 资助金额:
    $ 14.05万
  • 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
  • 批准号:
    8497027
  • 财政年份:
    2013
  • 资助金额:
    $ 14.05万
  • 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
  • 批准号:
    8605161
  • 财政年份:
    2013
  • 资助金额:
    $ 14.05万
  • 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
  • 批准号:
    8786047
  • 财政年份:
    2013
  • 资助金额:
    $ 14.05万
  • 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
  • 批准号:
    8298518
  • 财政年份:
    2011
  • 资助金额:
    $ 14.05万
  • 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
  • 批准号:
    8175145
  • 财政年份:
    2011
  • 资助金额:
    $ 14.05万
  • 项目类别:
BIOSPECIFIC POLYMER ENZYME CONJUGATES FOR DRUG DELIVERY
用于药物输送的生物特异性聚合物酶缀合物
  • 批准号:
    6262537
  • 财政年份:
    2001
  • 资助金额:
    $ 14.05万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了