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:7598939
- 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
- 来源:
- 关键词:Amphotericin BAmphotericin B LiposomalAnti-Bacterial AgentsAntibioticsAntifungal AgentsAntifungal TherapyAntiviral TherapyCandidaCandida albicansCandidiasisClinicalCombined Modality TherapyContinuous InfusionDataDiseaseDoseDose-LimitingDrug CarriersDrug CombinationsDrug FormulationsDrug KineticsDrug effect disorderEthylene GlycolsFailureFlucytosineGoalsHydration statusImmunocompromised HostIn VitroIncidenceInferiorInfusion proceduresIntravenousIntravenous infusion proceduresKidneyLifeLipoproteinsLiposomesMaximum Tolerated DoseMeasuresMembraneMethodsMicellesMinorModelingMusOrganismPatientsPharmaceutical PreparationsPharmacodynamicsPharmacotherapyPhosphotransferasesPrecipitationResearchResearch PersonnelResistanceRiskRodentRouteSafetySepsisSirolimusSodiumSodium ChlorideSolutionsStagingSterilitySupplementationSurfaceTherapeuticTherapeutic IndexTimeToxic effectTreatment EfficacyUncertaintyUnited StatesWateramphotericin B-deoxycholateaqueousattributable mortalitycostethylene glycolimprovedin vivointravenous administrationnephrotoxicitynovelpathogenphosphoethanolamineprogramsresponsewater solubility
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(申请人提供):威胁生命的系统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,高可归因性死亡率(约38%至49%)和高治疗失败率(约20%至50%)突显了抗真菌治疗进展的未得到满足的需求。两性霉素B(Amb)是一种独特的广谱抗生素,尽管其水溶性较差,在配方和给药方面存在挑战,特别是在其标准配方Fungizone(R)和不良毒性(剂量限制肾毒性)方面,但仍是首选药物。我们的研究表明,DSPE-PEG胶束很容易溶解Amb并解聚这种膜作用药物,从而导致体外毒性的大幅降低和体内毒性的轻微降低。值得注意的是,与Fungizone(R)相比,AMB/DSPE-PEG在NaCI存在的情况下可以溶于水,并且与水溶性抗真菌药物5-FC和难溶抗真菌药物雷帕霉素相容,雷帕霉素也被DSPE-PEG胶束增溶。因此,拟议的研究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一静脉通路进行联合药物治疗,增加安全性,降低成本,提高治疗效果。据推测,AMB/DSPE-PEG的毒性比Fungizone(R)小,因为药物解聚、持续输注和钠补充(0.9%NaCI)一起在同一含水载体中输注。还假设AMB/DSPE-PEG可以与5-FC或雷帕霉素/DSPE-PEG一起在0.9%NaCI中通过相同的静脉通路安全地给予,从而增加抗真菌效果(相加或协同效应)。具体目的是用肉汤微量稀释法评价AMB/DSPE-PEG、5-FC、雷帕霉素/DSPE-聚乙二醇组分对白色念珠菌的体外药效;以Fungizone(R)为对照,确定AMB/DSPE-PEG在无菌NaCI载体中的体内毒性;确定AMB/DSPE-PEG、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代动力学;在验证的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;在验证的1C小鼠模型中建立抗真菌药物组合的抗真菌活性:AMB/DSPE-PEG+5-FC或雷帕霉素/DSPE-PEG。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Glen S. Kwon其他文献
Polymeric micelle nanocarriers in cancer research
- DOI:
10.1007/s11705-016-1582-2 - 发表时间:
2016-08-21 - 期刊:
- 影响因子:4.500
- 作者:
Dae Hwan Shin;Yu Tong Tam;Glen S. Kwon - 通讯作者:
Glen S. Kwon
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
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{{ 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: