Artificial Polymeric Lipoproteins as Drug Carriers

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。

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.