Artificial Polymeric Lipoproteins as Drug Carriers

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。

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.