Artificial Polymeric Lipoproteins as Drug Carriers

描述（由申请人提供）：威胁生命的全身性真菌病的发病率不断上升，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，38%至49%），以及高治疗失败率（约。20%至50%）强调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，在制剂和给药方面存在挑战，特别是在其标准制剂Fungizone（r）中，以及不良毒性（剂量限制性肾毒性），但仍然是首选药物。我们的努力已经证明，DSPE-PEG胶束很容易溶解AmB和解聚这种膜作用药物，导致在体外毒性的大幅度降低和体内毒性的轻微降低。值得注意的是，已经证明AmB/DSPE-PEG在NaCl存在下可溶于水，与Fungizone（r）相反，并且与5-FC（一种水溶性抗真菌药物）和雷帕霉素（一种水溶性差的抗真菌药物，其也被DSPE-PEG胶束增溶）相容。因此，拟议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一IV接入线进行联合药物治疗，提高安全性，降低成本并提高疗效。假设AmB/DSPE-PEG的毒性比Fungizone（r）小，这是由于药物的解聚、连续输注和钠补充（0.9%NaCl），在相同的水性载体中一起输注.还假设AmB/DSPE-PEG可以与5-FC或雷帕霉素/DSPE-PEG在0.9%NaCl中通过相同的IV接入线安全地施用，从而增加抗真菌功效（累加或协同效应）。具体目的是使用肉汤微量稀释棋盘法评估AmB/DSPE-PEG、5-FC、雷帕霉素/DSPE-PEG组合对抗白色念珠菌分离株的体外功效;使用Fungizone（r）作为对照，定义在含有和不含5-FC或雷帕霉素/DSPE-PEG的无菌NaCl媒介物中施用的AmB/DSPE-PEG的体内毒性;确定AmB/DSPE-PEG、AmB/DSPE-PEG + 5-FC和AmB/ DSPE-PEG +雷帕霉素/DSPE-PEG在啮齿动物中的药代动力学;在经验证的IC小鼠模型中确定AmB/DSPE-PEG、5-FC或雷帕霉素/DSPE-PEG的抗真菌活性;并确定抗真菌剂组合的抗真菌活性：AmB/DSPE-PEG + 5-FC或雷帕霉素/DSPE-PEG在经验证的1C小鼠模型中的作用。

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.