Inhalable amphotericin B nanodisk therapy for aspergillosis in HIV-infected patie

描述（由申请方提供）：烟曲霉是一种机会致病真菌，主要感染免疫功能低下患者。它是HIV患者、器官移植受者和癌症患者感染性肺炎死亡的最常见原因。A. HIV感染患者中的烟曲霉感染是最相关的，这是由于异常高的死亡率（>75%在感染的第一年内死亡）。由于患者往往过于脆弱，无法接受侵入性或毒性治疗，因此治疗变得复杂。目前治疗曲霉病的一线药物是曲霉素B（AMB），但它具有高度肾毒性且不溶性。其肾毒性可能是导致死亡的重要因素。因此，AMB对其治疗应用提出了一系列挑战。为了解决这个问题，我们开发了NanoTM，一种用于溶解和递送疏水性药物的脂质和蛋白质的新型制剂。纳米脂质体是直径8 - 15 nm的盘状结构，由稳定化载脂蛋白或肽模拟物限制的脂质双层组成。当AMB被纳入纳米颗粒（ND-AMB）时，我们观察到溶解度的急剧增加和毒性的降低。与AMB的主要商业脂质体制剂（AmBisome）相比，ND-AMB对曲霉菌的最小抑制浓度低25倍，并且在播散性念珠菌病的动物模型中，ND-AMB在低5倍的剂量下有效。由于曲霉菌感染的正常途径是通过吸入分生孢子，因此曲霉病可能对针对肺部的治疗最有反应。该SBIR提案的I期结果表明，ND-AMB可以冻干、研磨成粉末并再水合，而不会损失生物活性、复合物完整性或AMB毒性衰减。因此，我们假设纳米颗粒能够通过吸入有效地肺部和全身递送用于治疗A。烟曲霉肺部和全身播散性感染。我们将研究ND-AMB作为吸入治疗的整体能力。具体而言，我们将表征ND-AMB在吸入后进入血流的能力、其药代动力学分布、毒性和在小鼠模型系统中治疗肺部和全身真菌感染的功效。我们希望用AMB作为利什曼病治疗复制我们的成功，其中我们通过将AMB重新配制成ND-AMB将AMB从边缘有效的治疗转化为有效的治疗。来自该研究的结果对于开发用于治疗曲霉病的改进的可吸入的基于AMB的疗法是必不可少的;曲霉病是HIV感染患者的严重健康问题，其中中位生存期为3个月。使用可吸入的ND-AMB，我们相信我们将带来对死亡率极高（> 75%）的疾病的有效治疗。

DESCRIPTION (provided by applicant): Aspergillus fumigatus is an opportunistic pathogenic fungus that predominantly infects immunocompromised patients. It is the most common cause of infectious pneumonic mortality in HIV patients, organ transplant recipients, and cancer patients. A. fumigatus infection in HIV infected patients is most pertinent due to the exceptionally high mortality rate (>75% die within the first year of infection). Treatment is complicated by the fact that patients are often too fragile for invasive or toxic therapies. The current first-line treatment for aspergillosis is amphotericin B (AMB) but it is both highly nephrotoxic and insoluble. Its nephrotoxicity can be a significant contributing factor to mortality. Thus, AMB presents an array of challenges to its therapeutic application. In response to this problem, we have developed NanoDisks(tm), a novel preparation of lipid and protein for the solubilization and delivery of hydrophobic drugs. NanoDisks are 8 - 15 nm diameter disc-shaped structures composed of a lipid bilayer circumscribed by a stabilizing apolipoprotein or peptide mimetic. When AMB is incorporated into NanoDisks (ND-AMB), we observe a dramatic increase in solubility and reduction in toxicity. In comparison to a leading commercial liposomal formulation of AMB (AmBisome), the minimal inhibitory concentration of ND-AMB against Aspergillus is 25-fold lower and in an animal model of disseminated Candidiasis, ND-AMB is effective at 5-fold lower doses. Because the normal route of Aspergillus infection is through inhalation of conidia, aspergillosis may be most responsive to therapies that are directed to the lung. Phase I results of this SBIR proposal demonstrated that ND-AMB could be lyophilized, milled into powder and reyhydrated without loss of biological activity, complex integrity or AMB toxicity attenuation. Therefore we hypothesize that NanoDisks are capable of effective pulmonary and systemic delivery via inhalation for the treatment of A. fumigatus pulmonary and systemically disseminated infection. We will examine the overall capability of ND-AMB as an inhaled therapy. Specifically, we will characterize ND-AMB's ability to enter the bloodstream after inhalation, its pharmacokinetic distribution, toxicity and efficacy in treating pulmonary and systemic fungal infection in murine model systems. We hope to replicate our success with AMB as a leishmaniasis therapy, wherein we converted AMB from a marginally effective treatment to a potent cure by reformulating AMB into ND-AMB. Results from this study are essential for the development of an improved inhalable AMB-based therapy for the treatment of aspergillosis; a serious health issue for HIV infected patients, wherein median survival is 3 months. With inhalable ND-AMB we believe we will bring to bear an effective cure to a disease, wherein mortality rates are extremely high (> 75%).