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

描述（由申请人提供）：烟曲霉是一种机会致病性真菌，主要感染免疫功能低下的患者。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。由于极高的死亡率（约75%的患者在感染后一年内死亡），艾滋病毒感染患者的烟曲霉感染是最相关的。由于患者往往太脆弱，无法进行侵入性或毒性治疗，治疗变得复杂。目前治疗曲霉病的一线药物是两性霉素B (AMB)，但它具有高肾毒性且不溶性。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。针对这一问题，我们开发了纳米磁盘（NanoDisks, tm），这是一种新型的脂质和蛋白质制剂，用于疏水药物的增溶和递送。纳米圆盘是直径8 - 15nm的圆盘状结构，由脂质双分子层组成，由稳定的载脂蛋白或模拟肽组成。当AMB掺入纳米片（ND-AMB）时，我们观察到其溶解度显著增加，毒性降低。与AMB （AmBisome）的主要商业脂质体制剂相比，ND-AMB对曲霉的最低抑制浓度低25倍，在播散性念珠菌病的动物模型中，ND-AMB的有效剂量低5倍。由于曲霉感染的正常途径是通过吸入分生孢子，曲霉病可能对针对肺部的治疗最敏感。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，我们假设纳米磁盘能够通过吸入有效的肺部和全身给药，以治疗烟曲霉肺部和全身弥散性感染。我们将检查ND-AMB作为吸入疗法的整体能力。具体来说，我们将在小鼠模型系统中描述ND-AMB吸入后进入血液的能力，其药代动力学分布，毒性和治疗肺部和全身真菌感染的功效。我们希望复制AMB作为利什曼病治疗的成功，通过将AMB重新配制成ND-AMB，我们将AMB从一种边际有效的治疗转变为一种有效的治疗。这项研究的结果对于开发一种改良的基于amb的可吸入治疗曲霉病的疗法至关重要；艾滋病毒感染者的严重健康问题，其中中位生存期为3个月。有了可吸入的ND-AMB，我们相信我们将有效地治愈这种死亡率极高（约75%）的疾病。

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%).