Inhalable amphotericin B nanodisk therapy for pulmonary aspergillosis

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 (ampB)，但它具有高肾毒性且不溶性。因此，ampB对其治疗应用提出了一系列挑战，其结果是成功率低得令人不安：30 - 50%。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ampB掺入纳米盘（ND-AMB）时，我们观察到其溶解度显著增加，毒性降低。与领先的商业ampB （AmBisome）脂质体制剂相比，NDAMB对曲霉的最低抑制浓度（MIC）降低了25倍，在播散性念珠菌病的动物模型中，ND-AMB的有效剂量降低了3至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。由于ND-AMB可以在不损失生物活性或复合物完整性的情况下进行冻干和再水化，我们假设纳米磁盘与干粉吸入递送兼容。我们提出测试假设，NDAMB可以制定成一个改进的可吸入治疗烟曲霉感染。我们将检查ND-AMB吸入给药的总体适用性，特别是ND-AMB与可吸入干粉合成的相容性以及ND-AMB通过肺泡上皮的能力。

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. 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 (ampB) but it is both highly nephrotoxic and insoluble. Thus, ampB presents an array of challenges to its therapeutic application and as a result successful outcomes are disturbingly low: 30 to 50%. 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 ampB 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 ampB (AmBisome), the minimal inhibitory concentration (MIC) of NDAMB against Aspergillus is 25-fold lower and in an animal model of disseminated Candidiasis, ND-AMB is effective at 3 to 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. Since ND-AMB can be lyophilized and rehydrated without loss of biological activity or complex integrity, we hypothesize that NanoDisks are compatible with dry powder inhalation delivery. We propose to test the hypothesis that NDAMB can be formulated into an improved inhaleable treatment for A. fumigatus infection. We will examine the overall suitability of ND-AMB for inhalation administration, specifically, ND-AMB compatibility with inhaleable dry powder synthesis and the ability of ND-AMB to transit the alveolar epithelium.