Inhalable amphotericin B nanodisk therapy for pulmonary aspergillosis

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。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（ampB），但它具有高度肾毒性且不溶性。因此，ampB对其治疗应用提出了一系列挑战，因此成功的结果低得令人不安：30 - 50%。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ampB被纳入Nanoparticles（ND-AMB），我们观察到溶解度显着增加和毒性降低。与ampB的主要商业脂质体制剂（AmBisome）相比，NDAMB对曲霉菌的最小抑制浓度（MIC）低25倍，在播散性曲霉病动物模型中，ND-AMB在低3至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。由于ND-AMB可以冻干和再水化而不损失生物活性或复合物的完整性，我们假设纳米颗粒与干粉吸入递送相容。我们建议测试的假设，NDAMB可以配制成一个改进的吸入治疗A。烟曲霉感染我们将检查ND-AMB用于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和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.