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

描述(申请人提供)：烟曲霉是一种机会致病真菌，主要感染免疫功能低下的患者。它是艾滋病毒患者、器官移植受者和癌症患者感染性肺炎死亡的最常见原因。由于异常高的死亡率(75%的人在感染第一年内死亡)，艾滋病毒感染患者中的烟雾菌感染是最相关的。患者往往太脆弱，无法进行侵入性或毒性治疗，这使得治疗变得复杂。目前治疗曲霉菌病的一线药物是两性霉素B(AMB)，但它对肾脏有高度毒性，而且不溶于水。它的肾毒性可能是导致死亡的一个重要因素。因此，AMB对其治疗应用提出了一系列挑战。针对这一问题，我们开发了纳米盘(TM)，这是一种用于增溶和输送疏水药物的脂类和蛋白质的新制剂。纳米盘是直径8-15 nm的盘状结构，由稳定的载脂蛋白或多肽模拟物包围的脂双层组成。当AMB被结合到纳米盘(ND-AMB)中时，我们观察到其溶解度显著增加，毒性降低。与AMB(AmBisome)的主要商业脂质体配方相比，ND-AMB对曲霉菌的最小抑制浓度低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。由于曲霉菌感染的正常途径是通过吸入分生孢子，曲霉菌病可能对针对肺部的治疗最敏感。该SBIR方案的第一阶段结果表明，ND-AMB可以被冷冻干燥、研磨成粉末并重新水化，而不会损失生物活性、络合物完整性或AMB毒性减弱。因此，我们假设纳米盘能够通过吸入有效的肺部和全身给药来治疗烟曲霉菌肺部和全身播散性感染。我们将检查ND-AMB作为吸入性治疗的整体能力。具体地说，我们将在小鼠模型系统中表征ND-AMB在吸入后进入血液的能力、其药代动力学分布、毒性和治疗肺部和系统性真菌感染的有效性。我们希望复制我们用AMB作为利什曼病治疗方法的成功，我们通过将AMB重新配方为ND-AMB，将AMB从轻微有效的治疗转变为有效的治疗。这项研究的结果对于开发一种改进的基于AMB的吸入性治疗曲霉病至关重要；曲霉病是艾滋病毒感染患者的一个严重的健康问题，中位生存期为3个月。有了吸入型ND-AMB，我们相信我们将为一种死亡率极高的疾病带来有效的治疗(&gt；75%)。

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%).