Inhalable amphotericin B nanodisk therapy for pulmonary aspergillosis

吸入性两性霉素 B 纳米盘治疗肺曲霉病

• 批准号: 6993209
• 负责人: TRUDY M FORTE
• 金额: $ 10万
• 依托单位: LYPRO BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6993209
• 关键词: Inhalable; amphotericin; nanodisk; therapy; pulmonary

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.

描述（由申请人提供）：曲曲霉是一种机会性的致病真菌，主要会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率的最常见原因。治疗使患者通常太脆弱或有毒疗法变得复杂。当前对曲霉病的一线治疗方法是两性霉素B（AMPB），但既高肾毒性又不溶。因此，AMPB对其治疗应用提出了一系列挑战，因此成功的结果令人不安：30％至50％。为了应对这个问题，我们开发了纳米虫（TM），这是一种脂质和蛋白质的新型制备，用于疏水药物的溶解和递送。纳米虫是直径为8 -15 nm的盘状结构，该结构由脂质双层组成，该结构由稳定的载脂蛋白或肽模拟物限制。当将AMPB纳入纳米虫（ND-AMB）中时，我们观察到溶解度和毒性降低的急剧增加。与AMPB（Ambisome）的领先商业脂质体制剂相比，NDAMB对曲霉的最小抑制浓度（MIC）低25倍，并且在传播念珠菌病的动物模型中，ND-AMB在3至5倍下的下剂量下降。由于曲霉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疗法最有反应。由于ND-AMB可以被冻干和补水而不会丧失生物学活性或复杂的完整性，因此我们假设纳米风险与干粉吸入递送兼容。我们建议检验以下假设，即可以将NDAMB用于改进的烟曲霉感染可吸入的治疗方法。我们将检查ND-AMB对吸入给药的整体适用性，特别是ND-AMB与可吸入的干粉合成的兼容性以及ND-AMB过渡肺泡上皮的能力。