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

吸入式两性霉素 B 纳米盘治疗 HIV 感染者的曲霉菌病

• 批准号: 7339016
• 负责人: TRUDY M FORTE
• 金额: $ 42.11万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339016
• 关键词: Adverse effects; Alveolar; AmBisome; Amphotericin B; Animal Model; Antibiotics; Antifungal Agents; Apolipoproteins; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological; Biological Models; Blood Circulation; Breathing; Caliber; Cancer Patient; Candida; Candidiasis; Cells; Complex; Development; Disease; Disseminated candidiasis; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Epithelial; Epithelial Cells; Epithelium; Freeze Drying; Growth; HIV; Health; Hepatic; Hepatotoxicity; Immunocompromised Host; In Vitro; Infection; Inhalation Drug Administration; Invasive; Kidney; Knowledge; Leishmaniasis; Lipid Bilayers; Lipids; Liposomes; Lung; Lung diseases; Membrane; Modeling; Mus; Mycoses; Nephrotoxic; Organ Transplantation; Pathology; Patients; Peptides; Performance; Pharmaceutical Preparations; Phase; Polyenes; Powder dose form; Preparation; Property; Proteins; Proxy; Rate; Relative (related person); Route; Shapes; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solubility; Stress; Structure; Systemic disease; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxic effect; Toxicity Attenuation; Transplant Recipients; Ursidae Family; amphotericin B-deoxycholate; base; concept; fungus; improved; in vivo; insight; mimetics; monolayer; mortality; nanodisk; nephrotoxicity; novel; particle; protein aminoacid sequence; response; size; success; water solubility

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%).

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。 HIV感染患者的烟曲霉感染是由于异常高死亡率（在感染的第一年内死亡> 75％），这是最相关的。治疗使患者通常太脆弱或有毒疗法变得复杂。目前对曲霉病的一线治疗是两性霉素B（AMB），但既高肾毒性又不溶。它的肾毒性可能是导致死亡率的重要因素。因此，AMB对其治疗应用提出了一系列挑战。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的圆盘形结构，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被限制。当将AMB纳入纳米风险（ND-AMB）中时，我们观察到溶解度和毒性降低的急剧增加。与AMB（Ambisome）领先的商业脂质体配方相比，ND-AMB对曲霉的最小抑制浓度低25倍，而在散布的念珠菌病的动物模型中，ND-AMB在5倍的剂量下可在5倍的剂量下有效。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。该SBIR提案的第一阶段结果表明，ND-AMB可以被冻干，铣削成粉末并重新水合而不会丧失生物学活性，复杂的完整性或AMB毒性衰减。因此，我们假设纳米虫能够通过吸入有效地进行肺和全身传递，以治疗烟曲霉肺和全身传播的感染。我们将研究ND-AMB作为吸入疗法的整体能力。具体而言，我们将表征ND-AMB吸入后进入血液的能力，其药代动力学分布，毒性和疗效在治疗鼠模型系统中的肺和全身真菌感染方面。我们希望将我们的成功复制为AMB作为利什曼病疗法，在其中，我们通过将AMB重新定义为ND-AMB，将AMB从边缘有效的治疗转变为有效的治疗方法。这项研究的结果对于开发改善了基于AMB的曲霉病治疗的可吸入疗法至关重要。艾滋病毒感染患者的严重健康问题，中位生存期为3个月。使用可吸入的ND-AMB，我们认为我们将带来有效的治疗方法，其中死亡率极高（> 75％）。