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）：烟曲霉是一种机会性致病真菌，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。 HIV 感染患者中的烟曲霉感染最为相关，因为其死亡率极高（>75% 在感染第一年内死亡）。由于患者往往太脆弱而无法进行侵入性或毒性治疗，因此治疗变得复杂。目前治疗曲霉病的一线药物是两性霉素 B (AMB)，但它具有高度肾毒性且不溶。其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NanoDisks(tm)，这是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。 NanoDisks 是直径 8 - 15 nm 的盘状结构，由稳定载脂蛋白或肽模拟物包围的脂质双层组成。当 AMB 融入 NanoDisks (ND-AMB) 中时，我们观察到溶解度显着增加并毒性降低。与领先的 AMB 商业脂质体制剂 (AmBisome) 相比，ND-AMB 对曲霉的最低抑制浓度低 25 倍，并且在播散性念珠菌病动物模型中，ND-AMB 在低 5 倍的剂量下即可有效。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敏感。该 SBIR 提案的第一阶段结果表明，ND-AMB 可以冻干、研磨成粉末并再水合，而不会损失生物活性、复合物完整性或 AMB 毒性减弱。因此，我们假设 NanoDisks 能够通过吸入有效地进行肺部和全身递送，以治疗烟曲霉肺部和全身播散性感染。我们将检查 ND-AMB 作为吸入疗法的整体能力。具体来说，我们将在小鼠模型系统中表征 ND-AMB 吸入后进入血液的能力、其药代动力学分布、毒性和治疗肺部和全身真菌感染的功效。我们希望复制 AMB 作为利什曼病治疗的成功，通过将 AMB 重新配制为 ND-AMB，将 AMB 从一种勉强有效的治疗方法转变为一种有效的治疗方法。这项研究的结果对于开发改进的可吸入 AMB 疗法来治疗曲霉病至关重要；对于 HIV 感染患者来说，这是一个严重的健康问题，其中中位生存期为 3 个月。我们相信，通过吸入式 ND-AMB，我们将能够有效治愈死亡率极高（> 75%）的疾病。