Nanocarrier with metal bridge for affinity based delivery of metal binding peptid

具有金属桥的纳米载体，用于基于亲和力的金属结合肽的递送

• 批准号: 7475033
• 负责人: Elijah M. Bolotin
• 金额: $ 19.97万
• 依托单位: PHARMAIN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475033
• 关键词: Address; Affinity; Animal Model; Animals; Antibiotic Resistance; Bacteria; Binding; Biodistribution; Biological Products; Blood; Blood Circulation; Blood specimen; Businesses; Cell Wall; Communities; Complex; Coupled; Data; Development; Dissociation; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Emergency Situation; Endocarditis; Endopeptidases; Enzymes; Evaluation; Funding; Furunculosis; General Hospitals; Genus staphylococcus; Goals; Half-Life; Human; Imidazole; In Vitro; Infection; Invasive; Legal patent; Licensing; Life; Lysostaphin; Massachusetts; Measurement; Mediating; Metal Binding Site; Metalloendopeptidases; Metals; Modeling; Multi-Drug Resistance; Nanotechnology; Osteomyelitis; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Pneumonia; Polymers; Proteins; Public Health; Range; Rattus; Research; Resistance; Serum; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staphylococcal Infections; Staphylococcus aureus; System; Systemic Therapy; Technology; Therapeutic; Time; Tissues; United States Food and Drug Administration; Vancomycin Resistance; Vascular Permeabilities; base; catheter related infection; commercialization; concept; copolymer; design; in vivo; nanocarrier; new technology; novel; success; treatment duration

DESCRIPTION (provided by applicant): Lysostaphin, a metalloendopeptidase that is bacteriolytic for Staphylococcus aureus, is a potential systemic therapy for treating multidrug-resistant S. aureus mediated infections. However, the short half life of this enzyme in vivo has precluded its development thus far as a systemic therapy. Our company, PharmaIN proposes to apply a novel drug delivery nanotechnology (drug nanocarrier) called Protected Graft Copolymers (PGC) coupled with PharmaIN's Reversible Binding (PRB), a new technology for the reversible formulation of peptides and/or proteins containing a metal binding site to the drug nanocarrier. Importantly, the fact that the nanocarrier concentrates at sites of increased vascular permeability affords the ability to concentrate associated agents at the site of infection. Our long-term goal is to develop this delivery system for lysostaphin that, considering its Zn-binding domain, appears to be particularly well suited for association with our carrier. The envisioned formulation would not only offer the ability to prolong the circulation time of the enzyme but also concentrate the agent at sites of infection, potentially increasing efficacy, decreasing overall dose over the entire treatment period and suppressing the emergence of resistance. In the Phase I project, we propose the following: Aim 1: Design, synthesis, purification and characterization of PGC with PRB. Aim 2: Formulation of lysostaphin with PGC/PRB and determination of (i) formation efficiency of PGC/PRB:lysostaphin complex, (ii) dissociation constant of lysostaphin from the PGC/PRB in the presence and absence of serum, (iii) the ability, in vitro, to release lysostaphin from carrier in the presence of imidazole and substrate and maintain its activity without denaturation. Aim 3: Comparison of in vivo pharmacokinetic parameters of PGC/PRB:lysostaphin complex and lysostaphin. The Phase II studies will involve a comprehensive evaluation of formulated lysostaphin including biodistribution (accumulation at sites of infection) and efficacy in an animal model of staphylococcal infection. The studies are aimed toward filing an IND for the envisioned product - lysostaphin in an optimal infection site-directed delivery system for the treatment of invasive staphylococcal infections. Public Health Relevance: The available therapies for antibiotic resistant S. aureus bacteria are limited and the emergence of numerous high-level vancomycin resistant bacteria predicts a dire public health situation if new treatments aren't developed. This Phase I application is aimed toward developing a life-saving product for use in life threatening emergency caused by invasive and systemic staphylococcal infections with the eventual goal of FDA filing of an IND application. The product will contain an enzyme (lysostaphin) to digest bacterial cell walls and a nanocarrier drug delivery system that would make the enzyme stable to clear infections in blood and tissue of the patients.

描述（由申请人提供）：lysostaphin是一种用于金黄色葡萄球菌的细菌性的金属肽酶，是一种用于治疗多种耐药性金黄色葡萄球菌介导的感染的潜在全身疗法。但是，这种酶在体内的短期寿命已经排除了它的发展，因为它是一种全身疗法。药剂公司建议我们使用一种新型药物递送纳米技术（药物纳米载体），称为受保护的移植共聚物（PGC），再加上药剂的可逆结合（PRB），这是一种可逆配制的肽和/或蛋白质的新技术，该技术含有含有药物nanocarier的金属结合位点。重要的是，纳米载体集中在增加血管通透性的部位的事实使人们有能力在感染部位浓缩相关剂。我们的长期目标是为lysostaphin开发这种交付系统，考虑到其Zn结合领域，似乎特别适合与我们的载体关联。设想的配方不仅可以提供延长酶循环时间的能力，而且还可以将剂在感染部位集中，从而有可能提高疗效，从而降低整个治疗期间的总剂量并抑制耐药性的出现。在第一阶段项目中，我们提出以下内容：目标1：使用PRB的PGC设计，合成，纯化和表征。 Aim 2: Formulation of lysostaphin with PGC/PRB and determination of (i) formation efficiency of PGC/PRB:lysostaphin complex, (ii) dissociation constant of lysostaphin from the PGC/PRB in the presence and absence of serum, (iii) the ability, in vitro, to release lysostaphin from carrier in the presence of imidazole and substrate and maintain its activity without denaturation. AIM 3：PGC/PRB体内药代动力学参数的比较：lysostaphin复合蛋白和lysostaphin。第二阶段的研究将涉及对包括生物分布（感染部位的积累）和葡萄球菌感染动物模型的疗效（包括生物分布（在感染部位的积累）的全面评估。这些研究旨在为所设想的产物-Lysostaphin提交最佳感染现场输送系统，以治疗侵入性葡萄球菌感染。 公共卫生相关性：抗生素抗生素链球菌细菌的可用疗法受到限制，并且许多高级万古霉素耐药细菌的出现预测，如果未开发新的治疗方法。该阶段I应用旨在开发挽救生命的产品，以用于侵入性和全身性葡萄球菌感染引起的生命威胁紧急情况，并最终将FDA提交IND应用程序。该产物将含有一种酶（lysostaphin），以消化细菌细胞壁和纳米载体药物输送系统，该酶将使酶稳定以清除患者的血液和组织中的感染。