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）：溶葡萄球菌酶是一种金属内肽酶，对金黄色葡萄球菌具有溶菌作用，是治疗多重耐药葡萄球菌的潜在全身疗法。金黄色葡萄球菌介导的感染。然而，这种酶在体内的半衰期短，阻碍了其作为全身治疗的发展。我们的公司PharmaIN提出应用一种称为保护接枝共聚物（PGC）的新型药物递送纳米技术（药物纳米载体），与PharmaIN的可逆结合（PRB）相结合，这是一种用于可逆配制含有金属结合位点的肽和/或蛋白质的新技术。重要的是，纳米载体在血管渗透性增加的部位浓缩的事实提供了在感染部位浓缩相关试剂的能力。我们的长期目标是开发这种溶葡萄球菌酶的递送系统，考虑到其锌结合结构域，似乎特别适合与我们的载体结合。设想的配方不仅能够延长酶的循环时间，而且还能将药剂集中在感染部位，从而可能提高功效，降低整个治疗期间的总剂量并抑制耐药性的出现。在第一阶段的研究中，我们提出了以下几点：目的1：设计、合成、纯化和表征含PRB的PGC。目标二：用PGC/PRB配制溶葡萄球菌酶并测定（i）PGC/PRB：溶葡萄球菌酶复合物的形成效率，（ii）在血清存在和不存在下溶葡萄球菌酶从PGC/PRB的解离常数，（iii）在咪唑和底物存在下从载体释放溶葡萄球菌酶并保持其活性而不变性的能力。目的3：比较PGC/PRB：溶葡萄球菌酶复合物和溶葡萄球菌酶的体内药动学参数。II期研究将涉及对配制溶葡萄球菌酶的全面评估，包括生物分布（在感染部位的积累）和葡萄球菌感染动物模型中的功效。这些研究旨在为设想的产品-溶葡萄球菌酶在最佳感染部位定向递送系统中用于治疗侵袭性葡萄球菌感染提交IND。 公共卫生相关性：抗生素耐药沙门氏菌的可用疗法。金黄色葡萄球菌是有限的，如果不开发新的治疗方法，许多高水平万古霉素耐药细菌的出现预示着可怕的公共卫生状况。该I期申请旨在开发一种挽救生命的产品，用于由侵入性和全身性葡萄球菌感染引起的危及生命的紧急情况，最终目标是向FDA提交IND申请。该产品将含有一种酶（溶葡萄球菌酶）来消化细菌细胞壁和一个纳米载体药物输送系统，使酶稳定，以清除患者血液和组织中的感染。