Fully Biodegradable Polymersome-encapsulated Hemoglobin as a Novel Nanoparticle-b

完全可生物降解的聚合物囊泡封装的血红蛋白作为新型纳米颗粒-b

• 批准号: 7926295
• 负责人: Paiman Peter Ghoroghchian
• 金额: $ 19.97万
• 依托单位: VINDICO NANOBIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-07 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926295
• 关键词: Accounting; Aerobic; Animal Model; Animals; Binding; Biocompatible Materials; Biodistribution; Blood; Blood Circulation; Blood Substitutes; Caliber; Characteristics; Chemicals; Clinic; Clinical Trials; Cost Savings; Data; Dependence; Development; Dimensions; Drug Formulations; Drug Kinetics; Economics; Encapsulated; Equilibrium; Erythrocyte Transfusion; Esters; Exhibits; Extravasation; FDA approved; Family; Half-Life; Healthcare Systems; Hemoglobin; Human; Hydrolysis; In Situ; In Vitro; Kinetics; Lead; Lipids; Liposomes; Marketing; Measures; Mechanics; Medical; Membrane; Methods; Molecular Weight; Morphology; Nitric Oxide; Occupations; Oxygen; Particle Size; Patient Care; Patients; Permeability; Pharmacodynamics; Phase; Physiological; Plasma; Polyethylene Glycols; Polymers; Production; Property; Proteins; Public Health; Radial; Reagent; Reducing Agents; Research; Solutions; Source; Stimulus; Structure; Suspension substance; Suspensions; TNFRSF5 gene; Technology; Therapeutic; Thermodynamics; Thick; Time; Tissues; Toxicology; Transfusion; United States; Vesicle; Viscosity; Weight; Work; animal data; base; chemical stability; clinical application; copolymer; cost; di-block copolymer; improved; in vivo; indexing; insight; meetings; mortality; nanobiotechnology; nanoparticle; nanoscale; novel; particle; polycaprolactone; pre-clinical; pressure; public health relevance; segregation; tissue oxygenation; uptake

DESCRIPTION (provided by applicant): Vindico NanoBioTechnology Inc. (Vindico) is developing a hemoglobin-based cellular oxygen therapeutic (blood substitute), NanoHeme, based on its proprietary nanoparticle-based delivery platform known as polymersome. Polymersomes are synthetic polymer vesicles that are formed in nanometric dimensions which can efficiently encapsulate oxygen-carrying proteins such as hemoglobin (Hb). The lead NanoHeme formulation comprises of a diblock copolymer comprising hydrophilic polyethylene oxide (PEO) and hydrophobic polycaprolactone (PCL). NanoHeme demonstrates all the characteristics of ideal oxygen therapeutic, such as tunable oxygen binding capacity, uniform and small size, viscosity and oncotic pressure characteristics similar to human blood as well as ease of mass production and storage. Encapsulation of Hb inside polymersome core protects surrounding tissues and blood components from direct contact with Hb and it also allows for the use of less expensive animal Hb. It also allows for manipulation of physicochemical properties of NanoHeme to improve its intravascular persistence and colloidal state. Additionally, NanoHeme exhibits several advantages over other cellular Hb-based oxygen carriers under development. PEO provides NanoHeme improved in vitro chemical stability, augmented in vivo bioavailablity and prolonged blood circulation half-lives over liposome-based oxygen therapeutics. PCL, a well-known implantable biomaterial, forms the vesicle membrane, and facilitates complete and safe in vivo degradation of resulting product by hydrolysis of its ester linkages. Polymersome membrane is significantly thicker than liposome which offers NanoHeme improved mechanical properties. Polymersomes are stable for several months in situ, and for several days in blood plasma without any changes in size and morphology. Thus, NanoHeme will build on the advantages while circumventing the limitations seen with synthetic oxygen therapeutics. The use of NanoHeme will meet a major unmet medical need by helping to alleviate the current US and worldwide blood shortage and by decreasing our dependence on human RBC transfusions. It will result in tremendous cost saving for transfusion centers on account of reduced reagent and labor costs and decreased costs of patient care on account of problems with RBC transfusions. It will have a market in excess of $1 billion per year in the United States alone resulting in enormous job creation and economic stimulus. Vindico's academic collaborators have demonstrated proof-of-principle encapsulation of hemoglobin in biodegradable polymersomes. In this work, we will optimize the construction of polymersome encapsulated Hb dispersions by exploring range of copolymers from the PEO-b-PCL family as composite building blocks, different hemoglobin sources and different production conditions to create an array of PEH dispersions. These dispersions will be rigorously characterized for particle size and morphology, hemoglobin encapsulation efficiency and methamoglobin (metHb) level, We will also characterize the functional properties of PEH dispersions such as their binding characteristics with oxygen and nitric oxide and their stability under physiological conditions over an extended period of time. PEH dispersions that meet our feasibility criteria will be advanced to Phase II to determine their pharmacokinetics, biodistribution, toxicology and tissue oxygenation in small-animal models. By the end of Phase II, we anticipate having collected sufficient data to determine an appropriate regulatory path to the clinic, and will have presented this plan to the FDA. By the end of the entire project, Vindico will have developed world's first effective, safe and reliable synthetic oxygen carrier for human and veterinary use. PUBLIC HEALTH RELEVANCE: Project Narrative This research will have a major impact on public health by providing a new synthetic oxygen therapeutic (blood substitute) that can be administered to patients. This product will overcome all the limitations associated with red blood cell transfusion and synthetic oxygen therapeutics under development. The use of this product will reduce the significant blood shortage in US and world. The end result will be an improved standard of patient care and less patient mortality. Significant additional advantages will be a tremendous cost savings to the health care system in reduced operating costs, as well as enormous job creation and economic stimulus.

描述（由申请人提供）： Vindico Nanobiotechnology Inc.（Vindico）基于其专有的基于纳米粒子的递送平台（称为多聚甲型剂量），开发了基于血红蛋白的细胞氧治疗（血液替代品）。聚合物体是在纳米尺寸中形成的合成聚合物囊泡，可以有效地封装携带氧气的蛋白质（如血红蛋白（HB））。铅纳米素制剂包括二嵌段共聚物，该共聚物包含亲水性聚乙烯氧化物（PEO）和疏水性聚苯乙烯（PCL）。 Nanoheme展示了理想氧治疗的所有特征，例如可调氧结合能力，均匀和小尺寸，粘度和肿瘤压力特征，类似于人类血液以及易于批量生产和储存。 HB内部多层核心的封装可保护周围的组织和血液成分与HB直接接触，并且还允许使用较便宜的动物HB。它还允许操纵纳米季的物理化学特性，以改善其血管内持久性和胶体状态。此外，与正在开发的其他基于HB的氧载体相比，Nanoheme具有多个优势。 PEO提供了纳米素改善的体外化学稳定性，增强体内生物可利用度，并长期血液循环半衰期在基于脂质体的氧气疗法上。 PCL是一种众所周知的可植入生物材料，形成囊泡膜，并通过水解其酯链接的水解来促进产生产生的完全安全降解。多膜膜比脂质体明显厚，后者提供了纳米素改善的机械性能。聚合物体稳定了几个月的原位，并且在血浆中几天没有大小和形态的变化。因此，Nanoheme将基于优势，同时规避合成氧疗法所见的局限性。通过帮助减轻美国和全世界的血液短缺，并减少我们对人类RBC输血的依赖，可以通过帮助减轻美国和全球的血液短缺来满足非满足医疗需求。由于RBC输血问题，由于降低了试剂和人工成本以及降低患者护理成本，这将为输血中心节省大量成本。仅在美国，它将每年的市场超过10亿美元，从而产生巨大的就业机会和经济刺激。 Vindico的学术合作者已经证明了可生物降解聚合物体中血红蛋白的原理封装。在这项工作中，我们将通过探索PEO-B-PCL家族的共聚物范围作为复合构建块，不同的血红蛋白来源和不同的生产条件来优化多聚体封装的HB分散体的构建，以创建PEH分散量。这些分散体将以粒径和形态，血红蛋白包封效率和甲基糖蛋白（MECHB）水平进行严格的特征，我们还将表征PEH分散体的功能性能，例如在长时间的时间内，在物理条件下，在物理条件下，其结合特性与氧化物的结合特性，均具有结合特性。在小动物模型中，符合我们可行性标准的PEH分散剂将推进第二阶段，以确定其药代动力学，生物分布，毒理学和组织氧合。到第二阶段结束时，我们预计已经收集了足够的数据来确定诊所的适当调节途径，并将将此计划介绍给FDA。到整个项目结束时，Vindico将开发世界上第一个用于人类和兽医使用的有效，安全和可靠的合成氧载体。 公共卫生相关性： 项目叙述这项研究将通过提供可用于患者的新合成氧治疗（血液替代品），从而对公共卫生产生重大影响。该产品将克服与正在开发的红细胞输血和合成氧疗法有关的所有局限性。该产品的使用将减少美国和世界的严重血液短缺。最终结果将是改善患者护理和患者死亡率较低的标准。在降低运营成本以及巨大的创造就业和经济刺激方面，卫生保健系统的巨大成本节省将是巨大的成本节省。