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纳米生物技术公司（Vindico）正在开发一种基于血红蛋白的细胞氧治疗剂（血液替代品）NanoHeme，该药物基于其专有的基于纳米颗粒的递送平台，称为聚合物体。聚合物囊泡是以纳米尺寸形成的合成聚合物囊泡，其可以有效地包封携氧蛋白质如血红蛋白（Hb）。先导NanoHeme制剂由亲水性聚环氧乙烷（PEO）和疏水性聚己内酯（PCL）组成的二嵌段共聚物组成。NanoHeme展示了理想氧治疗剂的所有特性，例如可调的氧结合能力，均匀和小尺寸，粘度和与人体血液相似的oncebrance压力特性以及易于大规模生产和储存。将Hb包封在聚合物囊泡核心内保护周围组织和血液组分免于与Hb直接接触，并且它还允许使用较便宜的动物Hb。它还允许操纵NanoHeme的物理化学性质，以改善其血管内持久性和胶体状态。此外，NanoHeme比其他正在开发的基于Hb的细胞氧载体具有几个优点。PEO为NanoHeme提供了改善的体外化学稳定性，增强的体内生物利用度和基于脂质体的氧治疗剂的延长的血液循环半衰期。PCL是一种众所周知的可植入生物材料，形成囊泡膜，并通过水解其酯键促进所得产物的完全和安全的体内降解。聚合物膜比脂质体明显更厚，这为NanoHeme提供了更好的机械性能。多聚体在原位稳定数月，在血浆中稳定数日，大小和形态无任何变化。因此，NanoHeme将建立在优势的基础上，同时规避合成氧疗法的局限性。NanoHeme的使用将通过帮助缓解当前美国和全球血液短缺以及减少我们对人类RBC输注的依赖来满足主要未满足的医疗需求。这将导致输血中心的巨大成本节省，因为减少了试剂和劳动力成本，并减少了由于红细胞输血问题而导致的患者护理成本。仅在美国，它每年的市场就将超过10亿美元，从而创造巨大的就业机会和刺激经济。Vindico的学术合作者已经证明了血红蛋白在可生物降解聚合物囊泡中的原理性封装。在这项工作中，我们将通过探索PEO-b-PCL家族的共聚物作为复合结构单元，不同的血红蛋白来源和不同的生产条件来优化聚合物囊包封的Hb分散体的构建，以创建一系列PEH分散体。这些分散体将严格表征粒度和形态，血红蛋白包封效率和高铁血红蛋白（metHb）水平，我们还将表征PEH分散体的功能特性，如其与氧和一氧化氮的结合特性及其在生理条件下的长期稳定性。符合我们可行性标准的PEH分散体将进入II期，以确定其在小动物模型中的药代动力学、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，以确定一个适当的监管路径，以诊所，并将此计划提交给FDA。到整个项目结束时，Vindico将开发出世界上第一种有效，安全和可靠的人类和兽医用合成氧载体。 公共卫生相关性： 该研究将通过提供一种可用于患者的新的合成氧治疗剂（血液替代品）对公共卫生产生重大影响。该产品将克服与红细胞输注和正在开发的合成氧疗法相关的所有限制。该产品的使用将减少美国和世界的严重血液短缺。最终结果将是提高患者护理标准和降低患者死亡率。显著的额外优势将是通过降低运营成本为医疗保健系统节省大量成本，以及创造大量就业机会和刺激经济。