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

描述(由申请人提供)： VINDIO纳米生物技术公司(VINDIO)正在开发一种基于血红蛋白的细胞氧疗(血液替代品)--纳米血红素，该产品基于其专有的基于纳米颗粒的输送平台，称为聚合体。聚合体是在纳米尺度上形成的合成聚合物囊泡，可以有效地包裹携带氧气的蛋白质，如血红蛋白(Hb)。所述纳米血红素铅配方由两嵌段共聚物组成，所述两嵌段共聚物包括亲水性聚氧乙烯(PEO)和疏水性聚己内酯(PCL)。纳米血红素展示了理想氧疗的所有特征，如可调的氧结合能力、均匀且小的尺寸、类似于人类血液的粘度和肿胀压力特性以及易于大规模生产和储存。将Hb包裹在多聚体核心内，保护周围组织和血液成分不与Hb直接接触，并允许使用价格较低的动物Hb。它还允许操纵纳米血红素的物理化学性质，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细胞Hb的氧气载体相比，Nanoheme显示出几个优点。与脂质体氧疗相比，PEO提供了更好的体外化学稳定性、体内生物利用度和延长血液循环半衰期的纳米血红素。PCL是一种著名的植入性生物材料，它形成囊泡膜，通过其酯键的水解促进产物在体内的完全和安全降解。聚合物膜明显厚于脂质体，后者提供了更好的机械性能。聚合体在原位稳定几个月，在血浆中稳定几天，大小和形态没有任何变化。因此，纳米血红素将建立在优势的基础上，同时绕过合成氧气疗法的局限性。纳米血红素的使用将通过帮助缓解目前美国和世界范围内的血液短缺，并通过减少我们对人类红细胞输注的依赖，来满足一个主要的未得到满足的医疗需求。这将为输血中心带来巨大的成本节约，因为试剂和劳动力成本的降低，以及由于红细胞输注问题导致的患者护理成本的降低。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经济刺激。维迪诺的学术合作者已经证明了将血红蛋白封装在可生物降解的聚合体中的原理。在这项工作中，我们将通过探索PEO-b-PCL家族的各种共聚物作为复合构建块、不同的血红蛋白来源和不同的生产条件来优化聚合物微囊Hb分散体的结构，以创建一系列PEH分散体。这些分散体将严格表征颗粒大小和形态、血红蛋白包封率和高铁血红蛋白(MetHb)水平，我们还将表征PEH分散体的功能特性，如它们与氧和一氧化氮的结合特性，以及它们在较长一段时间的生理条件下的稳定性。符合我们可行性标准的PEH分散体将进入第二阶段，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来确定通往临床的适当监管路径，并将向FDA提交这一计划。到整个项目结束时，Vindo将开发出世界上第一个有效、安全和可靠的合成氧气载体，供人类和兽医使用。 公共卫生相关性： 项目简介这项研究将通过提供一种新的可供患者使用的合成氧气疗法(血液替代品)，对公众健康产生重大影响。该产品将克服与红细胞输注和正在开发的合成氧疗相关的所有限制。该产品的使用将缓解美国和世界上严重的血液短缺。最终结果将是患者护理标准的提高和患者死亡率的降低。显著的额外好处将是在降低运营成本方面为医疗保健系统节省大量成本，以及创造巨大的就业机会和经济刺激。

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.