Development of Next Generation Stabilization Agents for Cell based Therapeutics

开发用于细胞治疗的下一代稳定剂

• 批准号: 8030836
• 负责人: GLORIA D ELLIOTT
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030836
• 关键词: Anions; Behavior; Bio-Base; Biocompatible; Biological; Biological Markers; Biological Preservation; Cations; Cell Therapy; Cell membrane; Cells; Characteristics; Chemicals; Cryoprotective Agents; Dehydration; Development; Disaccharides; Dissociation; Drug Formulations; Ensure; Equipment; Excipients; Future; Glass; High temperature of physical object; Individual; Industry; Life; Liquid substance; Malignant Neoplasms; Mammalian Cell; Mannitol; Medicine; Methods; MicroRNAs; Molecular; National Cancer Institute; Nitrogen; Osmolalities; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Proteins; Reaction; Research; Salts; Science; Small Interfering RNA; Sodium Chloride; Solutions; Solvents; Sorbitol; Stem cells; Sugar Alcohols; Technology; Temperature; Therapeutic; Time; Tissue Engineering; Tissues; Toxic effect; Transition Temperature; Transportation; Trehalose; Viscosity; Water; base; biobank; chemical reaction; cost; cryogenics; cytotoxicity; design; functional group; gene therapy; meetings; melting; next generation; physical property; prevent; small molecule; stem cell therapy; success; sugar; therapeutic gene; trend

DESCRIPTION (provided by applicant): We have recently demonstrated that low melting point organic salts, called ionic liquids, can be rationally designed to stabilize proteins against thermal denaturation by modulating solvent properties. By judicious choice of cation, anion, and functional groups, not only can the stabilization characteristics be tuned, but a range of physical properties, such as the pH, viscosity, and the extent of dissociation of the salt (i.e osmolality) can also be tailored to the application. We have also been able to modulate the cytotoxicity of ionic liquids by rational selection of anions. We propose to extend these exciting results to cellular applications, where many of the same features are desired in a cell stabilizing formulation. The determination and application of 'task-specific' molecular design rules will move preservation science beyond the standard trial and error approach with existing materials towards rationally designed cell protectants for specific tissue and storage requirements. Specifically we seek to: Aim #1: Determine the structural features and physical properties of ionic liquids that result in stabilizing associations and penetration of mammalian cell membranes. Aim #2: Determine the thermal-physical behavior and glass-forming characteristics of biocompatible ionic liquids in composition with water and sugar-based stabilizing molecules, such as trehalose. Aim #3: Establish the post preservation viability and shelf-life of cells stored in ionic liquid based preservation solutions using three different preservation methods: slow-cooling, rapid-cooling, and dehydration. PUBLIC HEALTH RELEVANCE: Cell-based therapeutics (e.g. stem cells used to treat certain cancers) must be stored at cryogenic temperatures, which results in very high storage and transportation costs. This research seeks to reduce these costs by investigating new materials that can enable cell-based therapies to be stored at higher temperatures.

描述（由申请人提供）：我们最近证明了低熔点有机盐，称为离子液体，可以通过调节溶剂性质来合理设计以稳定蛋白质，防止热变性。通过明智地选择阳离子、阴离子和官能团，不仅可以调整稳定特性，还可以调整一系列物理性质，如pH、粘度和盐的解离程度（即渗透压），也可以根据应用进行调整。我们还能够通过合理选择阴离子来调节离子液体的细胞毒性。我们建议将这些令人兴奋的结果扩展到细胞应用中，在细胞稳定配方中需要许多相同的功能。“特定任务”分子设计规则的确定和应用将使保存科学超越使用现有材料的标准试错方法，转向针对特定组织和储存要求合理设计细胞保护剂。具体来说，我们寻求：目标1：确定离子液体的结构特征和物理性质，从而稳定结合并穿透哺乳动物细胞膜。目标2：确定与水和糖基稳定分子（如海藻糖）组成的生物相容性离子液体的热物理行为和玻璃形成特性。目的#3：利用三种不同的保存方法：缓慢冷却、快速冷却和脱水，建立细胞在离子液体保存溶液中保存后的活力和保质期。