Protein Stabilization in Ionic Liquids

离子液体中的蛋白质稳定性

• 批准号: 7640589
• 负责人: GLORIA D ELLIOTT
• 金额: $ 18万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640589
• 关键词: Achievement; Adverse effects; Amino Acids; Anions; Biocompatible; Bone Transplantation; Bovine Serum Albumin; Cations; Characteristics; Chemicals; Clinical; Coagulants; Complement Factor B; Cytochromes; Databases; Development; Disease; Dose; Drug Formulations; Drug Monitoring; Ensure; Etanercept; Excipients; Factor IX; Family; Food Additives; Future; Goals; Health; Hemophilia A; Home environment; Human; Hydrogen Bonding; Injection of therapeutic agent; Ions; Knowledge; Liquid substance; Muramidase; Nature; Oral; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Process; Proteins; Publishing; ReFacto; Recombinants; Research; Research Personnel; Rheumatoid Arthritis; Safety; Salts; Science; Simulect; Social Welfare; Solubility; Solvents; Stress; Subcutaneous Injections; Temperature; Testing; Therapeutic; Time; Toxic effect; United States Food and Drug Administration; United States National Institutes of Health; Visit; Water; Work; aqueous; base; basiliximab; biomaterial compatibility; bone; compliance behavior; cost; cytochrome c; design; dosage; drug candidate; ethylammonium nitrate; factor A; high risk; human disease; innovation; intravenous administration; liquid formulation; meetings; novel; oxidation; prevent; protein structure function; public health relevance; reconstitution; reconstruction; small molecule; sugar; therapeutic protein

DESCRIPTION (provided by applicant): Protein-based therapeutic drugs have demonstrated significant efficacy in controlling and curing disease. Unlike traditional small molecule-based drug therapies, a major hurdle in the development of protein drugs is the challenge of maintaining the protein in the folded state throughout processing and also during storage at the end point-of-use. Patient compliance decreases as the complexity of administration increases, consequently liquid formulation of parenterals is highly preferred over lyophilized dosages that require reconstitution by the patient. Ionic liquids (ILs) are a class of materials that have considerable potential to provide advances in liquid formulation of protein pharmaceuticals. ILs is materials that have ionic character yet are in liquid form at room temperature. Although traditional ILs are synthesized from imidazolium-based actions and highly fluorinated anions, ILs can also be formulated from salts, sugars, amino acids, and biomolecules that exist in nature - many of which have already been approved as excipients. The exciting feature of ILs is that, because they consist of chemically distinct ions, the hydrogen-bonding character and the water miscibility can effectively be `tuned' to the application depending on the nature of the action and anion in the mixture. The following specific aims represent the critical steps in identifying potential ILs for use as protein stabilizers in liquid formulations: Aim #1: To evaluate the cyto-toxicity and water miscibility of a panel of rationally designed ILs to identify the least toxic, most hydrophilic compounds for continued studies. Aim #2: To identify the most solubilizing ILs for cytochrome C, lysozyme, and bovine serum albumin from the subset of ILs prioritized in Aim #1. Aim #3: To determine if the selected ILs can preserve protein structure and function in liquid formulation over long periods of storage and also under short term physical and chemical stresses. Broader Impact: The proposed work fits well with the goals of the NIH because it will advance our understanding of protein stabilization in liquids as it pertains to drug formulation. Furthermore, successful achievement of the proposed goals will support, promote, and sustain advances in the economical formulation of protein-based therapeutics for the treatment of human disease. This will have a direct and immediate impact on national health and welfare issues. PUBLIC HEALTH RELEVANCE: Protein-based therapeutic drugs have demonstrated significant efficacy in controlling and curing disease. Unlike traditional small molecule-based drug therapies, a major hurdle in the development of protein drugs is the challenge of maintaining the protein in the folded state throughout processing and also during storage at the end point-of-use. Ionic liquids (ILs) are a class of materials that have considerable potential to provide advances in liquid formulation of protein pharmaceuticals. This project involves the synthesis, characterization, and optimization of newly designed biocompatible ionic liquids to facilitate solubilization and stabilization of proteins, and ultimately stable long-term storage and delivery of protein-based therapeutics. The proposed work will advance our understanding of protein stabilization in liquids as it pertains to drug formulation. Furthermore, successful achievement of the proposed goals will support, promote, and sustain advances in the economical formulation of protein-based therapeutics for the treatment of human disease. This will have a direct and immediate impact on national health and welfare issues.

描述（由申请人提供）：基于蛋白质的治疗药物在控制和治疗疾病方面表现出显著的功效。与传统的基于小分子的药物疗法不同，蛋白质药物开发的一个主要障碍是在整个加工过程中以及在最终使用点的储存过程中保持蛋白质处于折叠状态的挑战。随着给药复杂性的增加，患者的依从性降低，因此胃肠外液体制剂比需要患者重构的冻干剂量更优选。离子液体（Ionic Liquids，IL）是一类具有相当大的潜力来提供蛋白质药物的液体制剂的进展的材料。离子液体是具有离子特性但在室温下呈液体形式的材料。虽然传统的离子液体是由咪唑鎓基化合物和高度氟化的阴离子合成的，但离子液体也可以由自然界中存在的盐、糖、氨基酸和生物分子配制而成，其中许多已经被批准作为赋形剂。离子液体的令人兴奋的特点是，因为它们由化学上不同的离子组成，氢键特性和水溶性可以根据混合物中的作用和阴离子的性质有效地“调整”到应用中。以下具体目标代表了鉴定用作液体制剂中蛋白质稳定剂的潜在IL的关键步骤：目标#1：评价一组合理设计的IL的细胞毒性和水溶性，以鉴定毒性最小、最亲水的化合物用于继续研究。目的#2：从目的#1中优先考虑的IL子集中鉴定细胞色素C、溶菌酶和牛血清白蛋白的最增溶IL。目标3：确定所选择的离子液体是否可以在长期储存以及短期物理和化学应力下保持液体制剂中的蛋白质结构和功能。更广泛的影响：拟议的工作非常符合NIH的目标，因为它将促进我们对液体中蛋白质稳定性的理解，因为它涉及药物制剂。此外，所提出的目标的成功实现将支持、促进和维持用于治疗人类疾病的基于蛋白质的治疗剂的经济制剂的进展。这将对国家卫生和福利问题产生直接和立即的影响。公共卫生相关性：基于蛋白质的治疗药物在控制和治疗疾病方面表现出显着的疗效。与传统的基于小分子的药物疗法不同，蛋白质药物开发的一个主要障碍是在整个加工过程中以及在最终使用点的储存过程中保持蛋白质处于折叠状态的挑战。离子液体（Ionic Liquids，IL）是一类具有相当大的潜力来提供蛋白质药物的液体制剂的进展的材料。该项目涉及新设计的生物相容性离子液体的合成、表征和优化，以促进蛋白质的溶解和稳定，并最终稳定长期储存和递送基于蛋白质的治疗剂。拟议的工作将推进我们对液体中蛋白质稳定性的理解，因为它涉及药物制剂。此外，所提出的目标的成功实现将支持、促进和维持用于治疗人类疾病的基于蛋白质的治疗剂的经济制剂的进展。这将对国家卫生和福利问题产生直接和立即的影响。

项目成果

Structure and function of proteins in hydrated choline dihydrogen phosphate ionic liquid.

• DOI: 10.1039/c1cp22965f
• 发表时间: 2012-01
• 期刊: Physical chemistry chemical physics : PCCP
• 作者: K. D. Weaver;Regina M. Vrikkis;Matthew P Van Vorst;Jonathan Trullinger;R. Vijayaraghavan;D. Foureau;I. McKillop;D. Macfarlane;J. Krueger;G. Elliott

In vitro assessment of choline dihydrogen phosphate (CDHP) as a vehicle for recombinant human interleukin-2 (rhIL-2).

• DOI: 10.1007/s12195-012-0243-x
• 发表时间: 2012-12-01
• 期刊: CELLULAR AND MOLECULAR BIOENGINEERING
• 影响因子: 2.8
• 作者: Foureau, David M.;Vrikkis, Regina M.;Jones, Chase P.;Weaver, Katherine D.;MacFarlane, Douglas R.;Salo, Jonathan C.;McKillop, Iain H.;Elliott, Gloria D.
• 通讯作者: Elliott, Gloria D.