New Strategy for Controlled Release of Liposomal Contents

脂质体内容物受控释放的新策略

• 批准号: 1005515
• 负责人: Yan Zhao
• 金额: $ 42万
• 依托单位: Iowa State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1005515&HistoricalAwards=false
• 关键词: New; Strategy; Controlled; Release; Liposomal

ID: MPS/DMR/BMAT(7623) 1005515 PI: Zhao, Yan ORG: Iowa State UniversityTitle: New Strategy for Controlled Release of Liposomal ContentsINTELLECTUAL MERIT: The objective of this proposal is to design and synthesize oligomers capable of forming nanometer-sized hydrophilic pores in lipid bilayers. The central hypothesis is that facially amphiphilic oligomers developed recently in the PI's laboratory have several critical features as pore-forming materials. This hypothesis is based on structural features found in natural pore-forming proteins and in preliminary studies. To test the central hypothesis and accomplish the overall objective of this proposal, the PI proposes to pursue the following two specific objectives: (1) Control the conformation of pore-forming oligomers in lipid bilayers. In the preliminary study, the PI has prepared oligocholate foldamers with nanometer-sized internal hydrophilic channels. When incorporated into lipid bilayers, the proper matching between the chain length of the foldamer and the thickness of the membrane was found critical to the folding. Four independent strategies (i.e., hydrophilic anchoring, hydrophobic matching, pi-pi interactions, and ion-pairing) are proposed to control the folding of the oligomers in lipid bilayers. The conformations of these molecules will be characterized by fluorescence resonance energy transfer (FRET), fluorescence quenching, UV-vis, and solid-state NMR spectroscopy. (2) Control the permeability of lipid bilayers by pore-forming oligomers. The foldamers in question form helical structures with a hydrophilic pore and a cholesterol-like exterior. A dodecamer and a cyclic trimer were found to allow the passage of carboxyfluorescein (CF) across lipid bilayers in the preliminary study. By controlling the conformation of the oligocholates, reversible ligation of shorter foldamer strands, and reversible aggregation of cyclic oligomers, the PI expects to regulate the traffic through the pore by temperature, metal ions, and molecular or redox signals. BROADER IMPACTS: The proposed research is expected to have several broad impacts in the chemical and pharmaceutical industries. Liposomes are already used clinically to deliver drugs (e.g., doxorubicin); pore-forming materials may improve the efficacy of the drugs by controlling the timing and location of release. Delivery of hydrophilic molecules across a hydrophobic membrane barrier is not only important to drug delivery but also to clinical research, molecular biology, and sensor development. Pore-forming materials that can be easily synthesized will open up many avenues in these applications. The two PIs bring complementary expertise to the proposed research. The Zhao group is experienced with design and synthesis of conformationally controllable materials and the Hong group with biophysical characterization of membrane-bound peptides and proteins. Collaboration will not only help the PIs explore research areas difficult for either one alone but also challenge the students to think more creatively. Working together with co-workers with dissimilar backgrounds, students will be exposed to very different thinking and problem-solving styles. This kind of collaboration will prepare them to work effectively in a team environment in their future careers and tackle problems that require coordinated efforts from multiple disciplines. Both PIs already have undergraduate students working in the lab. In the past summers, underrepresented undergraduate students recruited through ISU?s Program for Women in Science and Engineering (PWSE) have participated in the research. The PIs will continue this effort, taking advantage of the attractiveness of biomimetic chemistry to attract students to science.

ID: MPS/DMR/BMAT(7623) 1005515皮：赵燕ORG：爱荷华州立大学标题：脂质体内容物控释的新策略智力优势：本提案的目的是设计和合成能够在脂质双层中形成纳米级亲水性孔的低聚物。中心假设是，最近在PI实验室开发的表面两亲性低聚物具有几个关键特征，作为孔隙形成材料。这一假设是基于在天然成孔蛋白和初步研究中发现的结构特征。为了验证中心假设并实现本提案的总体目标，PI建议追求以下两个具体目标：(1)控制脂质双分子层中成孔低聚物的构象。在初步研究中，PI制备了具有纳米级内部亲水性通道的低聚巧克力折叠物。当加入到脂质双层中时，折叠蛋白链长度和膜厚度之间的适当匹配对折叠至关重要。提出了四种独立的策略（即亲水锚定，疏水匹配，pi-pi相互作用和离子配对）来控制脂质双层中低聚物的折叠。这些分子的构象将通过荧光共振能量转移（FRET），荧光猝灭，紫外-可见和固态核磁共振波谱来表征。(2)通过成孔低聚物控制脂质双分子层的通透性。所讨论的文件夹形成具有亲水性孔和胆固醇样外观的螺旋结构。初步研究发现十二聚体和环三聚体允许羧基荧光素（CF）通过脂质双分子层。通过控制低聚胆酸酯的构象、短折叠链的可逆连接和环状低聚物的可逆聚集，PI期望通过温度、金属离子和分子或氧化还原信号来调节通过孔的交通。更广泛的影响：拟议的研究预计将对化学和制药工业产生几个广泛的影响。脂质体已在临床上用于输送药物（如阿霉素）；成孔材料可以通过控制药物释放的时间和位置来提高药物的疗效。亲水分子在疏水膜屏障上的传递不仅对药物传递很重要，而且对临床研究、分子生物学和传感器开发也很重要。易于合成的成孔材料将为这些应用开辟许多途径。这两个pi为拟议的研究带来互补的专业知识。Zhao组在构象可控材料的设计和合成方面经验丰富，Hong组在膜结合肽和蛋白质的生物物理表征方面经验丰富。合作不仅可以帮助pi探索任何一方都难以单独完成的研究领域，还可以挑战学生的创造性思维。与不同背景的同事一起工作，学生将接触到非常不同的思维和解决问题的方式。这种合作将使他们在未来的职业生涯中有效地在团队环境中工作，并解决需要多学科协调努力的问题。这两个项目都有本科生在实验室工作。在过去的夏天，通过国际州立大学招收的代表性不足的本科生？美国科学与工程女性项目（PWSE）参与了这项研究。pi将继续这一努力，利用仿生化学的吸引力来吸引学生学习科学。