New Strategy for Controlled Release of Liposomal Contents

ID：MPS/DMR/BMAT(7623)1005515 PI：赵，严ORG：爱荷华州立大学标题：脂质体内容控制释放的新策略目的：本方案的目标是设计和合成能够在脂双层中形成纳米亲水孔的低聚物。中心的假设是，最近在PI的实验室开发的面部两亲性低聚物具有几个作为成孔材料的关键特征。这一假说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这一建议的总体目标，PI建议追求以下两个具体目标：(1)控制脂双层中形成孔的低聚物的构象。在初步研究中，PI制备了具有纳米级内部亲水通道的低聚胆酸盐折叠体。当加入到脂质双层中时，发现折叠分子的链长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)来控制低聚物在脂双层中的折叠。这些分子的构象将通过荧光共振能量转移(FRET)、荧光猝灭、UV-Vis和固体核磁共振光谱来表征。(2)用造孔性低聚物控制脂双层的通透性。所讨论的折叠体形成螺旋结构，具有亲水性的孔和胆固醇样的外部。在初步研究中，发现一个十二聚体和一个环三聚体允许羧基荧光素(CF)通过脂双层。通过控制低聚胆酸盐的构象、较短折叠分子链的可逆连接和环状低聚物的可逆聚集，PI有望通过温度、金属离子和分子或氧化还原信号来调节通过毛孔的交通。更广泛的影响：拟议的研究预计将在化学和制药行业产生几个广泛的影响。脂质体已经用于临床给药(例如阿霉素)；造孔材料可以通过控制释放的时间和位置来提高药物的疗效。亲水性分子通过疏水膜屏障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的开发也很重要。易于合成的造孔材料将在这些应用中开辟许多途径。这两项指标为拟议的研究带来了互补的专业知识。赵组在构象可控材料的设计和合成方面经验丰富，而Hong组在膜结合多肽和蛋白质的生物物理表征方面经验丰富。合作不仅将帮助PI探索任何一个单独难以完成的研究领域，还将挑战学生更具创造性的思维。与不同背景的同事一起工作，学生们将接触到非常不同的思维和解决问题的方式。这种协作将为他们在未来的职业生涯中在团队环境中有效地工作做好准备，并解决需要多个学科协调努力的问题。两个私人侦探都已经有本科生在实验室工作。在过去的夏天，通过南洋理工大学S女性项目招收的未被充分代表的本科生参与了这项研究。私人投资者将继续这一努力，利用仿生化学的吸引力来吸引学生学习科学。

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.