Collaborative Research: The Use of Amphiphilic Polypeptoids to Connect Nanoparticle containing Lipid Rafts onto Liposomes and Erythrosomes through Self-Assembly

合作研究：利用两亲性多肽通过自组装将含有脂筏的纳米粒子连接到脂质体和红细胞体上

• 批准号: 1804861
• 负责人: Donghui Zhang
• 金额: $ 20.02万
• 依托单位: Louisiana State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1804861&HistoricalAwards=false
• 关键词: Collaborative; Research; Use; Amphiphilic; Polypeptoids

Polypeptoids are small protein-like molecules that self-assemble to form nanoparticles in solution. Polypeptoids can be synthesized with a high degree of precision and are entirely biocompatible, leading to significant potential uses in therapeutics and drug delivery. In such applications, the polypeptoid based drug carriers must effectively deliver the drug within the cell, thus requiring a detailed understanding of their interactions with cell membranes. This work seeks to engineer the interactions of specific polypeptoid systems with cell membranes using membrane models known as liposomes. These are small submicron particles in solution that contain an interior compartment with a cell-wall-like flexible external membrane. The investigators will experimentally study the formation and disruption of single and multi-layer liposomes to engineer a variety of systems to deliver drugs to cells in a targeted way. As part of this work, undergraduate and graduate students will be trained in the use of sophisticated experimental tools. In addition, the investigators are committed to outreach activities to K-12 students through hands-on demonstrations. A strong aspect of the outreach will be to expose process technology students in the New Orleans Community College system to the molecular aspects that drive chemical, petrochemical, and pharmaceutical operations. The specific class of polypeptoids that will be developed in this work include the hydrophobically modified polypeptoids or HMPs, which interact with the lipid bilayers through hydrophobe insertion into the bilayers, and thus disrupt the bilayer to form HMP+lipid fragments or rafts. The remarkable aspect of the manifestation of the hydrophobic effect is the propensity of these HMP+lipid rafts to reattach onto intact liposomes to form additional layers. Preliminary experimental observations indicate that there is a sheet-like winding and assembly of these rafts onto liposomes leading to double and multiple layers on liposomes. The connectivity of hydrophobes in a polymeric amphiphile such as HMP brings about a high density of insertions leading to rupture of liposomes into perhaps intact bilayer fragments. The reattachment of fragments is also a previously unrecognized manifestation of the hydrophobic interaction. Thus, a fundamental study of this phenomenon will lead to control over building layers onto liposomes and therefore lead to the development of new classes of fully biocompatible polymer-lipid assemblies. The potential to build bilayers onto liposomes and erythrosomes using a designed connective polymeric amphiphile has significant technical implications. These concepts have relevance to the attachment of drug-containing lipid entities to cell membranes and to vesicle systems. The ability of HMPs to remodel liposomes is a novel aspect of multilayer self-assembly with significant applications to using liposomes as multiple drug carriers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

多肽是一种类似蛋白质的小分子，在溶液中自组装形成纳米颗粒。多肽可以以高精度合成，并且完全具有生物相容性，在治疗和药物输送方面具有重要的潜在用途。在这些应用中，多肽类药物载体必须在细胞内有效地递送药物，因此需要详细了解它们与细胞膜的相互作用。这项工作旨在利用脂质体的膜模型来设计特定多肽系统与细胞膜的相互作用。这些是溶液中的小亚微米颗粒，含有一个内部隔间和细胞壁样的柔性外膜。研究人员将通过实验研究单层和多层脂质体的形成和破坏，以设计各种系统，以有针对性的方式将药物输送到细胞中。作为这项工作的一部分，本科生和研究生将接受使用复杂实验工具的培训。此外，调查人员还致力于通过实践示范向K-12学生推广活动。外展的一个重要方面是让新奥尔良社区学院系统中的工艺技术学生接触到驱动化学、石化和制药操作的分子方面。本研究将开发的特定多肽类包括疏水修饰的多肽类或HMPs，它们通过疏水插入到脂质双层中与脂质双层相互作用，从而破坏双层，形成HMP+脂质碎片或筏。疏水效应表现的显著方面是这些HMP+脂筏倾向于重新附着在完整的脂质体上形成额外的层。初步的实验观察表明，脂质体上有一个片状的缠绕和这些筏的组装，导致脂质体上的双层和多层。疏水分子在聚合物两亲体（如HMP）中的连通性带来了高密度的插入，导致脂质体破裂成可能完整的双层碎片。碎片的再附着也是以前未被认识到的疏水相互作用的表现。因此，对这一现象的基础研究将导致控制脂质体上的构建层，从而导致开发新型完全生物相容性聚合物-脂质组装体。利用设计的结缔组织两亲性聚合物在脂质体和红质体上构建双分子层的潜力具有重要的技术意义。这些概念与含有药物的脂质实体附着于细胞膜和囊泡系统有关。HMPs重塑脂质体的能力是多层自组装的一个新方面，在利用脂质体作为多种药物载体方面具有重要的应用。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。