Lipid Based Self Assembled Materials Synthesis and Characterization

脂质自组装材料的合成与表征

• 批准号: 10490411
• 负责人: Colby Shad Thaxton
• 金额: $ 27.52万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490411
• 关键词: Address; Affinity; Anti-Inflammatory Agents; Apolipoprotein A-I; Binding; Biological; Biological Process; Biological Products; Caliber; Cell model; Cells; Chemicals; Chemistry; Cholecalciferol; Cholesterol; Clinic; Collaborations; Cream; Data; Development; Drug Delivery Systems; Epithelial; Epithelial Cells; Exposure to; Eye; Eye Injuries; Eyedrops; Formulation; Generations; Goals; Gold; High Density Lipoproteins; Hydrogen Bonding; Hydrophobicity; Imaging Techniques; Immune; Inflammation; Inflammatory; Infrastructure; Injury; Innate Immune System; Libraries; Lipids; Location; Mechlorethamine; Methods; MicroRNAs; Mustard; Mustard Gas; Nucleic Acids; Pathway interactions; Peptides; Pharmaceutical Preparations; Phospholipids; Process; Property; Proteins; Serum; Skin; Skin injury; Small Interfering RNA; Solid; Sterols; Structure; Surface; Technology; Therapeutic; Topical application; Translations; Universities; Vitamin D; Work; arm; base; cell type; cellular imaging; drug release profile; flexibility; healing; hydrophilicity; immune system function; in vivo; in vivo evaluation; keratinocyte; keratinocyte differentiation; lipid metabolism; nanoGold; nanoparticle; nanotherapeutic; novel; novel therapeutics; receptor; scaffold; scavenger receptor; screening; self assembly; severe injury; small molecule; targeted treatment; uptake; wound healing

SUMMARY The overall goal of the Lipid-Based Self-Assembled Materials and Characterization Core (LBSAMCC) is to synthesize, characterize, and deliver highly novel therapeutics for ameliorating the devastating effects of nitrogen and sulfur mustards to the eye (Project 1) and skin (Project 2). High-density lipoproteins (HDL) are small nanoparticles that solubilize and transport cholesterol and lipids, are integral in modulating the innate immune system, and function to enhance the integrity of epithelial barriers. The development and delivery of novel materials that mimic these key functional features of HDLs and, importantly, enable targeting of appropriate cell types (e.g. innate immune cells, keratocytes, and keratinocytes) in the eye and skin, highly differentiate this platform from others to ameliorate injuries caused by mustards. The Thaxton lab pioneered the synthesis of HDL-like synthetic biologics (HDL NPs) with an inert, solid core gold nanoparticle (AuNP) upon which the self- assembly of lipid and protein cargos of HDLs can chemically attach. The overall size and surface chemistry can be strictly controlled to resemble native HDLs enabling these first-generation materials to be tailorable, such that any number of phospholipids, sterols, and/ or small molecule drugs (e.g. siRNA or microRNA) may be added. Recent collaborations between the Thaxton and Nguyen labs further demonstrated that the AuNP of first- generation materials can be swapped out for size-controlling organic core (oc) scaffolds, which can be used to control biological function (e.g. cholesterol uptake and anti-inflammatory) and opens up the opportunity to load and unload the core of these targeted materials with relevant therapies (e.g. vitamin D). Ultimately, synthetic HDL biologics offer a tremendous opportunity for developing novel therapies against eye and/or skin injuries that occur due to exposure to mustards. The LBSAMCC will be directly responsible for synthesizing a suite of organic cores (Specific Aim 1) to be used as templates to produce a library of ocHDL NPs with and without small- molecule and lipid-conjugated drugs and formulated to be topically applied to the eye and skin (Specific Aim 2). Furthermore, the LBSAMCC will facilitate the complete physicochemical and functional screening of the ocHDL NPs (Specific Aim 3) so that they can be confidently delivered and further developed in each of the Projects. As such, the LBSAMCC will deliver effective ocHDL NPs to remediate chemical mustard injuries to the eye and skin. The impact of this work is that a rigorous approach and step-wise method will produce effective topically delivered therapies for ameliorating the devastating injuries caused to the eye and skin by nitrogen and sulfur mustard.

概括 脂质自组装材料和表征核心 (LBSAMCC) 的总体目标是 合成、表征和提供高度新颖的疗法，以减轻氮的破坏性影响 硫芥对眼睛（项目 1）和皮肤（项目 2）的影响。高密度脂蛋白（HDL）很小 纳米粒子可溶解和运输胆固醇和脂质，是调节先天免疫的重要组成部分 系统和功能以增强上皮屏障的完整性。小说的开发和交付 模仿 HDL 的这些关键功能特征的材料，重要的是，能够靶向适当的细胞 眼睛和皮肤中的类型（例如先天免疫细胞、角质细胞和角质形成细胞），高度区分这种细胞 向其他人提供平台以减轻芥末造成的伤害。 Thaxton 实验室率先合成了 类 HDL 合成生物制品 (HDL NP) 具有惰性、实心金纳米颗粒 (AuNP)，其上具有自 HDL 的脂质和蛋白质货物的组装可以通过化学方式附着。整体尺寸和表面化学性质可以 严格控制以类似于原生 HDL，使这些第一代材料能够进行定制，例如 可以添加任意数量的磷脂、甾醇和/或小分子药物（例如siRNA或microRNA）。 Thaxton 和 Nguyen 实验室最近的合作进一步证明，AuNP 的第一- 生成材料可以替换为尺寸控制的有机核心（oc）支架，该支架可用于 控制生物功能（例如胆固醇摄取和抗炎）并打开加载的机会 并用相关疗法（例如维生素D）卸载这些靶向材料的核心。最终合成 HDL 生物制剂为开发针对眼睛和/或皮肤损伤的新疗法提供了巨大的机会， 由于接触芥末而发生。 LBSAMCC将直接负责合成一套有机化合物 核心（具体目标 1）用作模板来生成带有或不带有小颗粒的 ocHDL NP 库。 分子和脂质结合药物，并配制为局部应用于眼睛和皮肤（具体目标 2）。 此外，LBSAMCC 将促进 ocHDL 的完整理化和功能筛选 NP（具体目标 3），以便可以在每个项目中自信地交付并进一步开发它们。作为 因此，LBSAMCC 将提供有效的 ocHDL NP 来修复化学芥子气对眼睛的损伤 皮肤。这项工作的影响在于，严格的方法和逐步的方法将产生有效的主题 提供治疗方法以减轻氮和硫对眼睛和皮肤造成的毁灭性伤害 芥末。