Lipid Based Self Assembled Materials Synthesis and Characterization

脂质自组装材料的合成与表征

• 批准号: 10282408
• 负责人: Colby Shad Thaxton
• 金额: $ 39.81万
• 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/10282408
• 关键词: Address; Affinity; Anti-Inflammatory Agents; Apolipoprotein A-I; Binding; Biological; Biological Process; 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.

摘要 基于脂质的自组装材料和表征核心(LBSAMCC)的总体目标是 合成、表征和提供用于改善氮气破坏性影响的高度新颖的疗法 和硫磺芥末对眼睛(项目1)和皮肤(项目2)。高密度脂蛋白(高密度脂蛋白)很小 溶解和运输胆固醇和脂类的纳米颗粒在调节先天免疫方面是不可或缺的。 系统，和功能，以增强上皮屏障的完整性。小说的发展与传递 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，先天性免疫细胞、角质形成细胞和角质形成细胞)高度区分这一点 来自他人的平台，以减轻由芥末引起的伤害。塔克斯顿实验室率先合成了 类高密度脂蛋白合成生物制品(高密度脂蛋白NPs)具有惰性的、固体核心的金纳米颗粒(AuNP)，在该颗粒上自身 高密度脂蛋白的脂类和蛋白质可以化学结合。总尺寸和表面化学成分可以 被严格控制为类似于本地HDL，从而使这些第一代材料可以裁剪，从而 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)。 塔克斯顿实验室和阮氏实验室最近的合作进一步证明，First- 新一代材料可以被大小可控的有机核心(Oc)支架取代，这种支架可以用于 控制生物功能(如胆固醇摄取和抗炎)，并打开加载的机会 并将这些靶向材料的核心与相关疗法(例如维生素D)一起卸载。最终，合成的 高密度脂蛋白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 由于暴露在芥末中而发生。LBSAMCC将直接负责合成一套有机 核心(特定目标1)将被用作模板，以产生具有和不具有小的- 分子和脂质结合的药物，并配制成局部应用于眼睛和皮肤(特定目标2)。 此外，LBSAMCC将促进ocHDL的全面物理化学和功能筛选 NPS(具体目标3)，以便能够在每个项目中自信地交付和进一步发展。AS 这样，LBSAMCC将提供有效的ocHDLNPs来修复化学芥末对眼睛的伤害，并 皮肤。这项工作的影响是，严格的方法和循序渐进的方法将产生局部有效的 提供治疗以改善氮和硫对眼睛和皮肤造成的破坏性伤害 芥末。