Lipid Based Self Assembled Materials Synthesis and Characterization

脂质自组装材料的合成与表征

• 批准号: 10682620
• 负责人: Colby Shad Thaxton
• 金额: $ 27.6万
• 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/10682620
• 关键词: Address; Affinity; Anti-Inflammatory Agents; Apolipoprotein A-I; Binding; Biological; Biological Process; Biological Products; Cell model; Cells; Chemicals; Chemistry; Cholecalciferol; Cholesterol; Clinic; Collaborations; Cream; Data; Development; Diameter; Drug Delivery Systems; Epithelial Cells; Epithelium; 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; Organic Synthesis; Pathway interactions; Peptides; Pharmaceutical Preparations; Phospholipids; Process; Property; Proteins; Serum; Skin; Skin injury; Small Interfering RNA; Solid; Sterols; Structure; Surface; Therapeutic; Topical application; Translations; Universities; Vitamin D; Work; arm; cell type; cellular imaging; drug release profile; flexibility; healing; hydrophilicity; in vivo; in vivo evaluation; keratinocyte; keratinocyte differentiation; lipid metabolism; nanoGold; nanoparticle; nanotherapeutic; novel; novel therapeutics; receptor; remediation; scaffold; scavenger receptor; screening; self assembly; severe injury; small molecule; targeted treatment; technology platform; uptake; wound healing; Address; Affinity; Anti-Inflammatory Agents; Apolipoprotein A-I; Binding; Biological; Biological Process; Biological Products; Cell model; Cells; Chemicals; Chemistry; Cholecalciferol; Cholesterol; Clinic; Collaborations; Cream; Data; Development; Diameter; Drug Delivery Systems; Epithelial Cells; Epithelium; 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; Organic Synthesis; Pathway interactions; Peptides; Pharmaceutical Preparations; Phospholipids; Process; Property; Proteins; Serum; Skin; Skin injury; Small Interfering RNA; Solid; Sterols; Structure; Surface; Therapeutic; Topical application; Translations; Universities; Vitamin D; Work; arm; cell type; cellular imaging; drug release profile; flexibility; healing; hydrophilicity; in vivo; in vivo evaluation; keratinocyte; keratinocyte differentiation; lipid metabolism; nanoGold; nanoparticle; nanotherapeutic; novel; novel therapeutics; receptor; remediation; scaffold; scavenger receptor; screening; self assembly; severe injury; small molecule; targeted treatment; technology platform; 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 基于脂质的自组装材料和表征核心（LBSAMCC）的总体目标是 合成，表征和提供高度新颖的治疗剂，以改善氮的毁灭性作用 和眼睛（项目1）和皮肤（项目2）的硫磺芥末。高密度脂蛋白（HDL）很小 溶解和运输胆固醇和脂质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。小说的发展和交付 模仿HDLS的这些关键功能特征的材料，重要的是，可以靶向适当的单元 眼睛和皮肤中的类型（例如，先天免疫细胞，角膜细胞和角质形成细胞），高度区分 芥末造成的平台从其他人改善伤害。 Thaxton实验室开创了合成 HDL样合成生物制剂（HDL NP），带有惰性的固体核心金纳米颗粒（AUNP） HDLS的脂质和蛋白质货物的组装可以化学附着。整体尺寸和表面化学可以 严格控制类似于本地HDL，使这些第一代材料可以量身定制，以便 可以添加任何数量的磷脂，固醇和/或小分子药物（例如siRNA或microRNA）。 Thaxton和Nguyen Labs之间的最新合作进一步证明，第一的AUNP 可以将生成材料换成尺寸控制的有机芯（OC）脚手架，可用于 控制生物学功能（例如胆固醇吸收和抗炎），并打开了加载的机会 并使用相关疗法（例如维生素D）卸载这些靶向材料的核心。最终，合成 HDL Biologics为开发针对眼睛和/或皮肤损伤的新型疗法提供了巨大的机会 由于暴露于芥末而发生。 LBSAMCC将直接负责合成一套有机的套件 核心（特定目标1）用作模板，以产生有没有小的OCHDL NP库 分子和脂质偶联的药物，并配制为局部应用于眼睛和皮肤（特定的AIM 2）。 此外，LBSAMCC将促进OCHDL的完整理化和功能筛选 NP（特定目标3），以便可以自信地交付并在每个项目中进一步发展。作为 这样，LBSAMCC将提供有效的OCHDL NP，以补救眼睛的化学芥末损伤，并 皮肤。这项工作的影响是一种严格的方法和逐步的方法将局部产生有效 提供的疗法可以改善氮和硫给眼睛和皮肤造成的破坏性损伤 芥末。