A universal multi-drug encapsulation and delivery system employing supramolecular nanogels that self-assemble via dynamic sulfone bonding

一种通用的多药物封装和递送系统，采用通过动态砜键自组装的超分子纳米凝胶

• 批准号: 10457457
• 负责人: Evan A. Scott
• 金额: $ 43.84万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457457
• 关键词: Address; Adjuvant; Antigens; Area; Bacteria; Biochemical; Biocompatible Materials; Biodistribution; Biological Assay; Biological Products; Biomimetics; Chemicals; Chemistry; Circular Dichroism; Complex; Contrast Media; DNA; Data Reporting; Development; Drug Delivery Systems; Drug Formulations; Employment; Environment; Equilibrium; Experimental Models; Flow Cytometry; Gel; Grain; Histology; Hydration status; Hydrogels; Hydrophobicity; Immunotherapy; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Leucine Zippers; Maps; Methodology; Methods; Microscopy; Modeling; Molecular; Morphology; Mus; NanoGel; Nanostructures; Nature; Nucleic Acids; Organ; Peptide Hydrolases; Pharmaceutical Preparations; Population Heterogeneity; Process; Property; Proteins; Proteomics; RNA; Recording of previous events; Reporting; Reproducibility; Series; Solvents; Spatial Distribution; Specific qualifier value; Structure; Sulfones; System; Testing; Therapeutic; Toxic effect; Tracer; Vaccines; Vertebral column; Vesicle; Water; amphiphilicity; aqueous; biomaterial compatibility; chemotherapy; clinical translation; copolymer; crystallinity; experience; experimental study; fluorophore; hydrophilicity; immunogenicity; in vivo; innovation; insight; molecular dynamics; nanobiomaterial; nanofabrication; nanoscale; novel; propylene; protein complex; research clinical testing; scale up; self assembly; simulation; small molecule; tool; vaccine efficacy; vaccine formulation; vaccine immunogenicity; vaccine platform

PROJECT SUMMARY Significance: Nanostructure formation by supramolecular self-assembly primarily involves the hydrophobic/hydrophilic equilibrium of amphiphiles within aqueous environments. The biocompatibility and chemical versatility permitted by block copolymer amphiphiles have allowed the fabrication of a wide range of nanoscale biomaterials (NBMs). Despite these advances, considerable challenges remain. Self-assembled NBMs experience substantial difficulties with the encapsulation of molecules, with many (often difficult to express or expensive) proteins and hydrophilic small molecules achieving low encapsulation efficiencies well below 20%. Furthermore, the multicomponent structure of these amphiphiles often requires employment of complex block copolymer chemistries, which can present difficulties when scaling up synthesis and purification for practical clinical testing and translation. Innovation: A novel means of supramolecular self-assembly that employs a single, simple, water-soluble homopolymer that achieves >90% encapsulation efficiency universally for multiple hydrophilic (and hydrophobic) small molecules and biologics simultaneously will be modeled, optimized and validated. The unique network self-assembly of poly(propylene sulfone) (PPSU) homopolymers, which are simultaneously both soluble and crystallizable in water, has not been previously reported. By adjusting solvent polarity, intra- and interchain segments of noncovalent sulfone-sulfone bonds form along the PPSU backbone, biomimetic of DNA hybridization and leucine zippers in proteins. Preliminary experiments and simulations of this process revealed dynamic sulfone-sulfone interactions to form an interconnected physical gel network that can solidify into either macroscale hydrogels or collapse into nanogels of diverse morphologies. Using this rapid and scalable methodology, uniform populations of diverse nanogel morphologies can be specified, including spheres, vesicles and filamentous bundles. Importantly, drugs (regardless of their physicochemical properties) are efficiently and universally captured within PPSU nanogels during network collapse. This novel mechanism of molecular encapsulation demonstrates an exceptionally high loading efficiency for all molecules tested and combinations thereof, including proteins, DNA, RNA, fluorophores, contrast agents and small molecule drugs. Two independent aims are proposed to optimize and validate PPSU NBMs as a novel controlled delivery platform for biomedical applications. Aim 1: Employ molecular dynamics simulations and analytical nanoscale microscopy to mechanistically understand PPSU self-assembly and therapeutic loading. Aim 2: Develop universal molecular encapsulation by PPSU as a tool for the optimization of a model NBM vaccine formulation.

项目概要 意义：超分子自组装形成纳米结构主要涉及 水性环境中两亲物的疏水/亲水平衡。生物相容性和 嵌段共聚物两亲物所允许的化学多功能性允许制造各种 纳米级生物材料（NBM）。尽管取得了这些进展，但仍然存在相当大的挑战。自组装 NBM 在分子封装方面遇到了巨大的困难，其中许多（通常难以表达） 或昂贵的）蛋白质和亲水性小分子的封装效率远低于 20%。 此外，这些两亲物的多组分结构通常需要使用复杂的嵌段 共聚物化学，在扩大合成和纯化用于实际应用时可能会带来困难 临床测试和翻译。 创新：一种新颖的超分子自组装方法，采用单一、简单、水溶性 均聚物对于多种亲水性（和疏水性）普遍实现 >90% 的封装效率 小分子和生物制剂将同时进行建模、优化和验证。独特的网络 聚（丙烯砜）（PPSU）均聚物的自组装，同时具有可溶性和可溶性 能在水中结晶，此前未见报道。通过调整溶剂极性、链内和链间 非共价砜-砜键片段沿着 PPSU 主链形成，仿生 DNA 蛋白质中的杂交和亮氨酸拉链。该过程的初步实验和模拟揭示了 动态的砜-砜相互作用形成互连的物理凝胶网络，可以固化成 宏观水凝胶或塌陷成不同形态的纳米凝胶。使用这种快速且可扩展的 方法，可以指定不同纳米凝胶形态的统一群体，包括球体、囊泡 和丝状束。重要的是，药物（无论其理化性质如何）能够有效且有效地发挥作用。 在网络崩溃期间普遍捕获在 PPSU 纳米凝胶中。这种新颖的分子机制 封装对所有测试的分子和组合表现出极高的装载效率 其中包括蛋白质、DNA、RNA、荧光团、造影剂和小分子药物。 提出了两个独立的目标来优化和验证 PPSU NBM 作为新型受控交付平台 用于生物医学应用。目标 1：采用分子动力学模拟和纳米级分析 显微镜以机械方式了解 PPSU 自组装和治疗负荷。目标 2：发展 PPSU 的通用分子封装作为优化 NBM 疫苗配方模型的工具。