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: 10626132
• 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/10626132
• 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; Dimethyl Sulfoxide; Drug Delivery Systems; Drug Formulations; Employment; Encapsulated; Environment; Equilibrium; Flow Cytometry; Gel; Grain; Histology; Hydration status; Hydrogels; Hydrophobicity; Immunotherapy; In Vitro; Individual; 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; Publishing; 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; experience; experimental study; fabrication; fluorophore; hydrophilicity; immunogenicity; in vivo; innovation; insight; molecular dynamics; nanobiomaterial; nanofabrication; nanoscale; novel; propylene; research clinical testing; scale up; self assembly; simulation; small molecule; stem; 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.

项目总结 意义：超分子自组装形成的纳米结构主要涉及 水环境中两亲分子的疏水/亲水平衡。它的生物兼容性和 嵌段共聚物两亲性所允许的化学多样性使其能够制造出广泛的 纳米生物材料(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在分子的封装方面遇到了很大的困难，许多(通常难以表达 或昂贵)蛋白质和亲水性小分子，实现远低于20%的低包封率。 此外，这些两亲分子的多组分结构通常需要使用复杂的嵌段 共聚物化学，这在放大合成和提纯实际应用时会带来困难 临床测试和翻译。 创新：一种新的超分子自组装方法，它使用单一的、简单的、水溶性的 对多种亲水性(和疏水性)具有90%包封率的均聚物 将同时对小分子和生物制品进行建模、优化和验证。独一无二的网络 聚丙基砜(PPSU)均聚体的自组装 可在水中结晶，以前未见报道。通过调整溶剂极性、链内和链间 沿着DNA仿生的PPSU骨架形成非共价的砜-砜键片段 蛋白质中的杂交和亮氨酸拉链。这一过程的初步实验和模拟揭示了 动态的磺酸-磺酸相互作用形成相互连接的物理凝胶网络，该网络可以固化为 大尺度水凝胶或崩塌成不同形貌的纳米凝胶。使用这种快速且可扩展的 方法学，可以指定不同纳米凝胶形态的均匀群体，包括球体、囊泡 和丝状束。重要的是，药物(不管它们的物理化学性质)是有效的和 在网络崩溃期间，在PPSU纳米凝胶中普遍捕获。这一新的分子机制 对于所有测试的分子和组合，封装法显示出极高的负载效率 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 NBMS作为一种新型的受控交付平台 用于生物医学应用。目标1：使用分子动力学模拟和分析纳米尺度 显微镜从机械上理解PPSU的自组装和治疗负荷。目标2：发展 PPSU的通用分子封装作为优化模型NBM疫苗配方的工具。