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

项目摘要 意义：通过超分子自组装形成纳米结构主要涉及 两亲物在水环境中的疏水/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已经允许制造宽范围的 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在包封分子方面遇到了很大的困难，其中许多（通常难以表达）分子被包封。 或昂贵的）蛋白质和亲水性小分子，从而实现远低于20%的低包封效率。 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，这在放大合成和纯化以用于实际应用时可能存在困难。 临床测试和翻译。 创新：一种新的超分子自组装手段，采用单一的，简单的，水溶性的 均聚物实现>90%的包封效率，对于多种亲水性（和疏水性） 小分子和生物制剂将同时进行建模、优化和验证。所述唯一网络 聚（丙烯砜）（PPSU）均聚物的自组装，所述均聚物同时是可溶的和 可在水中结晶，以前没有报道过。通过调节溶剂极性， 非共价砜-砜键的片段沿着PPSU主链形成，DNA的仿生 杂交和亮氨酸拉链。初步的实验和模拟这一过程显示， 动态砜-砜相互作用，形成相互连接的物理凝胶网络， 宏观尺度的水凝胶或塌陷成不同形态的纳米凝胶。利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均匀群体，包括球体、囊泡 和丝状束。重要的是，药物（无论其物理化学性质如何）是有效的， 在网络崩溃期间普遍捕获在PPSU纳米凝胶内。这种新的分子机制 包封证明了对所有测试的分子和组合的异常高的装载效率 其包括蛋白质、DNA、RNA、荧光团、造影剂和小分子药物。 提出了两个独立的目标，以优化和验证PPSU NBM作为一种新的控制交付平台 用于生物医学应用。目标1：采用分子动力学模拟和分析纳米尺度 显微镜来机械地理解PPSU自组装和治疗负载。目标2：发展 PPSU的通用分子包封作为优化模型NBM疫苗制剂的工具。

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.