Shape Control and Transport Properties of DNA-Copolymer Micelles

DNA 共聚物胶束的形状控制和传输特性

• 批准号: 9498629
• 负责人: Erik Luijten
• 金额: $ 0.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9498629
• 关键词: Address; Biodistribution; Blood; Blood Circulation; Blood capillaries; Characteristics; Complex; Computer Simulation; Computers; DNA; DNA Computations; DNA delivery; Detection; Development; Diffuse; Diffusion; Disseminated Malignant Neoplasm; Drug or chemical Tissue Distribution; Engineering; Environment; FOLH1 gene; Fluorescence; Genes; Human; Image; In Vitro; Kidney; Kinetics; Knowledge; Ligands; Liver; Lung; Malignant Neoplasms; Maps; Medicine; Methods; Micelles; Microfluidics; Modeling; Mus; Nature; Neoplasm Metastasis; Particle Size; Periodicity; Physiological; Process; Property; RGD (sequence); Research; Role; Shapes; Spectrum Analysis; Stream; System; Techniques; Testing; Time; Treatment Efficacy; Viral; Virion; Water; Work; base; bone; capillary; copolymer; ethylene glycol; hydrodynamic model; immune clearance; improved; in vivo; in vivo imaging; intravenous administration; molecular dynamics; mouse model; nanoparticle; nanotherapeutic; particle; physical property; plasmid DNA; polycation; programs; public health relevance; simulation; targeted delivery; theranostics; therapeutic gene; tool; trafficking; vector

 DESCRIPTION: Micellar nanoparticles that mimic the size and shape of viral particles are attractive as a DNA delivery vehicle because of their improved colloidal stability and transport properties, ability to evade immune clearance, and high payload packaging capacity. Moreover, nanoparticle shape has explicitly been identified as an important factor determining their transport properties and delivery efficiency. However, there is no available nanoparticle synthesis method for packaging plasmid DNA payloads while allowing sufficient control over particle size and shape. Recently, we have shown that distinct shape control and tuning for DNA micelles can be achieved through complexation of plasmid DNA with engineered block or graft copolymers of polycation and poly (ethylene glycol) under controlled assembly conditions. In this proposed study, we will develop a synergistic research program comprising parallel and integrated experimental and computational strategies to (1) develop and understand new methods for DNA micelle assembly that permit scalable, high-uniformity synthesis with shape control and high stability; (2) reveal shape-dependent nanoparticle diffusion and transport properties in physiologically media in vitro and in vivo; and (3) demonstrate the delivery efficiency of a theranostic vector by shape-controlled DNA micelles and their imaging and therapeutic efficacy using mouse models of human metastatic cancers. The proposed study brings together a unique combination of expertise in DNA nanoparticle assembly, microfluidics-based single-particle analysis/fluorescence correlation spectroscopy, in vivo imaging, cancer theranostics, and computer simulations to address a crucial knowledge gap in the engineering and delivery of DNA nano-therapeutics. It will not only offer a new, generalizable method for synthesizing shape-controlled DNA micelles, but also provide a mechanistic understanding of shape- dependent transport properties of nanoparticles. Moreover, the integrated nature of our experimental and computational approach establishes a new paradigm that will greatly accelerate the discovery and development of new DNA nanoparticle systems for efficient gene medicine delivery.

 描述：模仿病毒颗粒大小和形状的胶束纳米颗粒作为 DNA 递送载体很有吸引力，因为它们具有改进的胶体稳定性和运输特性、逃避免疫清除的能力以及高有效负载包装能力。此外，纳米粒子的形状已被明确确定为决定其运输特性和递送效率的重要因素。然而，没有可用的纳米颗粒合成方法来包装质粒 DNA 有效负载，同时允许对颗粒大小和形状进行充分控制。最近，我们已经证明，通过在受控组装条件下将质粒 DNA 与聚阳离子和聚乙二醇的工程嵌段或接枝共聚物复合，可以实现 DNA 胶束的独特形状控制和调整。在这项拟议的研究中，我们将开发一个协同研究计划，包括并行和集成的实验和计算策略，以（1）开发和理解 DNA 胶束组装的新方法，允许可扩展、高度均匀的合成，具有形状控制和高稳定性； (2)揭示形状依赖性纳米颗粒在体外和体内生理介质中的扩散和传输特性； (3) 使用人类转移性癌症的小鼠模型证明形状控制 DNA 胶束的治疗诊断载体的递送效率及其成像和治疗功效。拟议的研究汇集了 DNA 纳米颗粒组装、基于微流体的单颗粒分析/荧光相关光谱、体内成像、癌症治疗诊断和计算机模拟方面的专业知识，以解决 DNA 纳米治疗的工程和实施中的关键知识差距。它不仅为合成形状控制的 DNA 胶束提供了一种新的、可推广的方法，而且还提供了对纳米颗粒形状依赖性传输特性的机械理解。此外，我们的实验和计算方法的综合性质建立了一个新的范式，将大大加速新的 DNA 纳米颗粒系统的发现和开发，以实现高效的基因药物传递。

项目成果

Systematic coarse-grained modeling of complexation between small interfering RNA and polycations.

• DOI: 10.1063/1.4937384
• 发表时间: 2015-12
• 期刊: The Journal of chemical physics
• 作者: Zonghui Wei;Erik Luijten

Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors.

用于生产慢病毒载体的尺寸控制且货架稳定的 DNA 颗粒。

• DOI: 10.1021/acs.nanolett.1c01421
• 发表时间: 2021-07-14
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Hu Y;Zhu Y;Sutherland ND;Wilson DR;Pang M;Liu E;Staub JR;Berlinicke CA;Zack DJ;Green JJ;Reddy SK;Mao HQ
• 通讯作者: Mao HQ