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：模仿病毒颗粒的大小和形状的胶束纳米颗粒作为DNA输送车具有吸引力，因为它们的胶体稳定性和运输特性提高，逃避免疫通量的能力以及高有效载荷包装能力。此外，纳米颗粒的形状已明确被确定为确定其运输特性和输送效率的重要因素。但是，没有用于包装质粒DNA有效载荷的纳米颗粒合成方法，同时允许对粒径和形状进行足够的控制。最近，我们已经表明，通过在受控的装配条件下，质粒DNA与工程块或工程块或移植物共聚物的络合可以实现DNA胶束的独特形状控制和调整。在这项拟议的研究中，我们将开发一项协同研究计划，汇编平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，该方法允许具有形状控制和高稳定性的可扩展，高均匀性合成； （2）揭示了体外和体内物理培养基中依赖形状的纳米颗粒扩散和转运特性； （3）使用人类转移性癌症的小鼠模型，通过形状控制的DNA胶束及其成像和治疗效率来证明疗法载体的递送效率。拟议的研究汇集了DNA纳米颗粒组装中专业知识，基于微纤维化学的单粒子分析/荧光相关光谱，体内成像，癌症热和计算机模拟的独特组合，以解决DNA Nano-therapeutics的工程和传递中的重要知识差距。它不仅将提供一种合成形状控制的DNA胶束的新的，可推广的方法，而且还提供了对纳米颗粒的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种新的范式，该范式将大大加快和开发新的DNA纳米颗粒系统，以进行有效的基因医学传递。

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