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: 9206501
• 负责人: Erik Luijten
• 金额: $ 54.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206501
• 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.