Hybrid Nanoparticles for Kinetically Controlled Cancer Targeting Using Biomimetic Cell Rolling and Multivalent Binding

利用仿生细胞滚动和多价结合用于动力学控制癌症靶向的混合纳米颗粒

• 批准号: 1741560
• 负责人: Seungpyo Hong
• 金额: $ 12.61万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1741560&HistoricalAwards=false
• 关键词: Hybrid; Nanoparticles; Kinetically; Controlled; Cancer

Non-Technical Part:This award by the Biomaterials Program in the Division of Materials Research, and co-funded by the Thermal Transport Processes Program (CBET/ENG) to the University of Illinois, Chicago, is to create a class of novel dendrimer-polymer hybrid nano-particles that utilizes a combination of biomimetic tumor targeting strategies of cell rolling and multivalent binding. The present project will mimic naturally occurring processess (cell rolling and multivalent binding) for enhanced tumor targeting, integrated within a signle hybrid NP system. This "mothership" approach will have major implications and potentially high reward in the emerging area of biomimetic nanotechnology. Successful achievement of the proposed study will: i) significantly advance the understanding of cancer targeting using multiple targeting mechanisms in a kinetically controlled manner; ii) establish a database describing the effects of spatial construction of targeting agents, targeting kinetics, particle properties, polymer degradation rates, multivalent effect, nanoparticle rolling, and tumor penetration on targeting efficacy; and potentially iii) present a novel, transformative platform technology for targeted cancer therapy. The PI will develop and expand education and outreach activities involving, among others, high-school internship programs in underserved areas, and research experiences for undergraduates and teachers. Additionally, the research results and experimental techniques developed in this program will be disseminated via publications and proceedings at international conferences as well as via integration into classroom instruction, both at the undergraduate and graduate levels.Technical Part: Although recent advances in nanotechnology have culminated in a number of promising delivery platforms for tumor targeting, successful clinical implementation of such technologies has been hindered largely due to a lack of fundamental understanding on nano-bio interactions, resulting in clinically unmet targeting efficacy. The multifaceted nature of cancer has often caused ineffective targeting of nanocarriers that rely on one, or less commonly two, of currently available targeting strategies, i.e., passive and active targeting. This award is to support an effort to develop a new nanocarrier system that integrates multiple targeting mechanisms within a single delivery platform through hybridization of poly(amidoamine) (PAMAM) dendrimers and polymeric nanoparticles (NPs). It is hypothesized that overall targeting efficacy of the novel hybrid nanoparticles (NPs), or nanohybrids, will be substantially enhanced using biomimetic targeting approaches in a kinetically controlled manner. Through chemical, physical, and biological studies, sequential utilization of three targeting mechanisms will be explored: i) Recruiting of the hybrid NPs from bloodstream to angiogenic endothelia through leukocyte-mimicking rolling; ii) Extravasation of the size-controlled hybrid NPs (~100 nm in diameter) to tumors, facilitated by the dynamic rolling and the enhanced permeability and retention effect; and iii) Multivalent targeting and efficient tumor penetration of targeted dendrimers to individual tumor cells upon release through diffusion from and degradation of the NP shell. The new design of the nanocarriers will be validated through a series of physicochemical and biological assays.

Non-Technical Part:This award by the Biomaterials Program in the Division of Materials Research, and co-funded by the Thermal Transport Processes Program (CBET/ENG) to the University of Illinois, Chicago, is to create a class of novel dendrimer-polymer hybrid nano-particles that utilizes a combination of biomimetic tumor targeting strategies of cell rolling and multivalent binding. 本项目将模仿自然发生的过程（细胞滚动和多价结合），以增强肿瘤靶向，并集成在标志混合NP系统中。这种“母舰”方法将在仿生纳米技术的新兴领域具有重大影响和潜在的高度奖励。拟议研究的成功实现将：i）以动力学控制的方式使用多种靶向机制显着提高对癌症靶向的理解； ii）建立一个数据库，描述靶向剂的空间构建，靶向动力学，颗粒特性，聚合物降解速率，多价效应，纳米颗粒滚动和肿瘤渗透对靶向功效的影响；并有可能iii）提出了一种用于靶向癌症治疗的新型，变革性的平台技术。 PI将开发和扩大涉及服务不足领域的高中实习计划的教育和外展活动，以及针对本科生和教师的研究经验。此外，该计划中开发的研究结果和实验技术将通过国际会议的出版物和诉讼以及在本科和研究生级别的课堂教学中的整合到课堂教学中进行分散。技术技术的最新进展：纳米技术的最新进展已在纳米技术方面取得了成功，在成功的临床平台中，纳米技术的范围已导致了许多有前途的临床范围，这些技术是在许多方面的范围，这些技术是在许多方面的范围，这些技术是在许多方面的范围，这些技术的实施率是众多的，这些技术的范围已成为众多技术的责任。对纳米生物相互作用的基本了解，导致临床未满足的靶向功效。癌症的多方面性质通常导致纳米载体的靶向无效，而纳米载体依赖于当前可用的靶向策略，即被动和主动靶向的纳米载体。该奖项是为了支持开发一种新的纳米载体系统，该系统通过杂交聚（amidoamine）（PAMAM）（PAMAM）树枝状聚合物和聚合物纳米颗粒（NPS）将多种靶向机制集成到单个输送平台中。假设新型杂交纳米颗粒（NP）或纳米杂交的总体靶向疗效将通过动力学控制方式实质上增强。 通过化学，物理和生物学研究，将探讨三种靶向机制的顺序利用：i）通过模拟白细胞滚动募集从血液从血液到血管生成内皮的杂种NP； ii）将尺寸控制的杂化NP（直径约100 nm）渗入肿瘤，并通过动态滚动和增强的渗透性和保留效果促进； iii）通过从NP壳的扩散和降解释放后，靶向树状聚合物对单个肿瘤细胞的多价靶向和有效的肿瘤渗透。纳米载体的新设计将通过一系列物理化学和生物学测定得到验证。