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: 1409161
• 负责人: Seungpyo Hong
• 金额: $ 32.4万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1409161&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.

非技术部分：该奖项由材料研究部的生物材料计划和热传输过程计划(CBET/ENG)共同资助给芝加哥伊利诺伊大学，旨在创造一种新型的树枝状大分子-聚合物杂化纳米粒子，它利用细胞滚动和多价结合的仿生肿瘤靶向策略的组合。本项目将模拟自然发生的过程(细胞滚动和多价结合)，以增强肿瘤靶向，集成在单杂交NP系统中。这种“母舰”方法将在新兴的仿生纳米技术领域产生重大影响和潜在的高额回报。拟议研究的成功将：i)以动力学控制的方式使用多种靶向机制大大促进对癌症靶向的理解；ii)建立一个数据库，描述靶向剂的空间结构、靶向动力学、颗粒特性、聚合物降解率、多价效应、纳米颗粒滚动和肿瘤穿透对靶向效果的影响；以及iii)潜在地为靶向癌症治疗提供一种新颖的、变革性的平台技术。PI将发展和扩大教育和外联活动，除其他外，涉及服务不足地区的高中实习计划，以及本科生和教师的研究经验。此外，在该计划中开发的研究成果和实验技术将通过出版物和国际会议会议记录以及通过整合到本科生和研究生的课堂教学中传播。技术部分：尽管最近纳米技术的进步最终形成了一些有希望的肿瘤靶向交付平台，但这些技术的成功临床实施在很大程度上是由于对纳米生物相互作用缺乏基本了解，导致临床靶向效果未得到满足。癌症的多面性往往导致对纳米载体的无效靶向，这些纳米载体依赖于当前可用的靶向策略中的一种或两种，即被动和主动靶向。该奖项旨在支持开发一种新的纳米载体系统，该系统通过聚酰胺胺(PAMAM)树枝状大分子和聚合物纳米颗粒(NP)的杂交，在单一传递平台中集成多种靶向机制。假设新型杂化纳米颗粒(NPs)或纳米杂化颗粒的整体靶向效率将通过使用仿生靶向方法以动力学控制的方式得到显著提高。通过化学、物理和生物学研究，将探索三种靶向机制的顺序利用：i)通过仿白细胞滚动将杂交NPs从血流招募到血管生成内皮；ii)通过动态滚动以及增强的通透性和滞留效应，促进大小可控的杂交NPs(直径~100 nm)渗入肿瘤；以及iii)靶向树枝状大分子通过NP壳的扩散和降解释放，从而多价靶向和有效地渗透到单个肿瘤细胞。新设计的纳米载体将通过一系列物理化学和生物测试进行验证。