Biomimetic Dendrimer-Exosome Hybrid Nanoparticles for Efficient Cancer Targeting

用于有效癌症靶向的仿生树状聚合物-外泌体混合纳米颗粒

• 批准号: 1808251
• 负责人: Seungpyo Hong
• 金额: $ 35.62万
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808251&HistoricalAwards=false
• 关键词: Biomimetic; Dendrimer; Exosome; Hybrid; Nanoparticles

Non-Technical Part: The present program is unique in that it will mimic a naturally occurring targeting mechanism of exosomes (are cell-derived vesicles) and take advantage of efficient targeting and tumor penetration behaviors of dendrimers. This approach will have implications, and potentially high reward in the emerging area of Biomimetic Nanotechnology. Successful achievement of the proposed study will: i) significantly advance the understanding on cancer targeting using multiple targeting mechanisms; ii) establish a database describing biotic/abiotic combinations that control the biological responses; and ultimately iii) present a novel, transformative platform technology for targeted cancer therapy in a truly personalized manner.The study of the proposed biomimetic hybrid nanoparticles will lead to a new paradigm for designing a personalized medicine with maximum targeting efficacy, without immunogenicity issues, which will ultimately offer an effective therapeutic delivery platform for patients suffering from cancers and other debilitating disease. The PI will create and expand the education and outreach activities. First, this proposed study will provide excellent opportunities in interdisciplinary training and career development of graduate students. Second, this project intimately incorporates research training for undergraduate students from University of Wisconsin-Madison as well as other local community colleges that have limited resources. Third, this research program will be integrated with an outreach plan that aims to provide hands-on science experiences to K-12 students and teachers to spark their interests in STEM. For broader dissemination, we will produce a couple of YouTube videos highlighting basic polymer chemistry and our nanocarrrier research.Technical Abstract:Although recent advances in nanotechnology have culminated in a myriad of promising delivery platforms for tumor targeting, successful clinical implementation of such technologies has been hindered largely due to a lack of understanding on nano-bio interactions, resulting in unmet targeting efficacy, immunogenicity, and toxicity of nanocarriers. Here a novel delivery system is proposed that integrates engineered poly(amidoamine) (PAMAM) dendrimers and biologically extracted exosomes derived from human mesenchymal stem cells (hMSCs). It is hypothesized that overall tumor targeting of the novel biomimetic hybrid nanoparticles, or BioHNPs, will be significantly enhanced, with minimized potential immunogenicity or toxicity concerns. Specifically, BioHNPs will take advantage of three unique mechanisms: i) hMSC homing to inflamed tissue, involving rolling, firm adhesion, and extravasation, which is frequently observed in activated, angiogenic cancerous regions; ii) dendrimer-mediated multivalent targeting; and iii) efficient penetration of dendrimers across tumor tissue. In addition, using such exosomes derived from individual patients as outer layers of the nanocarriers, this approach will ultimately achieve truly personalized medicine, which will be potentially transformative in designing and engineering not only BioHNPs proposed here but also other novel nanocarriers. The new design of the nanocarriers will be validated via a series of physicochemical and biological assays through achieving three objectives: i) Functionalization and hybridization of hMSC-derived exosomes and PAMAM dendrimers; ii) In vitro selectivity tests of BioHNPs against endothelial and cancer cells; and iii) Tumor spheroid model study for tissue penetration and diffusion of BioHNPsThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术部分：本计划的独特之处在于，它将模拟外体(细胞衍生的囊泡)的自然靶向机制，并利用树枝状大分子的有效靶向和肿瘤穿透行为。这种方法将对新兴的仿生纳米技术领域产生影响，并可能带来高额回报。这项拟议研究的成功成果将：i)显著提高对使用多种靶向机制进行癌症靶向的理解；ii)建立一个描述控制生物反应的生物/非生物组合的数据库；以及最终iii)以真正个性化的方式呈现一种新颖的、变革性的靶向癌症治疗平台技术。对拟议的仿生杂化纳米颗粒的研究将导致一种新的范式，用于设计具有最大靶向效率的个性化药物，而不存在免疫原性问题，这将最终为癌症和其他致衰性疾病的患者提供有效的治疗输送平台。国际和平协会将创建和扩大教育和外联活动。首先，这项拟议的研究将为研究生的跨学科培训和职业发展提供良好的机会。其次，该项目紧密结合了对威斯康星大学麦迪逊分校的本科生以及其他资源有限的当地社区学院的本科生的研究培训。第三，这项研究计划将与一个旨在为K-12学生和教师提供实践科学体验的外展计划相结合，以激发他们对STEM的兴趣。为了更广泛地传播，我们将制作几个YouTube视频，重点介绍基础聚合物化学和我们的纳米载体研究。技术摘要：尽管最近纳米技术的进步产生了无数有希望的肿瘤靶向传递平台，但这些技术的成功临床应用在很大程度上是由于缺乏对纳米生物相互作用的了解，导致纳米载体的靶向性、免疫原性和毒性未得到满足。本文提出了一种新型的递送系统，该系统集成了工程聚酰胺胺(PAMAM)树枝状大分子和从人骨髓间充质干细胞(HMSCs)生物提取的外切体。据推测，新型仿生杂化纳米颗粒(BioHNPs)的整体肿瘤靶向性将显著增强，潜在的免疫原性或毒性问题将降至最低。具体地说，BioHNPs将利用三种独特的机制：i)hMSC归巢于炎症组织，涉及滚动、牢固的粘连和外渗，这在激活的血管生成癌症区域中经常被观察到；ii)树状大分子介导的多价靶向；以及iii)树突状大分子有效地穿透肿瘤组织。此外，使用这种来自个体患者的外切体作为纳米载体的外层，这种方法最终将实现真正的个性化药物，这不仅将对本文提出的生物HNPs的设计和工程产生潜在的变革，也将对其他新型纳米载体的设计和工程产生潜在的变革。纳米载体的新设计将通过一系列物理化学和生物学测试进行验证，以实现三个目标：i)hMSC衍生的外切体和PAMAM树枝状大分子的功能化和杂交；ii)BioHNPs对内皮细胞和癌细胞的体外选择性测试；以及iii)BioHNPs组织渗透和扩散的肿瘤球体模型研究该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Tumor penetration of Sub-10 nm nanoparticles: effect of dendrimer properties on their penetration in multicellular tumor spheroids

• DOI: 10.1016/j.nano.2019.102059
• 发表时间: 2019-10-01
• 期刊: NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
• 影响因子: 5.4
• 作者: Bugno, Jason;Poellmann, Michael J.;Hong, Seungpyo
• 通讯作者: Hong, Seungpyo

Nanoparticle Conjugation Stabilizes and Multimerizes β-Hairpin Peptides To Effectively Target PD-1/PD-L1 β-Sheet-Rich Interfaces

• DOI: 10.1021/jacs.9b10160
• 发表时间: 2020-01-29
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Jeong, Woo-jin;Bu, Jiyoon;Hong, Seungpyo
• 通讯作者: Hong, Seungpyo

Immunoavidity-Based Capture of Tumor Exosomes Using Poly(amidoamine) Dendrimer Surfaces

• DOI: 10.1021/acs.nanolett.0c00950
• 发表时间: 2020-08-12
• 期刊: NANO LETTERS
• 影响因子: 10.8
• 作者: Poellmann, Michael J.;Nair, Ashita;Hong, Seungpyo
• 通讯作者: Hong, Seungpyo