Biomimetic Dendrimer-Exosome Hybrid Nanoparticles for Efficient Cancer Targeting

非技术部分：本程序的独特之处在于它将模拟外泌体（细胞衍生的囊泡）的自然发生的靶向机制，并利用树状大分子的有效靶向和肿瘤穿透行为。这种方法在仿生纳米技术这一新兴领域具有重要意义和潜在的高回报。该研究的成功完成将：i)显著推进对使用多种靶向机制的癌症靶向的理解；Ii)建立一个数据库，描述控制生物反应的生物/非生物组合；最终iii)以真正个性化的方式为靶向癌症治疗提供一种新颖的，变革性的平台技术。拟制的仿生混合纳米颗粒的研究将为设计具有最大靶向效果的个性化药物提供新的范例，而不存在免疫原性问题，最终将为患有癌症和其他衰弱性疾病的患者提供有效的治疗递送平台。PI将创建和扩大教育和外展活动。首先，本研究将为研究生的跨学科训练和职业发展提供良好的机会。其次，该项目密切结合了威斯康星大学麦迪逊分校和其他资源有限的当地社区学院的本科生的研究培训。第三，该研究项目将与一个旨在为K-12学生和教师提供动手科学体验的推广计划相结合，以激发他们对STEM的兴趣。为了更广泛的传播，我们将制作几个YouTube视频，重点介绍基本的聚合物化学和我们的纳米载体研究。技术摘要：尽管近年来纳米技术的进步使无数有希望的肿瘤靶向递送平台达到高潮，但由于缺乏对纳米生物相互作用的理解，这些技术的成功临床实施受到阻碍，导致纳米载体的靶向效果，免疫原性和毒性未得到满足。本文提出了一种新的递送系统，该系统整合了工程聚氨基胺（PAMAM）树突状分子和从人间充质干细胞（hMSCs）中提取的生物外泌体。据推测，新型仿生杂交纳米颗粒（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最小化。具体来说，BioHNPs将利用三种独特的机制：1)hMSC归巢到炎症组织，包括滚动、牢固粘附和外渗，这在激活的血管生成癌区经常观察到；Ii)树突状分子介导的多价靶向；树突状分子在肿瘤组织中的有效渗透。此外，使用这些来自个体患者的外泌体作为纳米载体的外层，这种方法将最终实现真正的个性化医疗，这将在设计和工程上具有潜在的变革，不仅是本文提出的生物hnps，还有其他新型纳米载体。新设计的纳米载体将通过一系列的物理化学和生物分析来验证，通过实现三个目标：1)hmsc衍生的外泌体和PAMAM树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试验；该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，认为值得支持。

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.