Single-Step Manufacture of Affinity Nanodiscs for Drug Delivery

该项目旨在开发一种新的方法，能够以简单但非常有效的方式大规模生产基于脂质的亲和纳米盘。用于靶向给药的亲和纳米载体的制造在纳米技术领域引起了极大的关注。最广泛研究的纳米载体之一是抗体功能化脂质体。然而，载药亲和脂质体的合成通常需要耗时和多步骤，导致大规模生产成本高昂。此外，脂质体中的水核不利于疏水药物的包埋。在这个项目中，核酸适体和疏水药物将被引入到水溶液中自组装的脂基纳米盘中。预计这类载体具有靶向特定细胞并携带大量疏水分子的能力。初步研究表明，经过化学偶联后，可以得到稳定的纳米盘，并且适配子具有功能。基于这些令人信服的结果，本项目包括(1)合成和表征新型亲和纳米盘，(2)模拟纳米盘的生长动力学和动态相互作用，以及(3)了解亲和纳米盘的生物学功能。这一跨学科研究的预期结果是为分子自组装的动力学和热力学提供见解，并开发一种用于制备疏水药物的亲和纳米载体的变革性方法。这项研究将带来几个科学和经济影响。首先，新型纳米盘的一步制造将大大降低大规模生产的成本，使相关的靶向化疗更容易为公众所负担。其次，由于超过40%的抗癌新药是疏水的，这个输送平台将为输送特别是癌症化疗的疏水药物铺平一条新的途径。第三，将产生的数据将进一步丰富纳米技术、分子识别和胶体科学的知识。这一项目对教育的广泛影响也将体现在我们对教育和人力资源发展的坚定承诺上。首先，这个项目将为学生提供一个独特的跨学科环境，学习纳米技术、药物输送、胶体科学、生物分子工程、动力学分析和数学建模。所有参与的学生将有模块化的科学问题来学习，并将在联合小组会议上讨论他们的研究成果。学生将不仅能够获得实际操作的研究技能，还将学习分析、沟通、协作和创新技能。此外，专业督学将把这项研究的结果纳入他们的教学课程(“软材料的结构表征”和“药物输送”)。其次，私人投资机构将继续参与在康涅狄格州大学设立的外展计划。这些外展工作将提高K-12学生对科学和工程的兴趣，并促进将新的工作台工作转移到生物制药行业。第三，研究结果将通过同行推荐的期刊上的出版物和在专业会议上的陈述来广泛传播。

This project is aimed to develop a novel method that enables the mass production of lipid-based affinity nanodiscs in a simple but very effective manner. Manufacturing of affinity nanocarriers for targeted drug delivery has attracted significant attention in the field of nanotechnology. One of the most widely studied nanocarriers is antibody-functionalized liposomes. However, the synthesis of drug-loaded affinity liposomes usually requires time-consuming and multiple-step process, resulting in costly mass production. Moreover, the aqueous core within liposomes is not favorable for encapsulating hydrophobic drugs. In this project, nucleic acid aptamers and hydrophobic drugs will be incorporated to the self-assembled lipid-based nanodiscs in aqueous solutions. It is expected that such vehicles have the capability of targeting specific cells and carrying a large amount of hydrophobic molecules. Preliminary studies have shown that stable nanodiscs are attainable and the aptamers are functional after chemical conjugation. Based on the compelling results, this project includes (1) synthesizing and characterizing the novel affinity nanodiscs, (2) modeling the growth kinetics and dynamic interactions of the nanodiscs, and (3) understanding the biological functions of the affinity nanodiscs. The anticipated outcomes of this interdisciplinary study are to provide insights into the kinetics and thermodynamics of molecular self-assembly and to develop a transformative method for preparing affinity nanocarriers for hydrophobic drugs. This research will lead to several scientific and economic impacts. First, the one-step manufacturing of the novel nanodiscs will greatly reduce the cost of mass production, making the relevant targeted chemotherapy more affordable to the general public. Second, since more than 40 percent of the new anti-cancer drugs are hydrophobic, this delivery platform will pave a new way of delivering hydrophobic drugs especially for cancer chemotherapy. Third, the data to be generated will further enrich the knowledge of nanotechnology, molecular recognition, and colloidal science. The broader educational impacts of this project will also be evident in our strong commitment to education and human resource development. First, this project will provide students with a unique interdisciplinary environment to learn nanotechnology, drug delivery, colloidal science, biomolecular engineering, kinetic analysis, and mathematical modeling. All participating students will have modularized scientific questions to study and will discuss their research findings in joint group meetings. The students will be able to not only acquire hands-on research skills, but also learn analytical, communication, collaboration, and innovation skills. In addition, the PIs will incorporate the results from this research into their teaching courses ("structural characterization of soft materials" and "drug delivery"). Second, the PIs will continuously participate in the outreach programs established at UConn. These outreach efforts will raise K-12 students' interests in science and engineering and facilitate the transfer of the novel bench work to biopharmaceutical industries. Third, the research findings will be widely disseminated through publications in peer-refereed journals and presentations at professional conferences.