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。用于靶向药物递送的亲和纳米载体的制造在纳米技术领域中引起了显著的关注。研究最广泛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过程，导致成本高的大规模生产。此外，脂质体内的水性核不利于包封疏水性药物。在这个项目中，核酸适体和疏水性药物将被纳入水溶液中的自组装脂质纳米盘。预期此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，可以获得稳定的纳米盘，并且适体在化学缀合后是功能性的。基于令人信服的结果，该项目包括（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）理解亲和纳米盘的生物学功能。这项跨学科研究的预期成果是提供深入了解分子自组装的动力学和热力学，并开发一种变革性的方法来制备疏水药物的亲和纳米载体。这项研究将产生若干科学和经济影响。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接受。其次，由于超过40%的新型抗癌药物是疏水性的，因此这种递送平台将为递送疏水性药物，特别是癌症化疗药物铺平新的道路。第三，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。这一项目的更广泛的教育影响也将体现在我们对教育和人力资源开发的坚定承诺中。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研究，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动手研究技能，还可以学习分析，沟通，协作和创新技能。此外，PI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”）。第二，PI将继续参与在康州大学建立的外展计划。这些推广工作将提高K-12学生对科学和工程的兴趣，并促进将新的工作转移到生物制药行业。第三，研究结果将通过在同行评审的期刊上发表文章和在专业会议上发表演讲而广泛传播。

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.