Biodegradable Nanomaterials by Thiol-Ene Miniemulsion Reactions

高分子纳米粒子（NPs）和纳米胶囊（NCs）在生物医学和其他领域的潜在应用引起了人们的极大兴趣。在纳米模板内控制交联使得这些具有三维共价结构的纳米材料得以合成。相应地，合成效率不仅取决于反应或聚合技术，还取决于模板条件。相对于其他模板方法，基于微乳化的方法通常是简单和环保的，但可能在精确控制所产生的纳米结构方面存在缺陷。特别是，尽管纳米碳可以很容易地通过微乳液界面交联得到，但可能会发生剧烈的界面不稳定，从而产生不明确的产物。本项目旨在开发一种最先进的微型乳液技术，用于高效环保地制备具有良好定义的NPs和NCs。该合成策略包含三个主要的设计考虑：1)将紫外线诱导的硫醇烯点击化学与透明微乳液相结合，以实现高合成效率；2)通过选择性交联分散相中的聚合物块，实现对NPs和NCs的精确结构控制，使界面不稳定最小化；3)利用环境友好的试剂和反应条件制备生物可降解纳米材料。在最初的概念验证研究中，利用透明微乳液反应体系的短（30分钟）紫外线照射，通过巯基交联前驱聚合物，即烯丙基功能化PLA和PEO-b-PLA，获得了可生物降解的NPs和NCs。每个试验的反应程度几乎完全被FTIR分析证实。通过DLS、TEM和AFM表征验证了NPs和NCs的纳米结构。通过酶降解研究证实了其生物降解性。系统地研究这些纳米材料的合成是为了精确地控制它们的纳米尺度、内部交联结构和功能。多种功能化NPs和NCs，包括带阳离子基团的NPs和NCs，将通过巯基功能化策略制备。优化工艺方法和工艺条件，进一步提高合成效率。将研究这些纳米材料的胶体稳定性、降解和包封/释放行为。为了进一步评估这些纳米材料作为生物医学载体的可行性，将进行体外细胞摄取和细胞毒性研究，并检查siRNA与阳离子NPs和NCs复合物的转染效率。原则上，除了烯烃功能化聚合物外，多功能小分子烯烃也可以在透明微乳液中通过巯基烯反应很容易地转化为纳米材料。该研究结果可进一步为热诱导的硫醇-烯微乳液反应以及其他乳液体系中的硫醇-烯反应提供重要指导。本研究开发的透明微乳液模板可能应用于其他类型的光诱导反应，以达到较高的合成效率。更广泛的影响：该研究项目可能在材料合成和加工研究领域带来变革性的影响。由此产生的可生物降解纳米材料可以通过帮助改善国民健康和维护环境来为社会带来重大利益。特别是，具有酸不稳定交联的基于PEO/ pla的nc可能非常有用，可作为制造抗癌纳米药物的支架；阳离子NPs和NCs可用于药物和基因的共递送。该项目的研究成果将促进pi的跨学科合作。研究聚合物的生物医学应用，并有可能在与工业伙伴合作的基础上实现噻吩微乳液技术的商业化。为了广泛传播聚合物合成技术，将制作有关聚合物制备的视频并在线播放。纽约州立大学布法罗分校将开设一门新的高分子纳米材料研究生课程，以加强材料教育和研究。此外，还将开展促进地区初高中理工科学生教育和准备的外联活动。

Proposal Number: 1133737PI: Cheng, Chong Intellectual MeritPolymeric nanoparticles (NPs) and nanocapsules (NCs) have attracted significant interest for potential applications in biomedical and other areas. Controlled cross-linking within nanoscopic templates has allowed the synthesis of these nanomaterials with three-dimensional covalent architectures. Correspondingly, synthetic efficiency depends not only on the reaction or polymerization techniques but also on the template conditions. Relative to other templating approaches, miniemulsion-based methods typically are facile and eco-friendly, but may suffer deficiency in precise control over the resulting nanostructures. Particularly, although NCs can be readily obtained by miniemulsion interfacial cross-linking, dramatic interfacial destabilization may occur to yield ill-defined products. This project is to develop a state-of-art miniemulsion technology for the highly efficient and environmentally friendly preparation of well-defined NPs and NCs. The synthetic strategy incorporates three major design considerations: 1) UV-induced thiol-ene click chemistry is combined with transparent miniemulsions to achieve high synthetic efficiency; 2) interfacial destabilization is minimized by selective cross-linking of polymer blocks in the dispersed phase to exert accurate structural control of NPs and NCs; and 3) biodegradable nanomaterials are produced using environmentally benign reagents and reaction conditions. In the initial proof-of-concept studies, biodegradable NPs and NCs were obtained by thiol-ene cross-linking of precursor polymers, i.e. allyl-functionalized PLA and PEO-b-PLA, using short (30 min) UV irradiation of transparent miniemulsion reaction systems. Nearly complete extent of reaction was confirmed by FTIR analysis for each trial. Well-defined nanostructures of the NPs and NCs were verified by DLS, TEM, and AFM characterizations. Their biodegradability was also proven through enzymatic degradation study. Systematic studies on the synthesis of these nanomaterials are planned towards the goal of exerting accurate control over their nanoscopic dimensions, internal crosslinked structures, and functionalities. A broad variety of functional NPs and NCs, including these with cationic groups, will be prepared via thiol-ene functionalization strategy. The processing method and conditions will be optimized to further improve synthetic efficiency. Colloidal stability, degradation and encapsulation/release behaviors of these nanomaterials will be studied. To further evaluate the viability of these nanomaterials as carriers for biomedical delivery, in vitro cellular uptake and cytotoxicity studies will be conducted, and transfection efficiency of complexes of siRNA with cationic NPs and NCs will be examined. In principle, besides alkene-functionalized polymers, multifunctional small molecule alkenes may also be readily converted into nanomaterials by thiol-ene reactions in transparent miniemulsions. The results from this research could further provide an important guide for thermally-induced thiol-ene miniemulsion reactions, as well as thiol-ene reactions in other emulsion systems. Transparent miniemulsion templates developed in this work potentially may be applied for other types of photoinduced reactions to achieve high synthetic efficiency.Broader Impacts: The research program may bring transformative impacts in the research area of material synthesis and processing. The resulting biodegradable nanomaterials may be utilized to make significant benefits to society by helping to improve national health and maintain environment. Particularly, the PEO/PLA-based NCs with acid-labile cross-linkages may be very useful as scaffolds to create anti-cancer nanomedicines; the cationic NPs and NCs may be employed for the co-delivery of drug and gene. The research findings of this project will promote the interdisciplinary collaboration of the PIs? groups on biomedical applications of polymers, and potentially lead to the commercialization of the thiolene miniemulsion technology based on collaborative efforts with industrial partners. In order to broadly disseminate polymer synthetic technologies, videos on polymer preparation will be created and on-line broadcast. A new graduate course on polymeric nanomaterials will be developed to enhance material education and research at SUNY-Buffalo. Outreach will be conducted to promote the education and preparation of local middle and high school students in science and engineering fields.