Medical Nitric Oxide-Releasing Nanoporous Organic Polymers as Topical Therapeutic Agents

慢性伤口治疗是一个特别具有挑战性的临床问题，英国国家卫生研究所（NIHR）在2013年强调了国家卫生服务（NHS）患者未满足的需求。事实上，目前还没有有效的方法。慢性伤口主要是腿部溃疡、压疮和糖尿病足溃疡，对患者的生活质量产生不利影响，NHS每年花费20 - 30亿英镑用于伤口治疗。因此，如果我们能开发一种简单有效的方法，既能加速慢性伤口愈合，又能降低治疗成本，这将是非常有吸引力的。一氧化氮（NO）是燃烧过程中产生的一种众所周知的空气污染物，已被发现在神经、免疫和心血管系统的许多过程中起着重要的调节和中介作用。这些发现鼓励通路利用NO气体的有益功能来解决各种具有挑战性的医疗问题，其中之一是慢性伤口的治疗。伤口护理研究表明，通过体外和体内研究，气态NO在加速慢性伤口愈合方面具有突出的有效性。然而，由于NO气体的气体性质和毒性，输送NO气体是一项非常具有挑战性的任务。这需要开发一种特殊的“载体”，能够将所需数量的一氧化氮运送到局部伤口，并以安全和可控的方式排出一氧化氮。为了解决这一挑战，我们提出了一种基于纳米多孔有机聚合物（POP）作为新一代气态一氧化氮输送“载体”的新方法，以实现我们的抱负。持久性有机污染物是近年来被广泛研究的一类新型纳米多孔材料，如Cooper等人开发的共轭微孔聚合物（cmp）。通过碳-碳偶联或循环缩合反应，将有机分子构建块组装成二维或三维多孔网络，即可轻松合成POP材料。持久性有机污染物具有不同的多孔结构和功能以及相对较高的化学稳定性，在气体吸附/储存/分离和多相催化方面引起了越来越多的研究兴趣，并在治疗药物输送方面显示出良好的潜力。在这个项目中，我们将探索适合储存高容量NO气体的新型POP材料。随着持久性有机污染物与NO气体发生反应，在骨架中形成重氮二醇酯结构，NO气体预计会在多孔网络中被“化学压缩”。通过这种方式，可以达到高容量的NO存储，从而确保将所需数量的NO可控地输送到局部伤口部位。此外，通过调整活性功能的浓度和NO负荷条件，可优化持久性有机污染物中NO的储存量。通过合理选择分子结构单元和合成条件，调节骨架的孔径和亲疏水性，从而调整NO释放特性。我们将系统地描述POP材料结构，分析储存的NO物种并模拟NO释放动力学。所获得的相关信息将用于了解POP的结构、性质和合成条件对重氮二醇酯形成的影响，从而评估不同POP材料的性能，优化材料配方和合成条件。该项目所获得的成果将成为未来制造原型治疗产品的基础。到项目结束时，预计将开发出一种新的有前途的NO气体输送技术，旨在加速慢性伤口愈合。

The chronic wound treatment is a particularly challenging clinical problem, which has been highlighted as unmet need of the National Health Service (NHS) patients by the United Kingdom's National Institute for Health Research (NIHR) in 2013. In fact, currently no efficacious methods exist. The chronic wounds mostly leg ulcers, pressure ulcers, and diabetic foot ulcers adversely affect patients' quality of life, costs the NHS £2-3 billion annually for wound treatments. Therefore, if we develop a simple and effective method which can accelerate chronic wound healing and reduce the treatment cost, which would be very attractive. Nitric oxide (NO), a well-known air pollutant produced from combustion processes, has been found to play important roles as a regulator and mediator of numerous processes in the nerve, immune, and cardiovascular systems. These findings encourage pathways to utilise the beneficial functions of NO gas to tackle a variety of challenging medical issues, one of which is the treatment of chronic wounds. Wound care research has indicated the outstanding effectiveness of gaseous NO in accelerating chronic wound healing by in vitro and in vivo studies. However, delivering NO gas is very challenging task because of its gaseous nature and toxicity. This requires developing a specific 'vehicle' capable of carrying the desired amounts of NO to the local wound sites and discharging the NO in a safe and controllable manner. To address this challenge, we propose a new method based on nanoporous porous organic polymer (POP) as new generation of gaseous nitric oxide delivery 'vehicle' to fulfil our ambitions. POPs are a new class of nanoporous materials which have been widely investigated in recent years, for example the conjugated microporous polymers (CMPs) developed by Cooper et al. The facile synthesis of POP materials is by assembling organic molecular building blocks into two or three dimensional porous networks through carbon-carbon coupling or cyclic condensation reactions. The POPs possess diverse porous structures and functionalities as well as relatively high chemical stability, which have attracted increasing research interests in gas adsorption/storage/separation and heterogeneous catalysis, and show promising potential for drug delivery for therapeutics. In this project, we will explore new POP materials suitable for storing high capacities of NO gas. With POPs' reacting with NO gas to form diazeniumdiolate structures in the frameworks, the NO gas is expected to be 'chemically compressed' in the porous networks. In this manner, high capacity of NO storage is reached, which ensures a controllable delivery of a desired amount of NO to the local wound sites. Furthermore, the quantity of NO stored in the POPs will be optimised through adjusting the concentration of active functionalities and the NO loading conditions. The NO releasing characteristic profiles will be adjusted through judiciously choosing molecular building blocks and synthesis conditions to tune the pore size and the hydrophobicity/hydrophilicity of frameworks. We will systematically characterise the POP material structures, analyse the stored NO species and simulate the NO releasing kinetics. Relevant information obtained will be used for understanding the effects of POP structures , properties and synthesis conditions on the formation of diazeniumdiolates, so as to assess the performance of different POP materials, and optimise the material formulation and synthesis conditions. The results obtained from this project will become the foundations for manufacturing prototype therapeutic products in the future. By the end of this project, it is anticipated to develop a new promising NO gas delivery technology targeted for accelerating chronic wound healing.