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，英国国家健康研究所(NIHR)在2013年将其强调为国民医疗服务(NHS)患者的需求未得到满足。事实上，目前还没有有效的方法。慢性伤口主要是腿部溃疡、压疮和糖尿病足部溃疡，对患者的生活质量产生不利影响，每年花费NHS GB 20-30亿美元用于伤口治疗。因此，如果开发一种简单有效的方法来促进慢性创面的愈合，降低治疗成本，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，在神经、免疫和心血管系统的许多过程中发挥着重要的调节和调节作用。这些发现鼓励人们利用一氧化氮的有益功能来解决各种具有挑战性的医疗问题，其中之一就是慢性伤口的治疗。体内外研究表明，创面护理研究表明气态NO在促进慢性创面愈合方面具有显著效果。然而，由于气体的性质和毒性，不输送气体是一项非常具有挑战性的任务。这需要开发一种特定的“车辆”，能够将所需数量的NO运送到局部伤口处，并以安全和可控的方式排放NO。为了应对这一挑战，我们提出了一种基于纳米孔多孔有机聚合物(POP)的新方法，作为新一代气态一氧化氮输送‘载体’来实现我们的雄心壮志。POPs是近年来被广泛研究的一类新型纳米孔材料，如Cooper等人开发的共轭微孔聚合物(CMPS)。POP材料的简便合成是通过碳-碳偶联或循环缩合反应将有机分子构件组装成二维或三维多孔网络。POPs具有多样的孔结构和功能以及较高的化学稳定性，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，我们将探索适合于储存大容量NO气体的新型POP材料。由于持久性有机污染物与NO气体在骨架中反应形成重氮二元结构，NO气体有望在多孔网络中被化学压缩。以这种方式，达到了高容量的NO存储，这确保了可控制地将所需量的NO输送到局部伤口部位。此外，还将通过调整活性官能团的浓度和NO的负载条件来优化POPs中储存的NO的量。通过合理选择分子构筑单元和合成条件来调整骨架的孔径和疏水性/亲水性，从而调整NO的释放特性。我们将系统地表征POP材料的结构，分析储存的NO物种，并模拟NO的释放动力学。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酸盐形成的影响，从而评估不同POP材料的性能，并优化材料配方和合成条件。本项目所取得的成果将成为今后研制原型治疗产品的基础。到该项目结束时，预计将开发一种新的有前景的无气体输送技术，旨在加速慢性伤口的愈合。

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.