Novel Characterisation of Nanoparticles as Lung Surfactant Protein Substitutes towards New Treatments for Infant Respiratory Distress Syndrome

婴儿呼吸窘迫综合征(IRDS)是一种悲惨的健康状况，早产儿出生时无法自主呼吸。导致这种情况的原因是，包裹在我们肺部表面并允许我们呼吸的肥皂状分子，称为肺表面活性物质，在怀孕期间没有足够的时间成熟。肺表面活性物质的目的是降低我们肺部液体的表面张力，这反过来又减少了我们在呼吸时需要消耗的能量。如果怀孕期间没有产生足够的表面活性物质，患有IRDS的婴儿甚至没有第一次呼吸所需的力量。肺表面活性物质是一种复杂的生物分子混合物，早产儿体内缺失的关键成分是蛋白质。它有一种特殊的功能，当我们呼气时，由于表面积很小，它允许覆盖肺液的表面活性物质的其余部分聚集在小口袋中，使它们能够非常迅速地重组，并随着我们吸气时表面积的增加而保持液体的涂层。在没有蛋白质的情况下，表面活性分子在整个呼吸周期中难以保持液体的涂层，表面张力上升，肺衰竭。不幸的是，制药公司制造这种蛋白质太昂贵和困难，科学家们还没有成功设计出具有相同功能的替代分子。目前的药物是从动物肺中提取的粗提物，还没有设计出适合人类使用的药物。这些治疗方法很好，因为存活率很高，但严重的肠道疾病可能会产生严重的副作用，而且这些药物的保质期如此之短，以至于在发展中国家并不广泛获得。显然需要进一步的努力来开发新的和改进的治疗方法。这个研究项目建立在我作为科学家研究生物膜在水面上的行为时最近的两项发现的基础上。我从胶片上反射光线，就像我们可以用眼睛区分不同的物体一样，当我们看到从它们反射的光线时，我实验室的激光仪器的工作方式是相同的，只是信息是关于单层分子的。第一个发现是，当我挤压某些薄膜以减少表面积时，比如当我们呼气时，如果这些薄膜含有特定类型的称为纳米颗粒的微小颗粒，我就可以产生这些材料口袋。第二个发现是，当我制作肺表面活性物质本身的薄膜时，我第一次可以使用我的激光反射技术来观察在非常低的表面张力下形成的这些口袋的深度和直径。这些突破创造了一个令人兴奋的机会，利用反射技术来研究纳米颗粒的重要性质，这些特性可以帮助形成肺表面活性物质中至关重要的口袋物质。首先，该项目将考虑纳米颗粒的大小、电荷、亲和力(油与水)和膨胀度对其在没有蛋白质的情况下重现健康肺表面活性物质性能的影响。其次，最有希望的纳米粒子将被披上原始蛋白质相对廉价部分的斗篷，看看这是否可能是达到最佳性能的更好方式。该项目的总体目标是建立关于纳米粒子帮助重建健康肺部性能的能力的知识，以期未来设计治疗IRD的新药。开发这些新药的雄心是它们可以减少副作用和/或改善保质期，这反过来可以改善英国的健康状况或发展中国家的存活率。这项工作还将提供一个平台，以确立英国在治疗IRDS方面的科学和医学领先者地位，而英国目前在IRDS上缺乏存在。

Infant respiratory distress syndrome (IRDS) is a tragic health condition when premature babies cannot breathe by themselves at birth. The cause of the condition is that soap-like molecules that coat the surface of our lungs and allow us to breathe, called lung surfactant, have not had enough time to mature during pregnancy. The purpose of lung surfactant is to reduce the surface tension of the fluid in our lungs, which in turn reduces the energy we need to expend when we breathe. Without enough of the surfactant produced during pregnancy, babies who suffer from IRDS do not even have the strength they need to take their first breath.Lung surfactant is a complex mixture of biological molecules, and the key component missing in premature babies is a protein. It has a special function that allows the rest of the surfactant coating the lung fluid to gather in small pockets as the surface area is small when we breathe out, enabling them to reorganise very quickly and keep the fluid coated as the surface area increases when we breathe in. In the absence of the protein, the surfactant molecules struggle to keep the fluid coated throughout breathing cycles, the surface tension goes up, and the lungs collapse.Unfortunately, it is too expensive and difficult for drug companies to make this protein, and scientists have not yet managed to design replacement molecules that have the same function. Current medicines are crude extracts from animal lungs with no design efforts having been made to make them well suited for use in humans. These treatments are good in that survival rates are high, but a serious bowel condition can be a severe side effect, and the medicines have such poor shelf life they are not widely available in developing countries. Further efforts are clearly needed to develop new and improved treatments.This research project builds on two recent discoveries I have made whilst working as a scientist studying the behaviour of biological films on the surface of water. I reflect light off the films, and just like we can use our eyes to distinguish different objects when we see light that has reflected off them, the laser instruments in my lab work in the same way except that the information is about single layers of molecules. The first discovery was that when I squeezed certain films to reduce the surface area, like when we breathe out, I could generate these pockets of material if the films contained certain types of tiny particles called nanoparticles. The second discovery was that when I made films made of lung surfactant itself, I could use my laser reflection techniques to see the depth and diameter of these pockets formed at very low surface tension for the first time.These breakthroughs have created an exciting opportunity to use reflection techniques to work out the important properties of nanoparticles that can help form the vital pockets of material in lung surfactant. First, the project will consider effects of the size, charge, affinity (oil vs water) and degree of swelling of the nanoparticles in their ability to recreate the performance of healthy lung surfactant in the absence of the protein. Second, the most promising nanoparticles will be dressed up in a cloak of relatively cheap portions of the original protein to see if this could be an even better way to reach optimal performance.The overarching goal of the project is to establish knowledge on the ability of nanoparticles to help recreate the performance of healthy lungs with a view to the future design of new medicines to treat IRDS. The ambition of developing these new medicines is that they could result in fewer side effects and/or have an improvement in shelf-life, which in turn can lead to improvements in health here in the UK or in survival rates in developing countries. The work will also provide a platform to establish the UK as a scientific and medical leader in the treatment of IRDS on which it is currently missing presence.