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

纳米颗粒作为肺表面活性蛋白替代品的新表征，用于治疗婴儿呼吸窘迫综合征

• 批准号: EP/V029495/1
• 负责人: Richard Campbell
• 金额: $ 36.74万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV029495%2F1
• 关键词: Novel; Characterisation; Nanoparticles; Lung; Surfactant

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.

婴儿呼吸窘迫综合征（IRDS）是一种悲剧性的健康状况，当早产儿在出生时不能自己呼吸。造成这种情况的原因是，覆盖在我们肺部表面、让我们呼吸的肥皂状分子，称为肺表面活性剂，在怀孕期间没有足够的时间成熟。肺表面活性剂的作用是降低肺内液体的表面张力，从而减少我们呼吸时需要消耗的能量。没有足够的表面活性剂在怀孕期间产生，患有IRDS的婴儿甚至没有他们需要的第一次呼吸的力量。肺表面活性剂是一种复杂的生物分子混合物，早产儿缺少的关键成分是一种蛋白质。它有一种特殊的功能，当我们呼气时，表面活性剂的剩余部分聚集在小口袋里，使它们能够非常迅速地重组，并在我们吸气时，表面面积增加时保持液体的包裹。在缺乏蛋白质的情况下，表面活性剂分子在整个呼吸周期中努力保持液体的包裹，表面张力上升，肺部塌陷。不幸的是，对于制药公司来说，制造这种蛋白质过于昂贵和困难，科学家们还没有设法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取物，没有经过任何设计努力使其适合于人类使用。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很短，在发展中国家不能广泛使用。显然需要进一步努力开发新的和改进的治疗方法。这个研究项目建立在我最近的两个发现的基础上，当时我是一名科学家，研究生物薄膜在水面上的行为。我把光从薄膜上反射出来，就像我们可以用眼睛分辨不同的物体一样，当我们看到从它们反射回来的光时，我实验室里的激光仪器也以同样的方式工作，除了这些信息是关于单层分子的。第一个发现是，当我挤压某些薄膜来减少表面积时，比如当我们呼气时，我可以产生这些材料的口袋，如果这些薄膜包含某些类型的微小颗粒，称为纳米颗粒。第二个发现是，当我用肺表面活性剂制作薄膜时，我可以用激光反射技术第一次看到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粒子的重要特性，这些特性可以帮助形成肺表面活性剂中至关重要的物质口袋。首先，该项目将考虑纳米颗粒的大小、电荷、亲和力（油对水）和膨胀程度对它们在缺乏蛋白质的情况下重现健康肺部表面活性剂性能的影响。其次，最有前途的纳米粒子将被包裹在相对便宜的原始蛋白质部分的外衣中，看看这是否能更好地达到最佳性能。该项目的总体目标是建立关于纳米颗粒帮助重建健康肺部功能的能力的知识，以期未来设计治疗IRDS的新药。开发这些新药的目标是减少副作用和/或延长保质期，从而改善英国人的健康状况或提高发展中国家的存活率。这项工作还将提供一个平台，使英国成为目前缺乏的治疗IRDS的科学和医学领导者。

项目成果

Effects of Charge Density on Spread Hyperbranched Polyelectrolyte/Surfactant Films at the Air/Water Interface.

• DOI: 10.1021/acs.langmuir.3c01514
• 发表时间: 2023-10-24
• 期刊: LANGMUIR
• 影响因子: 3.9
• 作者: Carrascosa-Tejedor, Javier;Tummino, Andrea;Feher, Bence;Kardos, Attila;Efstratiou, Marina;Skoda, Maximilian W. A.;Gutfreund, Philipp;Maestro, Armando;Lawrence, M. Jayne;Campbell, Richard A.;Varga, Imre
• 通讯作者: Varga, Imre