Optically-Guided Nanoparticles and Cell Scalextrics

引导纳米粒子在人体细胞中的运输-为什么这很重要？病毒似乎毫不费力地进入组织和细胞，在体内被选择性地运输到它们可能造成最大伤害的部位。它们通过突破细胞屏障（如细胞的外膜或质膜）来实现这一点，并利用人类细胞机制来复制自己。另一方面，药物分子非选择性地在整个身体中扩散，从而在最需要它们的地方降低效果，并在不需要它们的地方引起不良副作用。其中一个原因是，与病毒不同，目前用于药物和诊断试剂的合成载体无法有效地穿过生物屏障，然后到达细胞内的特定部位。因此，一种可以以类似于病毒的方式通过组织运输，然后进入确定的细胞位置但不会引起疾病的人造颗粒将彻底改变医疗保健应用。这对于发展中国家和老龄化人口所需的早期诊断和治疗尤其重要。新型聚合物包覆的金纳米颗粒能提供什么？这些材料是本申请中描述的概念验证研究的最佳测试平台。首先，可以使用许多显微镜方法在细胞中跟踪金颗粒，包括该团队新开发的高灵敏度四波混合成像系统。它们可以用各种聚合物材料涂覆，这将有助于引导它们进入细胞和特定的细胞位置。我们以前已经表明，被功能性“钥匙”封端以进入天然细胞门户的聚合物可以通过温度的小幅升高来打开和关闭它们的入口，从而导致它们改变它们的构象。我们还表明，我们可以通过激光脉冲在细胞内的金纳米颗粒上产生这些温度升高，但不会损害细胞。通过将温度响应聚合物附着到黄金上，应该可以使用激光脉冲来打开和关闭功能键，并以这种方式引导颗粒到达指定的细胞位置。这将有助于解开物质在细胞中移动的机制，从而使我们能够将诊断和治疗引导到需要它们的地方。影响。有效治疗癌症、冠心病和神经退行性疾病等重大疾病负担的一个主要障碍是我们无法将基因和蛋白质等治疗分子定向到细胞内的特定组织和特定区域。这是这项应用的一个主要目标，这里的进展可能对学术界、工业界和他们所服务的社会产生广泛的影响。我们可以设想一种商业应用，其中结合成像和引导仪器（例如，超声探头和成像）与一组具有特定疾病标志物功能的纳米颗粒一起使用，具有真正选择性个性化治疗的潜力。还需要更好的诊断，以便更早地检测疾病，从而获得更好的医疗保健结果。这项工作的成功完成可以允许开发成像/检测平台，其中可以通过与金纳米颗粒上的选择性受体相互作用来检测疾病的特定标记物，通过局部激光加热方法将其引导到细胞内位点。当考虑到到2010年欧盟三分之一的人将直接或间接受到癌症的影响时，很明显，早期发现和干预将为患者带来显着的好处，长期的发展可以通过一种新的生物医学技术产生影响，即激光-引导治疗，其中通过聚焦超声的局部加热引导人体中的可生物降解的响应性纳米颗粒。

Steering nanoparticle transport in human cells - why is this important?Viruses seem to travel effortlessly into tissues and cells, being transported selectively in the body to reach the sites where they can cause most harm. They do this by breaching cellular barriers such as the outer or plasma membrane of cells and use human cellular machinery to make copies of themselves. Drug molecules on the other hand spread non-selectively throughout the body thus reducing effects where they are most needed, and causing adverse side-effects where they are not wanted. One reason for this is that current synthetic carriers for drugs and diagnostic agents, unlike viruses, are unable to effectively cross biological barriers and then reach specific sites inside cells. An artificial particle that could transport through tissue, in a manner analogous to a virus and then into defined cell locations but without causing disease, would therefore revolutionise healthcare applications. This would be particularly important for the early stage diagnostics and therapeutics needed in developing nations and for ageing populations.What do novel polymer-coated gold nanoparticles have to offer?These materials are an optimal test platform for proof-of-concept studies described in this application. Firstly, gold particles can be tracked in cells using a number of microscopic approaches including the newly developed highly sensitive four-wave mixing imaging system available to this team. They can be coated with a variety of polymeric materials that will help to guide them into cells and into specific cell locations. We have previously shown that polymers which are capped with functional 'keys' to enter natural cell portals can have their entry switched on and off by small increases in temperature which cause them to change their conformations. We also have shown that we can generate these temperature increases at gold nanoparticles inside cells through laser pulses but without damaging the cells. By attaching the temperature-responsive polymers to gold, it should be possible to use laser pulses to switch the functional keys on and off, and in this way guide particles to reach defined cellular locations. This will help to unravel the mechanisms by which materials travel in cells, thus enabling us to guide diagnostics and therapeutics to where they are required.Impact.A major hurdle to effective therapy against major disease burdens such as cancer, coronary heart disease and neurodegeneration is our inability to direct therapeutic molecules such as genes and proteins to specific tissue and defined compartments inside cells. This is a major objective of this application and progress here could have widespread implications for academia, industry and the society that they serve. One could envisage a commercial application in which a combined imaging and guiding instrument (e,g, ultrasonic probes and imaging) is used with a set of nanoparticles with functionality for specific disease markers, with a potential for truly selective personalised therapies.Better diagnostics are also needed that allow earlier detection of disease and thus better healthcare outcomes. Successful completion of this work could allow development of an imaging/detection platform where specific markers of disease could be detected through their interaction with selective receptors on gold nanoparticles guided to intracellular sites by the local laser-heating method. When it is considered that 1 in 3 individuals in the EU will be affected directly or indirectly by cancer by 2010, it is clear that earlier detection and intervention will bring marked benefits to patients, carers and society as a whole.Longer-term development could generate impact through a new biomedical technology i.e. laser-guided therapeutics wherein local heating by focused ultrasound guides biodegradable responsive nanoparticles in humans.