Pipe-line for rapid screening and rational improvement of nanoparticles for cancer imaging and therapy

在日本和德国，重离子束放射治疗已被证明是治疗多种癌症的高效方法。然而，这种方法需要大型，昂贵的设施，目前在英国还没有预见到。这种方法如此有效的原因有两个：i）因为这些束中的离子在它们静止之前存款了它们的大部分能量，它们可以被用来依次挑选肿瘤的每个部分，患者遭受的副作用比传统方法相关的副作用低得多，即它们的效果是高度靶向的。ii）束中的每个离子在停止之前对它所通过的细胞进行“穿孔”。这种冲击比传统放射疗法中使用的光子更强烈，更集中。这种局部冲击甚至可以击倒最有抵抗力的细胞。总之，这些重离子向病变细胞提供了一系列“靶向冲击”。精心设计的金纳米粒子有可能提供这两种好处，在传统的放射治疗中心提供同样的一系列靶向治疗，比如我们在英国各地的放射治疗中心。在为重离子治疗提供一种现实和经济的替代方案的同时，它们还可以提供额外的好处。为了实现这种方法，这些粒子将被赋予一种化学“斗篷”，使它们能够穿过患者的身体到达肿瘤。他们还将获得一种化学“钥匙”，可以识别并优先允许他们进入病变细胞。它们也可能被给予其他钥匙，以进入细胞的关键区域（例如细胞核）。一旦进入病变细胞，它们的存在可以在CT扫描中检测到，以显示肿瘤的位置。此外，在传统的放射疗法（使用直线加速器）中，它们可以吸收X射线束中的大部分能量，并将其转化为与离子束放射疗法相同的高度聚焦的冲击，摧毁癌细胞，同时使健康细胞基本不受影响。我们已经揭示了这些纳米粒子产生与德国和日本成功使用的重离子相同的冲击力的机制。我们还开发了一种技术，可以在细胞内快速成像。我们的成像方法的特点是它直接测量金核的存在，而不是放置在其上的其他标签。这很重要，因为标签可能会脱落，从而在其他方法中产生误导性结果。使这种疗法有效的下一步是尝试各种尺寸的金纳米颗粒，各种“斗篷”结构，并配备了不同的“钥匙”，以优化它们对癌细胞的吸收，同时最大限度地减少健康细胞的吸收。我们将围绕我们的新成像技术开发一个管道，以评估金纳米颗粒的摄取和定位程度，从而评估其适用性。此外，我们的成像技术可以用来显示金纳米颗粒是否在细胞中聚集在一起（一个常见的问题）。使用这个管道，我们将快速确定金纳米粒子的最佳尺寸，合适的隐形结构和一组“钥匙”，以提供进入病变细胞的通道。此外，我们还将扩展成像技术，使其能够在活细胞摄取纳米粒子时成像，为合理改进纳米粒子设计提供非常有用的信息。来自管道的优化纳米粒子设计将适合用于更大的研究项目和临床试验，以确定其治疗各种癌症的全部潜力。因此，该项目将作为一个跳板，从中将出现一种全新的治疗癌症的方法。

Heavy ion beam radiotherapy has been shown to be a highly effective way to treat many types of cancer, both in Japan and Germany. However, this approach requires large, expensive facilities of a kind not currently foreseen in the UK. There are two reasons for this approach being so effective:i) Because the ions in these beams deposit most of their energy just before they come to rest, they can be used to pick out each part of the tumour in turn, with the patient suffering much lower side effects than those associated with traditional approaches, i.e. their effect is highly targeted. ii) Each ion in the beam gives a 'punch' to the cells it passes through just before it stops. This punch is much more intense and highly focused than photons used in traditional radiotherapy. This localised punch can knock out even the most resistant cell.In summary, these heavy ions deliver a series of 'targeted punches' right to the diseased cells. Carefully designed gold nanoparticles have the potential to offer both of these benefits, delivering this same series of targeted punches at traditional radiotherapy centres such as those we have across the UK. Whilst offering a realistic and economic alternative to heavy ion therapy they can also offer additional benefits.To realise this approach, these particles would be given a chemical 'cloak' that will allow them to pass through the patient's body to the tumour. They would also be given a chemical 'key' which will recognize and preferentially allow them to enter the diseased cells. They might also be given other keys to pass into critical regions of the cell (e.g. the nucleus). Once inside the diseased cells, their presence can be detected in a CT scan to show where the tumour is located. Furthermore, during traditional radiotherapy (using linacs), they can take a large fraction of the energy in the X-ray beam and turn it into the same kind of highly focused punch that has proved so effective in ion beam radiotherapy, destroying the cancerous cells while leaving the healthy ones largely unaffected. We have revealed the mechanism whereby these nanoparticles give the same punch as the heavy ions used so successfully in Germany and Japan. We also have developed a technique to rapidly image them within cells. The particular feature of our imaging approach is that it measures the presence of the gold core directly rather than some other tag which has been placed upon it. This is important because the tag can detach giving misleading results in other approaches.The next step in making this therapy effective is to try gold nanoparticles of various sizes, various 'cloak' constructions and equipped with different 'keys' with a view to optimizing their uptake into cancerous cells whilst minimizing it for healthy cells. We will develop a pipeline built around our new imaging technique to assess the degree of uptake and localization of the gold nanoparticles, thereby assessing their suitability. Furthermore, our imaging technique can be used to show if the gold nanoparticles are clumping together in the cells (a common problem). Using this pipeline we will rapidly determine the optimum size of the gold nanoparticles, suitable cloaking constructions and a set of 'keys' to provide entry into the diseased cells. Furthermore, we will extend the imaging technique to image live cells as they take up the nanoparticles, providing very useful information for improving their design in a rational way.The optimized nanoparticle designs coming from the pipeline will be suitable to be taken forward into bigger research projects and clinical trials where their full potential for treating various cancers will be determined. Hence, this project will act as a springboard from which an entirely new approach to treating cancer will emerge.