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一种非常有效的方法。然而，这种方法需要大型、昂贵的设施，而英国目前还没有预见到这一点。这种方法之所以如此有效，有两个原因：i)因为这些光束中的离子在静止之前储存了大部分能量，它们可以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要低得多，即它们的效果具有高度的靶向性。Ii)束流中的每一个离子在停止之前都会给它所经过的细胞一个“重击”。这种冲压比传统放射治疗中使用的光子要强烈得多，也更聚焦。这种局部的打击甚至可以击倒最具抵抗力的细胞。总而言之，这些重离子向患病细胞发出了一系列“靶向打击”。精心设计的金纳米粒子有可能同时提供这两个好处，在传统的放射治疗中心提供同样的一系列靶向打击，比如我们在英国各地的那些中心。在提供重离子疗法的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。为了实现这一方法，这些颗粒将被赋予一种化学“斗篷”，使它们能够穿过患者的身体到达肿瘤。他们还将获得一把化学“钥匙”，该钥匙将识别并优先允许他们进入患病细胞。它们也可能被赋予其他钥匙，以传递到细胞的关键区域(例如细胞核)。一旦进入病变细胞，就可以在CT扫描中检测到它们的存在，以显示肿瘤的位置。此外，在传统的放射治疗中(使用直线加速器)，他们可以获取X射线束中的很大一部分能量，并将其转化为已被证明在离子束放射治疗中非常有效的那种高度聚焦的冲头，摧毁癌细胞，而健康细胞基本上不受影响。我们已经揭示了这些纳米粒子产生与德国和日本如此成功地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它们。我们的成像方法的独特之处在于，它直接测量金核的存在，而不是放置在它上面的其他标签。这一点很重要，因为标签可以分离出在其他方法中给出的误导性结果。使这种疗法有效的下一步是尝试不同大小、不同“斗篷”结构的金纳米颗粒，并配备不同的“钥匙”，以期优化它们对癌细胞的摄取，同时将其对健康细胞的摄取降至最低。我们将围绕我们的新成像技术开发一条管道，以评估金纳米颗粒的摄取和定位程度，从而评估它们的适合性。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(这是一个常见的问题)。利用这条管道，我们将快速确定金纳米颗粒的最佳大小、合适的遮盖结构和一套进入患病细胞的“钥匙”。此外，我们将把成像技术扩展到活细胞摄取纳米颗粒的过程中，为合理改进它们的设计提供非常有用的信息。来自管道的优化纳米颗粒设计将适合推进到更大的研究项目和临床试验中，以确定它们治疗各种癌症的全部潜力。因此，这个项目将作为一个跳板，从这个跳板上出现一种全新的癌症治疗方法。

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.