Bio-functional Magnetic Nanoparticles: Novel High-Efficiency Targeting Agents for Localised Treatment of Metastatic Cancers

当今世界面临的最大医疗挑战之一是转移性癌症的治疗。虽然我们知道很多关于如何治疗肿瘤，一旦他们生长超过几毫米的大小，这是看不见的转移，从原发部位蔓延，往往是致命的原因。我们不得不求助于全身性治疗，化疗和放疗，这使整个生理系统处于严重的压力之下，对健康细胞的影响几乎与对癌细胞的影响一样大。迫切需要可行的替代品，临床医生和科学家几十年来一直在追求这样的目标。虽然已经取得了成功，但在大多数情况下，不可能以足够高的剂量将治疗剂递送到转移部位。人们的注意力转向了“有效载荷”方法，即使用靶向生物分子将治疗剂携带到癌症中，并施加一些外部刺激来激活它。其中最好的方法是基于使用无机纳米粒子，这些纳米粒子在刺激下被设计为释放热量。这些热疗方法非常适合癌症，因为癌症对热诱导的细胞应激非常敏感。热疗作为一种辅助疗法也有很大的潜力，因为只有一两度的局部加热可以显着提高化疗和放疗的有效性，减少其所需的剂量，从而减少有害的副作用。即便如此，迄今为止，尽管有希望的实验室结果，但在尝试实施局部热疗方面几乎没有真实的成功。关键的失败在于治疗所需的剂量-反应特性，这超出了迄今为止尝试的最佳方法的能力。一种方法，使用兆赫施加场的磁性纳米颗粒的体积感应加热，本质上是有效的。然而，即使在这里，由于依赖于30年前的感应加热电子设备（更适合电弧焊车间而不是医院诊所），这些努力也受到了阻碍，因此只有一项临床试验尚未尝试。因此，难怪我们今年早些时候宣布的一项新的突破性发明-我们称之为磁交流热疗（MACH）系统的感应加热电路-受到了媒体的极大关注。MACH系统体现了三项突破性的创新，这三项创新共同实现了首次构建一个可在临床中可行使用的极高性能，坚固耐用的系统。特别值得注意的是，它允许将手持式线圈连接到加热器上，并允许对施用器进行消毒甚至插管。突然之间，热疗在转移性癌症治疗中的真实的临床应用以及在一个非常大的市场中广泛利用这种英国拥有的技术的前景变得非常广阔。要将这一承诺转化为成就，需要作出重大努力，最重要的是，需要作出重点明确的努力。为此，我们进行了广泛的咨询，并汇集了优秀的学者，临床医生和公司，从初创企业到企业集团，共同制定实施计划。该计划的关键是尽快取得临床成果，与患者、临床医生和卫生服务部门迅速接触，以建立疗效和可信度，并为未来几年的创新建立一个平台。我们选择采用双重方法：（1）证明MACH系统对两种特别适合的癌症样本-头颈癌和肺癌进行局部热疗的临床疗效;（2）开发适合静脉注射的“隐形”抗体标记的磁性纳米颗粒，并能够避开网状内皮系统并在转移部位积聚。这些就是我们纳米技术大挑战的目标。

One of the greatest healthcare challenges facing the world today is the treatment of metastatic cancer. Although we know a great deal about how to treat tumours once they grow more than a few millimetres in size, it is the unseen me-tastases that spread out from a primary site that more often than not are the cause of fatalities. We are forced to resort to systemic treatments, to chemotherapy and radiotherapy, which place the entire physiology under severe strain, af-fecting healthy cells almost as much as they do the cancer cells. There is a pressing need for viable alternatives, and clinicians and scientists have been pursuing such goals for decades. Although there have been successes, for the most part it has been impossible to deliver therapeutic agents to the sites of metastases in sufficiently high doses. Attention has turned to 'payload' methods, where the targeting biomolecule is used to carry a therapeutic agent to the cancer, and some external stimulus is applied to activate it. The best of these are based on the use of inorganic nanoparticles which, under stimulation, are designed to release heat. These hyperthermia approaches are ideally suited to cancers, which are highly susceptible to heat-induced cellular stress. Hyperthermia also has great potential as an adjuvant therapy, since just a degree or two of local heating can significantly increase the effectiveness of chemotherapy and radiotherapy, reducing their required doses and thereby reducing the harmful side-effects. Even so, to date there has been little real success in attempts to implement localised hyperthermia, despite promising bench results. The key failure lies in the required dose-response characteristics of the therapy, which exceed the capa-bilities of the best approaches attempted so far. One approach, volumetric induction heating of magnetic nanoparticles using megahertz applied fields, is intrinsically efficient. However, even here efforts are hampered by a reliance on 30-year-old induction heating electronics - more befitting an arc-welding workshop than a hospital clinic - so that only one clinical trial has yet been attempted. It is therefore no wonder that our announcement earlier this year of a new breakthrough invention - an induction heat-ing circuit we call the Magnetic Alternating Current Hyperthermia (MACH) system - was greeted with enormous media attention. The MACH system embodies three ground-breaking innovations which together enable, for the first time, construction of an extremely high performance, robust system that can feasibly be used in the clinic. Of particular note, it allows for a hand-held coil to be attached to the heater, and for miniaturisation or even catheterisation of the appli-cator. The prospects are suddenly wide open for real clinical application of hyperthermia to treat metastatic cancer, and for widespread exploitation of this UK-owned technology in an exceptionally large market. To translate this promise into achievement requires significant efforts, and most importantly, well-focused efforts. To this end we have consulted widely and brought together an excellent team of academics, clinicians and companies, from start-ups to conglomerates, to work together on an implementation plan. Key to this plan is to move as fast as possible to clinical outcomes, to engage quickly with patients, clinicians and health services to establish efficacy and credibility, and to build a platform for innovation for years to come. We have chosen to adopt a dual approach of (1) proving the clinical efficacy of the MACH system for localised hyperthermia on two especially well suited cancer exemplars - head and neck cancer and lung cancer; and (2) developing 'stealth' antibody-tagged magnetic nanoparticles suitable for intravenous injection, and able to evade the reticulo-endothelial system and accumulate at metastatic sites. These then are the goals of our Nanotechnology Grand Challenge.