Engineering Precision Medicine for the 21st Century

由于人口老龄化以及随之而来的癌症、中风、阿尔茨海默病和耐药性感染等疾病的增加，英国正面临着护理危机，这些疾病的患病率随着年龄的增长而增加。我们迫切需要更好的治疗方案来管理这些疾病，防止过早死亡，使患者能够继续独立生活，减轻护理人员的负担。我们在拟议研究中的目标是将来自量子物理和药物化学不同领域的科学家与生物医学工程师，免疫学家和临床医生聚集在一起，以提供这些解决方案。我们的方法是基于令人兴奋的新发现，即目前用作成像造影剂的微泡可以用低强度超声刺激产生光，为靶向治疗提供了一种独特的方法。虽然光活化疗法几十年来一直是临床前和临床研究的主题，但其有效性受到光穿透组织的不良影响。在我们的方法中，这个障碍被消除了。由于超声波可以从外部探头精确聚焦到身体的几乎任何地方，因此可以远程和非侵入性地触发光的产生，以提供高度局部化的治疗，并具有最小的脱靶毒性。这有可能改变癌症化疗，中风治疗，抗菌药物以及免疫刺激和光遗传疗法等新治疗方法的递送。初步概念验证阶段证实：在0.5-3 MHz的超声频率和0.1-1 MPa的峰值负压下，即在目前用于临床应用的范围内的条件下，微泡发出光;光发射是宽带的（300-600 nm）并且振幅与声发射成比例;光发射的光谱由于在特定光学波长处吸收的可光活化药物的存在而改变;并且在细胞培养物以及球状体模型中可以有效地产生癌细胞死亡。光发射的定量显示这些远低于光激活疗法中使用的激光产生的光发射。对这种差异的研究表明，这可能是由于超声驱动的微泡也促进药物分子通过组织和细胞内药物摄取的质量转运，这两者都增加了给定剂量的疗效。第二阶段将在这些有希望的发现的基础上：为我们的临床和工业合作者确定的关键临床靶点开发优化的光活化剂和药物微泡缀合物，这些靶点代表了迫切的需求并具有明确的转化途径;配置临床超声系统进行治疗并确定最佳暴露参数;阐明支持药物活化和作用的基本物理和生物学机制;并在相关疾病模型中生成临床前安全性和有效性数据。我们的总体目标是开发一个完整的治疗系统，包括新的治疗药物以及治疗和监测系统，为临床开发做好准备。这将为到2050年改变治疗交付的新治疗管道提供基础。

The UK is facing a care crisis due to its aging population and the concomitant increase in diseases such as cancer, stroke, Alzheimer's and drug resistant infections whose prevalence increases with age. We urgently need better therapeutic solutions to manage these conditions, prevent premature deaths, enable patients to continue living independently and ease the burden on care providers. Our aim in the proposed research is to bring together scientists from the disparate fields of quantum physics and pharmaceutical chemistry with biomedical engineers, immunologists, and clinicians in order to provide those solutions. Our approach is based upon the exciting new finding that microbubbles, currently used as imaging contrast agents can be stimulated with low intensity ultrasound to produce light, offering a unique method for delivery targeted therapy. Whilst photoactivated therapies have been the subject of both pre-clinical and clinical research for decades, their usefulness has been drastically hindered by the poor penetration of light through tissue. In our approach this barrier is eliminated. Since ultrasound can be precisely focused almost anywhere in the body from an external probe, light generation can be triggered remotely and non-invasively to deliver highly localised treatment with minimal off-target toxicity. This has the potential to transform the delivery of cancer chemotherapy, stroke treatment, antimicrobial agents and also newer treatments such as immunostimulatory and optogenetic therapies. The initial proof of concept phase confirmed that: light was emitted from microbubbles driven at ultrasound frequencies from 0.5-3 MHz with peak negative pressures 0.1-1 MPa, i.e. conditions that are well within the range currently used for clinical applications; that light emissions were broadband (300-600 nm) and proportional in amplitude to acoustic emissions; the spectrum of light emissions was altered by the presence of photoactivatable drugs absorbing at specific optical wavelengths; and that cancer cell death could be efficiently generated in cell culture and also spheroid models. Quantification of the light emissions showed these to be substantially lower than those produced by lasers used in light activated therapies. Investigation of this discrepancy indicated that this was likely due to the fact that ultrasound-driven microbubbles also promote mass transport of drug molecules through tissue and intracellular drug uptake, both of which increase the efficacy of a given dose. Phase II will build on these promising findings to: develop optimised photoactivatable agents and drug-microbubble conjugates for key clinical targets identified with our clinical and industrial collaborators as representing both an urgent need and having a clear translational pathway; configure a clinical ultrasound system for treatment delivery and identify optimal exposure parameters; elucidate the fundamental physical and biological mechanisms underpinning drug activation and effect; and generate pre-clinical safety and efficacy data in relevant disease models. Our overall goal is to develop a complete treatment system, consisting of new therapeutic agents together with systems for treatment delivery and monitoring, ready for clinical development. This will provide the foundations for a pipeline of new treatments to transform therapeutic delivery by 2050.