Matrix metalloproteinase activated Multimodal 'Theranostic' Drug Delivery Imaging Agents for thrombosis

中风是大脑动脉闭塞血栓的病理结果。这种闭塞会导致脑缺血，如果不治疗，还会造成脑损伤，可能会导致严重的精神症状、瘫痪和死亡。中风的终生风险为20%-30%。中风患者的早期治疗至关重要，因为未经治疗的血栓有更多聚合的纤维蛋白，使他们更能抵抗溶栓药物的降解。血管内动脉内给药(EID)溶栓剂或机械血栓破裂是非常有效的治疗方法，可在部分符合条件的患者中迅速进行血管再通，并有证据表明与药物治疗相比，功能结果有所改善。然而，开斋节很复杂，需要高度的操作员技能和训练有素的员工来提供一天24小时的服务。EID目前也只适用于出现症状的最初几个小时的患者。因此，EID只能在高度专业化的病房中提供，这需要患者前往该病房。这一点，再加上预先指定的提供eID的时间窗口和机械破坏，限制了向患者提供这种治疗。一种常见的溶栓剂是Alteplase，一种重组纤溶酶原激活剂。不幸的是，溶栓药物治疗的一个显著副作用是颅内出血(ICH)，发生率为2.4%-10%。这些患者的预后明显更差，死亡或残疾的风险增加。这项提议旨在开发一系列最先进的治疗性成像或“治疗”试剂，以推进中风患者的针对性和个性化治疗。重点介绍了基质金属蛋白酶(MMPs)激活的针对血栓的“智能消融”MR显像剂的发展。药物释放系统是智能的，因为它只会在血栓内激活一次，因为激活的血小板会释放MMPs，从而允许药物精确地靶向血栓。此外，由于溶栓药物的核磁共振成像能力，还可以对体内的溶栓药物进行非侵入性可视化。因此，这些智能溶栓药物的开发将有助于限制中风治疗的不良副作用，同时提高有效地对体内血栓进行成像的能力。预计这项工作的结果将大大有助于更好地了解药物传递，目的是开发用于缺血性中风个性化治疗的治疗造影剂。

Stroke is a pathological outcome of occlusive thrombi in the cerebral artery. This occlusion leads to ischaemia, and, if not treated, brain damage, potentially leading to profound mental symptoms, paralysis, and death. The lifetime risk of stroke is 20-30%. Early treatment for stroke patients is critical since untreated thrombi have more polymerised fibrin, making them more resistant to degradation by thrombolytic drugs. Endovascular intra-arterial delivery (EID) of thrombolytics or mechanical clot disruption are highly effective therapies resulting in rapid revascularisation in a proportion of eligible patients with evidence of improved functional outcomes compared to medical therapy. However EID is complex, requiring a high degree of operator skill and sufficiently trained staff to provide a 24 hour a day service. EID is also currently only indicated for patients presenting in the first few hours of symptom onset. Therefore EID can only be delivered in highly specialised units necessitating patient travel to the unit. This in combination with a prespecified time-window for the delivery of EID and mechanical disruption limits the delivery of this treatment to patients. A common thrombolytic is Alteplase, a recombinant plasminogen activator. Unfortunately, a notable side-effect of thrombolytic drug therapy, is intracranial haemorrhage (ICH) which occurs in 2.4%-10% of patients. These patients have significantly worse prognosis, with an increased risk of death or disability.This proposal sets out to develop a series of state of the art therapeutic imaging or 'theranostic' agents for advancing targeted and personalised therapy in stroke patients. It focuses on the development of Matrix metalloproteinase (MMP) activated 'smart theranostic' MR imaging agents targeting thrombi. The drug release system is 'smart' as it would only activate once present within the thrombus, due to release of MMPs by activated platelets, allowing for precise targeting of the drug to the thrombus. Furthermore, due to the MRI capability of the theranostic, it would also be possible to have the non-invasive visualization of thrombolytic drugs in-vivo.As such the development of these 'smart theranostic' agents, will help to limit the unwanted side-effects of stroke therapy, whilst simultaneously increasing the ability to image thrombi in vivo effectively. It is expected that the results of this work will significantly contribute to a better understanding of drug delivery with the aim to develop theranostic imaging agents for personalised treatments in ischemic stroke.