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

脑卒中是脑动脉血栓闭塞的病理结果。这种闭塞会导致缺血，如果不加以治疗，还会造成脑损伤，可能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含有更多的聚合纤维蛋白，使其更不易被溶栓药物降解。与药物治疗相比，血管内动脉内溶栓药物或机械凝块破裂是一种非常有效的治疗方法，可在一定比例的符合条件的患者中快速实现血运重建，并有证据表明功能结果有所改善。然而，EID是复杂的，需要高度的操作员技能和训练有素的工作人员提供一天24小时的服务。EID目前也只适用于在症状出现的最初几个小时内出现的患者。因此，EID只能在高度专业化的单位提供，需要患者前往该单位。这与预先指定的开颅动脉切开时间窗口和机械中断相结合，限制了对患者的治疗。常见的溶栓药物是阿替普酶，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），发生在2.4%-10%的患者中。这些患者预后明显较差，死亡或残疾的风险增加。该提案旨在开发一系列最先进的治疗成像或“治疗”药物，以推进中风患者的靶向和个性化治疗。它专注于开发基质金属蛋白酶（MMP）激活的靶向血栓的“智能治疗”MR显像剂。药物释放系统是“智能”的，因为它只会在血栓内激活，由于活化的血小板释放MMPs，允许药物精确靶向血栓。此外，由于MRI的治疗能力，也可能有溶栓药物在体内的无创可视化。因此，这些“智能治疗”药物的开发将有助于限制中风治疗的不良副作用，同时有效地提高体内血栓成像的能力。预计这项工作的结果将显著有助于更好地理解药物输送，目的是开发用于缺血性卒中个性化治疗的治疗显像剂。

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.