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

基质金属蛋白酶激活的多模式“治疗诊断”药物输送成像剂用于血栓形成

• 批准号: MR/T002573/1
• 负责人: Graeme Stasiuk
• 金额: $ 89.66万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT002573%2F1
• 关键词: Matrix; metalloproteinase; activated; Multimodal; Theranostic

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.

中风是脑动脉中闭塞性血栓的病理结果。这种闭塞会导致缺血，如果不治疗，会导致脑损伤，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是至关重要的，因为未经治疗的血栓具有更多的聚合纤维蛋白，使它们更能抵抗溶栓药物的降解。血管内动脉内输送（EID）溶栓剂或机械性凝块破裂是一种非常有效的治疗方法，可在一定比例的合格患者中实现快速血运重建，与药物治疗相比，有证据表明功能结局改善。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目前也仅适用于症状发作最初几小时内出现的患者。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。这与用于递送EID和机械破坏的预先指定的时间窗相结合限制了向患者递送这种治疗。一种常见的血栓溶解剂是阿替普酶，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。这些患者的预后明显较差，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“治疗诊断”试剂，以推进中风患者的靶向和个性化治疗。它的重点是开发基质金属蛋白酶（MMP）激活的“智能治疗诊断”磁共振成像剂靶向血栓。药物释放系统是“智能的”，因为它仅在血栓内存在时激活，这是由于激活的血小板释放MMP，从而允许药物精确靶向血栓。此外，由于治疗诊断的MRI功能，还可以实现溶栓药物在体内的非侵入性可视化。因此，这些“智能治疗诊断”药物的开发将有助于限制中风治疗的不良副作用，同时提高有效体内血栓成像的能力。预计这项工作的结果将大大有助于更好地了解药物输送，目的是开发治疗诊断成像剂，用于缺血性卒中的个性化治疗。

项目成果

Redox double-switch cancer theranostics through Pt(IV) functionalised manganese dioxide nanostructures.

• DOI: 10.1039/d3nr00076a
• 发表时间: 2023-06-30
• 期刊: NANOSCALE
• 影响因子: 6.7
• 作者: Brito, Beatriz;Ruggiero, Maria Rosaria;Price, Thomas W.;da Costa Silva, Milene;Genicio, Nuria;Wilson, Annah J.;Tyurina, Olga;Rosecker, Veronika;Eykyn, Thomas R.;Banobre-Lopez, Manuel;Stasiuk, Graeme J.;Gallo, Juan
• 通讯作者: Gallo, Juan

A Single-Pot Template Reaction Towards a Manganese-Based T 1 Contrast Agent

锰基 T 1 造影剂的单锅模板反应

• DOI: 10.1002/ange.202100885
• 发表时间: 2021
• 期刊: Angewandte Chemie
• 作者: Anbu S

Smart magnetic resonance imaging-based theranostics for cancer.

• DOI: 10.7150/thno.57004
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Brito B;Price TW;Gallo J;Bañobre-López M;Stasiuk GJ
• 通讯作者: Stasiuk GJ

Organometallic Chemistry - Volume 43

有机金属化学 - 第 43 卷

• DOI: 10.1039/9781788017077-00083
• 发表时间: 2020
• 作者: Brito B

Scandium calix[n]arenes (n = 4, 6, 8): structural, cytotoxicity and ring opening polymerization studies.

• DOI: 10.1039/d1dt01330k
• 发表时间: 2021-06
• 期刊: Dalton transactions
• 影响因子: 4
• 作者: A. F. Alshamrani;Orlando Santoro;T. Prior;Mohammed A. Alamri;G. Stasiuk;M. Elsegood;C. Redshaw