ICF: Enhancing Blood-Brain Barrier Opening with Ultrasound and Microwaves for Targeted Drug Delivery

ICF：利用超声波和微波增强血脑屏障开放以实现靶向药物输送

• 批准号: MR/Z503848/1
• 负责人: Sevan Harput
• 金额: $ 16.22万
• 依托单位: London South Bank University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ503848%2F1
• 关键词: ICF; Enhancing; Blood; Brain; Barrier

The blood-brain barrier (BBB) poses a significant challenge for delivering therapeutic agents to the brain, especially for the treatment of brain tumours such as glioblastomas. This research proposal employs phase change nanodroplets (PCN) to enhance BBB permeability and facilitate targeted drug delivery to the brain. The proposed mechanism includes the use of lipid-shelled PCNs with embedded therapeutics, which are carried in the blood as an inactive particle. The PCN are activated, i.e., converted to ~1-3 micrometre gas-cored microbubbles using microwaves, and ultrasound waves are used to oscillate the microbubbles in the proximity of endothelial cells inside the brain to open BBB. After becoming microbubbles, these agents provide excellent contrast for ultrasound and microwave imaging to enable image guided targeted drug delivery. This research builds upon advancements in microwave and ultrasound-mediated techniques and their ability to activate nanodroplets and facilitate BBB.The primary aim of this research proposal is to develop an initial prototype that can addresses the critical need for improved treatment strategies for brain tumours and neurological disorders. The specific objectives include:Development of a prototype by combining ultrasound transducers and microwave transmitters in a single setup with high-speed electronicsActivate different type of PCNs using this prototypeGenerate critical data on PCN activation for more substantial fundingThe potential applications of this research are broad and encompass various neurological disorders, with a particular focus on brain tumours. Nanodroplet-assisted BBB opening can enhance the delivery of chemotherapeutic agents, immunotherapies, targeted therapies, and gene therapies to brain tumours, improving treatment outcomes and patient survival rates. These benefits can extend beyond brain tumours, enabling the targeted treatment of other neurological disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Additionally, the combination of ultrasound and microwave enables precision medicine, where drugs can be specifically activated and delivered to individual patients based on the location of tumour and its characteristics.The research proposal offers several potential benefits. The use of activate-able nanodroplets instead of microbubbles provides important benefits, as using nanoscale carrier systems increases specificity in targeting diseases thanks to their size and longer lifetime in blood circulation in comparison to microbubbles. Additionally, the nanodroplet-assisted BBB opening can be combined with various therapeutic modalities, including chemotherapy, immunotherapy, and gene therapy, to maximize treatment effectiveness through synergistic approaches. Using these approaches brain tumours can be treated while the neighbouring healthy tissues remain unaffected, which could substantially improve the treatment outcomes and the management of the brain cancer.Most importantly, ultrasound waves and microwaves are non-invasive, practical, affordable and safe, as they do not use ionizing radiation. Their frequency and intensity can be tuned to temporarily open the BBB, avoiding the need for invasive surgical procedures and reducing associated risks. The on-demand activation of PCNs achieved by ultrasound and microwaves can allow for precise and targeted delivery of drugs to the brain, minimize off-target effects and reduce systemic toxicity.

血脑屏障（BBB）对向大脑输送治疗药物提出了重大挑战，特别是对于治疗胶质母细胞瘤等脑肿瘤。该研究提案采用相变纳米液滴 (PCN) 来增强 BBB 通透性并促进靶向药物递送至大脑。所提出的机制包括使用带有嵌入式治疗剂的脂质壳 PCN，这些 PCN 作为非活性颗粒携带在血液中。 PCN 被激活，即使用微波转化为约 1-3 微米的气芯微泡，并使用超声波使大脑内内皮细胞附近的微泡振荡以打开 BBB。成为微泡后，这些试剂为超声和微波成像提供出色的对比度，从而实现图像引导的靶向药物输送。这项研究建立在微波和超声介导技术的进步及其激活纳米液滴和促进血脑屏障的能力的基础上。这项研究提案的主要目的是开发一个初始原型，可以满足改进脑肿瘤和神经系统治疗策略的迫切需求失调。具体目标包括：通过将超声换能器和微波发射器与高速电子设备结合在一个装置中来开发原型使用该原型激活不同类型的 PCN 生成有关 PCN 激活的关键数据以获得更多实质性资金这项研究的潜在应用广泛且涵盖各种神经系统疾病，特别关注脑肿瘤。纳米液滴辅助的血脑屏障开放可以增强化疗药物、免疫疗法、靶向疗法和基因疗法对脑肿瘤的递送，改善治疗结果和患者生存率。这些益处不仅限于脑肿瘤，还可以有针对性地治疗其他神经系统疾病，如阿尔茨海默病、帕金森病和多发性硬化症。此外，超声波和微波的结合实现了精准医疗，可以根据肿瘤的位置及其特征专门激活药物并将其输送给个体患者。该研究提案提供了几个潜在的好处。使用可激活的纳米液滴代替微泡具有重要的好处，因为与微泡相比，纳米级载体系统的尺寸较大且在血液循环中的寿命更长，因此使用纳米级载体系统可以提高靶向疾病的特异性。此外，纳米液滴辅助打开血脑屏障可以与各种治疗方式相结合，包括化疗、免疫疗法和基因疗法，通过协同方法最大限度地提高治疗效果。使用这些方法可以治疗脑肿瘤，同时邻近的健康组织不受影响，这可以大大改善脑癌的治疗结果和管理。最重要的是，超声波和微波是非侵入性的、实用的、负担得起的和安全的，因为他们不使用电离辐射。它们的频率和强度可以调整以暂时打开血脑屏障，从而避免侵入性外科手术并降低相关风险。通过超声波和微波实现 PCN 的按需激活，可以将药物精确、有针对性地输送到大脑，最大限度地减少脱靶效应并降低全身毒性。