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

血脑屏障（BBB）对向脑递送治疗剂，特别是用于治疗脑肿瘤如胶质母细胞瘤提出了重大挑战。该研究方案采用相变纳米液滴（PCN）来增强BBB渗透性并促进靶向药物递送到大脑。所提出的机制包括使用具有嵌入式治疗剂的脂质壳PCN，其作为非活性颗粒在血液中携带。PCN被激活，即，使用微波将微泡转化为~1-3微米的气芯微泡，并且使用超声波在脑内的内皮细胞附近振荡微泡以打开BBB。在成为微泡后，这些试剂为超声和微波成像提供了优异的对比度，以实现图像引导的靶向药物递送。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BBB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，可以解决改善脑肿瘤和神经系统疾病治疗策略的迫切需求。具体目标包括：通过将超声换能器和微波发射器结合在一个具有高速电子的单一设置中来开发原型使用该原型激活不同类型的PCN生成关于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，包括各种神经系统疾病，特别关注脑肿瘤。纳米液滴辅助的BBB开放可以增强化疗剂、免疫疗法、靶向疗法和基因疗法向脑肿瘤的递送，从而改善治疗结果和患者存活率。这些益处可以扩展到脑肿瘤之外，从而能够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可以实现精准医疗，根据肿瘤的位置及其特征，药物可以被特定地激活并输送到个体患者。该研究提案提供了几个潜在的好处。使用可活化的纳米液滴代替微泡提供了重要的益处，因为与微泡相比，使用纳米级载体系统由于其尺寸和在血液循环中的更长寿命而增加了靶向疾病的特异性。此外，纳米液滴辅助的BBB开放可以与各种治疗方式（包括化疗、免疫治疗和基因治疗）组合，以通过协同方法使治疗效果最大化。使用这些方法可以治疗脑肿瘤，而邻近的健康组织不受影响，这可以大大改善治疗结果和脑癌的管理。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，因为它们不使用电离辐射。它们的频率和强度可以调节，以暂时打开BBB，避免需要侵入性外科手术并降低相关风险。通过超声波和微波实现的按需激活多氯化萘，可以精确和有针对性地将药物输送到大脑，最大限度地减少脱靶效应并降低全身毒性。

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.