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

血脑屏障（BBB）对向大脑输送治疗药物提出了重大挑战，特别是对胶质母细胞瘤等脑肿瘤的治疗。本研究方案采用相变纳米液滴（PCN）增强血脑屏障的通透性，促进靶向药物向大脑的传递。提出的机制包括使用脂质壳pcn与嵌入疗法，其作为非活性颗粒携带在血液中。使用微波激活PCN，即转化为~1-3微米的气芯微泡，并使用超声波振荡脑内内皮细胞附近的微泡以打开血脑屏障。在变成微泡后，这些药物为超声和微波成像提供了出色的对比度，从而实现了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以及它们激活纳米液滴和促进血脑屏障的能力之上。这项研究计划的主要目的是开发一个初始原型，可以解决改进脑肿瘤和神经系统疾病治疗策略的关键需求。具体目标包括：通过将超声换换器和微波发射器结合在一个高速电子装置中开发原型；使用该原型激活不同类型的PCN；生成PCN激活的关键数据，以获得更多的资金。本研究的潜在应用是广泛的，包括各种神经系统疾病，特别关注脑肿瘤。纳米微滴辅助血脑屏障打开可以增强化疗药物、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。这些益处可以扩展到脑肿瘤之外，使其他神经系统疾病，如阿尔茨海默病、帕金森病和多发性硬化症等得到靶向治疗。此外，超声波和微波的结合使精准医疗成为可能，在精准医疗中，药物可以根据肿瘤的位置和特征被特异性地激活并输送给个体患者。这项研究计划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好处，因为与微泡相比，纳米级载体系统的大小和在血液循环中的寿命更长，增加了靶向疾病的特异性。此外，纳米微滴辅助血脑屏障打开可以与多种治疗方式联合使用，包括化疗、免疫治疗和基因治疗，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，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整为暂时打开血脑屏障，避免了侵入性外科手术的需要，降低了相关风险。通过超声波和微波实现pcn的按需激活，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，减少全身毒性。

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.