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

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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.