Dual labelled phase change nanodroplets for ultrasound guided drug therapies

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Aim of the PhD Project:To develop multimodal smart imaging probes that will enable emerging imaging and image-guided interventions for cancer treatment.Objectives: To synthesise dual label MR and Near IR Fluorescence (NIRF) - nanodroplets, (iNDs) that undergo phase change when ultrasound is used (core changes from liquid to gas)To characterise iNDs for their MR and NIRF contrast enhancement, ultrasound imaging and focused ultrasound induced cavitation after the phase change.To investigate iNDs efficacy of improving drug distribution in phantom gels (tumour mimicking tissue) and in cells in culture.To develop a combination therapy of image guided iNDs and drugs as part of the lipid membrane in an in vivo murine tumour model.Project Description / Background:Image guided drug delivery has emerged as a novel tool for several treatments. Nanoparticles that image tumours have been widely used during the last two decades to improve drug delivery and efficacy. One category of these nanoparticles is the sono-responsive nanoparticles in combination with focused ultrasound. Phase change nanodroplets have appeared in research as a new chemical entity with the potential to improve imaging and drug delivery.Currently, commercially available gas-cored microbubbles are used as contrast enhancers for ultrasound imaging and experimentally in the clinic for cavitation induced drug delivery. But these bubbles have very limited blood half-life. Nanodroplets have been suggested to have a superior blood half life and a better penetration in lesions such as tumours due to their small size. They are characterised by chemical versatility and the ability to transform to microbubbles that oscillate and cavitate. Cavitation then promotes the propulsion of nanodroplet's components in cells and tissues. If these components contain therapeutics, then a superior localised drug delivery can be achieved.In our previous work we have developed lipid-based nanoparticles that respond to ultrasound and at the same time can be imaged with both MRI and NIRF imaging. In the current project we aim to prepare perfluorocarbon (PFC)-cored, lipid-shelled phase change nanodrolets (ND). These will be composed of lipids coupled to markers for MR and NIRF and lipids as therapeutics. These imaging NDs (iNDs) will have a small size (100-500 nm diameter) and will have a coat of a biocompatible polymer (e.g. PEG). The coating will allow for acceptable blood circulation times and the labels for their tracking in the tumour. Upon activation with ultrasound iNDs will inflate to ~1-3 micrometer gas-cored bubbles, which then provide excellent ultrasound contrast.Previous research has demonstrated that localised cavitation will enhance nanoparticle extravasation from tumour blood vessels and delivery of co-delivered or co-encapsulated therapeutic agents.These therapeutic agents will be embedded to the lipid shell. The lack of an aqueous core restricts drug delivery either to highly non-polar materials. The lipidic or lipophile-anchored therapeutics embedded into the ND shell will be carried in the blood as part of the inactive particle. Previous studies suggest that labelled lipids delivered in this way using lipid based nanoparticles and ultrasound are retained in tumour tissues for days to weeks. There is evidence they are also taken up into tumour cell membranes. This suggests a delivery/localisation mechanism that might combine well with tumour cell targeted drugs.This project will develop these dually labelled nanodroplets as a new class of imaging agents that respond and are able to provide superior targeted drug delivery to tumours.