Dual labelled phase change nanodroplets for ultrasound guided drug therapies

博士项目的目的：开发多模式智能成像探头，使新兴的成像和图像引导的干预癌症治疗。目标：合成双标记MR和近红外荧光（NIRF）纳米液滴（iND），当使用超声时，iND会发生相变（核心从液体变为气体）对于用于MR和NIRF对比增强的MRI和NIRF，超声成像和聚焦超声在相变后诱导空化。研究iND改善药物在体模凝胶中分布的功效（肿瘤模拟组织）和培养的细胞中。开发图像引导的iND和药物作为体内小鼠肿瘤模型中脂质膜的一部分的联合治疗。项目描述/背景：图像引导的药物递送已经成为几种治疗的新工具。在过去的二十年中，成像肿瘤的纳米颗粒已被广泛用于改善药物输送和功效。这些纳米颗粒的一个类别是与聚焦超声组合的声响应纳米颗粒。相变纳米液滴作为一种新的化学实体，具有改善成像和药物递送的潜力，目前，商业上可获得的气芯微泡被用作超声成像的对比增强剂，并且在临床上实验性地用于空化诱导的药物递送。但这些气泡的血液半衰期非常有限。纳米液滴由于其小尺寸而被认为具有优越的血液半衰期和在病变如肿瘤中的更好渗透。它们的特点是化学多功能性和转变为振荡和空化的微泡的能力。空化然后促进纳米液滴的组分在细胞和组织中的推进。如果这些成分中含有治疗药物，那么就可以实现上级局部给药。在我们以前的工作中，我们已经开发出了基于脂质的纳米颗粒，它对超声有反应，同时可以用MRI和NIRF成像。在目前的项目中，我们的目标是制备全氟化碳（PFC）核，脂质壳相变纳米颗粒（ND）。这些将由与MR和NIRF标记物偶联的脂质和作为治疗剂的脂质组成。这些成像ND（iND）将具有小尺寸（100 - 500 nm直径）并且将具有生物相容性聚合物（例如PEG）的涂层。涂层将允许可接受的血液循环时间和标签，用于在肿瘤中跟踪它们。在超声激活后，iND将膨胀至约1 - 3微米的气核气泡，然后提供优异的超声对比度。先前的研究表明，局部空化将增强纳米颗粒从肿瘤血管中外渗，并递送共递送或共包封的治疗剂。这些治疗剂将嵌入脂质壳。缺乏水性核限制了药物递送到高度非极性材料。包埋在ND壳中的亲脂或亲脂锚定的治疗剂将作为非活性颗粒的一部分携带在血液中。先前的研究表明，使用基于脂质的纳米颗粒和超声以这种方式递送的标记脂质在肿瘤组织中保留数天至数周。有证据表明它们也被肿瘤细胞膜吸收。这表明了一种可能与肿瘤细胞靶向药物联合收割机很好地结合的递送/定位机制。该项目将开发这些双重标记的纳米液滴作为一类新的成像剂，其响应并能够向肿瘤提供上级靶向药物递送。

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.