Dual labelled phase change nanodroplets for ultrasound guided drug therapies

博士项目的目标：开发多模态智能成像探针，使新兴的成像和图像引导干预能够用于癌症治疗。目的：合成双标记MR和近红外荧光(NIRF) -纳米液滴（iNDs），当超声使用时发生相变（核心从液体变为气体），表征iNDs在相变后的MR和NIRF对比度增强，超声成像和聚焦超声诱导空化。目的：探讨茚三酮改善药物在模拟肿瘤组织和培养细胞内分布的效果。目的：在小鼠体内肿瘤模型中，建立一种图像引导诱导蛋白与药物作为脂膜部分的联合治疗方法。项目描述/背景：图像引导给药已成为几种治疗的新工具。成像肿瘤的纳米颗粒在过去二十年中被广泛用于改善药物传递和疗效。其中一类纳米粒子是与聚焦超声相结合的声响应纳米粒子。相变纳米液滴作为一种具有改善成像和药物传递潜力的新型化学实体已经出现在研究中。目前，市售的气芯微泡被用作超声成像的对比度增强剂，并在临床实验中用于空化诱导药物输送。但是这些气泡的血液半衰期非常有限。纳米液滴被认为具有更长的血液半衰期，并且由于其体积小，在肿瘤等病变中具有更好的穿透性。它们的特点是化学上的通用性和转化为振荡和空化的微泡的能力。然后，空化会促进纳米液滴成分在细胞和组织中的推进。如果这些成分含有治疗药物，那么可以实现更好的局部给药。在我们之前的工作中，我们开发了基于脂质的纳米颗粒，它对超声波有反应，同时可以用MRI和NIRF成像进行成像。在目前的项目中，我们的目标是制备全氟碳（PFC）核，脂质壳相变纳米微球（ND）。这些将由脂质偶联到MR和NIRF标记物和作为治疗药物的脂质组成。这些成像nd （ind）将具有小尺寸（直径100-500纳米），并将具有生物相容性聚合物（例如PEG）的涂层。这种涂层将允许可接受的血液循环时间和标签在肿瘤中跟踪。超声激活后，iNDs将膨胀至1-3微米的充气气泡，然后提供出色的超声对比度。先前的研究表明，局部空化会增强纳米颗粒从肿瘤血管外渗和共递送或共封装治疗剂的递送。这些治疗剂将被嵌入到脂质外壳中。水芯的缺乏限制了药物递送到高度非极性的材料。嵌入ND壳中的脂质或亲脂性锚定疗法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，通过脂质纳米颗粒和超声波的方式，标记的脂质可以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。这表明一种递送/定位机制可能与肿瘤细胞靶向药物很好地结合。该项目将开发这些双重标记的纳米液滴，作为一种新型显像剂，对肿瘤有反应，并能够提供优越的靶向药物输送。

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.