Generation of Multi-Modal Imaging Mesenchymal Stem Cells

研究背景再生医学具有改变医学和在未满足需求的领域提供治疗和治愈的潜力。使用间充质干细胞（MSCs）的细胞疗法越来越多地应用于中风、心脏病和癌症辅助治疗等领域的临床试验。然而，在所有新兴技术中，评估其潜在有效性存在许多需要解决的障碍，其中包括靶向组织的局部递送和原位细胞的功能。我的研究计划的重点将是为互补成像技术提供多模式细胞标记剂，这些技术可以一起使用，以提供对功能细胞存活的传递和摄取机制的清晰理解，以便科学受益者(学者，临床医生，制药公司，生物技术公司，监管当局)能够充满信心地加速这些新药进入再生医学的其他领域，并将其转化为人类。一旦移植到患者体内，监测细胞的递送和追踪细胞的活力不仅对评估治疗效果的程度和持续时间，而且对患者的安全都具有特别重要的意义。确定最佳给药途径、细胞摄取的程度和寿命以及清除途径可以确定可能存在风险的器官，同时可能限制每位患者所需的重复注射或手术次数。氧化铁纳米颗粒在通过磁共振成像（MRI）将干细胞定位到特定的疾病区域方面显示出了希望，并且许多这些纳米颗粒先前已被批准用于临床应用。然而，它们目前还没有显示出追踪移植细胞或提供其体内功能信息所需的敏感性的必要特征。然而，其他成像方式，如核医学（SPECT/CT）能够跟踪整个身体的细胞，尽管分辨率较差，并且随着分子生物学的新发展，能够评估体内细胞活力。然而，目前一种成像方式和一种成像探针不能提供完整表征细胞治疗所需的信息。因此，我们提出的新技术将创新的分子生物学方法与纳米化学相结合，为体内成像和互补的临床前成像方式（MRI, SPECT/CT，光声和生物发光成像）生成多模态成像MSC。我们的目标是用报告基因和纳米粒子来标记细胞，将成像平台和成像探针结合起来，利用每一个最有利的成分，同时减少它们的局限性。然后，我们将利用这一点来量化输送，并监测移植细胞在临床相关肿瘤模型中的定位和活力。我们将确定最佳的给药途径和细胞存活的寿命，并应用这些知识来优化我们的治疗性MSCs作为抗癌递送载体的后续应用和给药方案。虽然这一建议是基于干细胞作为癌症的辅助治疗，但使用我们的细胞运输标记技术可以应用于其他干细胞和再生药物。将其与临床可翻译的MR成像终点相结合，以提供对细胞疗法疗效的全面评估，从而加速这些疗法进入主流临床实践。

Context of the ResearchRegenerative Medicine has the potential to transform medicine and provide treatments and cures in areas of unmet need. Cell therapies using mesenchymal stem cells (MSCs) are increasingly applied in clinical trials in areas such as stroke, heart disease and as adjuvant therapies for cancer. However, with all emerging technologies, there are a number of barriers to evaluating their potential effectiveness that need to be addressed, which is localised delivery to target tissue and functionality of the cells once in situ. The focus of my research programme will be to provide multi-modal cell labelling agents for complimentary imaging technologies that can be utilized together to provide a clear understanding of the mechanisms of delivery and uptake with functional cell survival so that scientific beneficiaries (academics, clinicians, pharmaceutical companies, biotechnology companies, regulatory authorities) are able to accelerate these new medicines to other areas of regenerative medicine as well as translation to the human population with full confidence.The monitoring the delivery and tracking the viability of cells once transplanted into patients is of particular importance not only for the assessment of both the degree and duration of therapeutic efficacy but also for patient safety. Identification of the optimal route of administration, the degree and longevity of cell uptake and routes of clearance can identify possible organs of risk while potentially limiting the number of repeat injections or surgeries required per patient. Iron oxide nanoparticle have shown promise in localizing stem cells to defined areas of disease by magnetic resonance imaging, MRI) and a number of these nanoparticles have been previously been approved for clinical use. However, they do not currently display the necessary characteristics for the sensitivity that is required to track transplanted cells or provide information on their functionality in vivo. However, other imaging modalities such as nuclear medicine (SPECT/CT) are capable of tracking cells throughout the body, albeit with poor resolution and with new developments in molecular biology are capable of assessing cell viability in vivo. However, at present one imaging modality and one imaging probe cannot provide the information required for the complete characterization of cell therapeutics. The new technologies we propose therefore combines innovative molecular biology approaches with nanochemistry to generate multi-modal imaging MSC for in vivo imaging with complimentary preclinical imaging modalities (MRI, SPECT/CT, photoacoustic and bioluminescent imaging). We aim to label cells with both reporter genes and nanopartlces, uniting imaging platforms and imaging probes to utilize the most favourable components of each while reducing their limitations. We will then utilize this to quantify delivery and monitor the localisation and viability of transplanted cells to clinically relevant models of tumours. We will identify the optimal routes of administration and the longevity of cell survival and apply this knowledge to optimize the subsequent application and dosing regimens of our therapeutic MSCs as anti-cancer delivery vehicles. Although this proposal is based on stem cells as adjuvant therapies for cancer the use of our labelling technologies for cell trafficking can be applied to other stem cells and regenerative medicines. Merge this with clinically translatable MR imaging endpoints to provide a full assessment of the efficacy of the cell therapy will therefore accelerate these therapies into mainstream clinical practise.