Monitoring Prodrug Delivery in Suicide Gene Therapy Using CEST MRI

描述（由申请人提供）：为了加速药物和基因递送纳米技术的发展，非常需要构建具有成像功能的纳米颗粒，以便可以通过医学成像方式监测和量化递送和释放的过程。尽管已经有成功的临床前研究表明这种监测的可能性，但对监测纳米颗粒介导的药物递送和释放的临床兼容成像方法的需求与当前的纳米颗粒标记策略（通常需要使用金属或放射性造影剂）之间显然存在差距。为了解决这一差距，生物有机分子最近被开发为“非标记”（即非放射性、非顺磁性或超顺磁性）示踪剂，可以通过化学交换饱和转移 (CEST) MRI 技术进行检测。我们研究的长期目标是利用生物有机药物或药物类似物作为 CEST MR 成像造影剂来标记纳米颗粒，并随后将这项新技术转化为临床应用。作为这一原则的初步论证， 该申请旨在开发一种无需额外成像探针的敏感 CEST MRI 可追踪脂质体系统，用于监测 5-FC 的肿瘤靶向递送，从而预测胞嘧啶脱氨酶 (CD)/5-FC 基因治疗的治疗效果。中心假设是5-FC携带的CEST信号可直接用于检测5-FC封装脂质体，从而能够利用CEST MRI对载药纳米颗粒进行监测和潜在定量。在强有力的初步数据的指导下，这一假设将通过三个具体目标进行检验：1）开发一种敏感的 CEST MRI 可追踪脂质体封装 5-FC 的前药； 2) 评估脂质体介导的前药递送的抗肿瘤作用； 3) 使用 CEST MRI 监测脂质体介导的前药递送。在第一个目标下，从已经证明具有足够CEST可检测性的脂质体配方开始，我们将优化脂质体配方以获得具有改进的CEST敏感性以及有利的药物递送特性的系统。在第二个和第三个目标下，我们将在实验动物上应用自追踪脂质体系统，评估抗肿瘤效果，并通过CEST MRI量化增强的药物输送。这些目标预计将产生一种可转化的纳米技术，以在 CD 自杀基因治疗中获得肿瘤靶向前药递送，并且可以通过非侵入性 CEST MRI 进行监测。这项研究的创新在于一种“非标记”方法，根据纳米粒子携带的药物来标记纳米粒子。拟议的研究意义重大，因为它有望将纳米颗粒介导的药物输送的 MR 成像标记策略的范式从金属制剂转变为生物有机药物类似物。最终，这种新型多功能纳米颗粒系统有潜力促进用于基因和药物输送的图像引导纳米颗粒系统的开发，无论是作为现有疗法的“效果增强剂”还是作为新疗法的引发剂

DESCRIPTION (provided by applicant): To accelerate the development of nanotechnologies for drug and gene delivery, it is highly desired to construct nanoparticles with imaging capabilities so that the process of delivery and release can be monitored and quantified with a medical imaging modality. Although there have been successful preclinical studies that showed the possibility of such monitoring, there is clearly a gap between the demand for clinically-compatible imaging methods to monitor the nanoparticle-mediated drug delivery and release and the current nanoparticle tagging strategies, which often require the use of metallic or radioactive contrast agents. To address this gap, bioorganic molecules have recently been developed as "non-labeled" (i.e., not radioactive, and not paramagnetic- or super-paramagnetic-) tracers that can be detected through Chemical Exchange Saturation Transfer (CEST) MRI technology. The long-term goal of our research is to exploit bioorganic drugs or drug analogues as CEST MR imaging contrast agents for tagging of nanoparticles, and subsequently translating this new technology to clinical applications. As an initial demonstration of such a principle, this application aims to develop, without the need for additional imaging probes, a sensitive CEST MRI-trackable liposome system to monitor tumor-targeted delivery of 5-FC, and consequently, to predict the therapeutic effect of cytosine deaminase (CD)/5-FC gene therapy. The central hypothesis is that the CEST signal carried by 5-FC can be directly used to detect 5-FC encapsulating liposomes, thus enabling the monitoring and potential quantification of drug-carrying nanoparticles with CEST MRI. Guided by strong preliminary data, this hypothesis will be tested through three specific aims: 1) To develop a sensitive CEST MRI-trackable liposome encapsulating prodrug for 5-FC; 2) to assess antitumor effects of liposome-mediated prodrug delivery; and 3) to monitor liposome-mediated prodrug delivery using CEST MRI. Under the first aim, starting from an already proven liposomal formulation with sufficient CEST detectability, we will optimize the liposomal formulation to obtain a system with improved CEST sensitivity as well as favorable characteristics for drug delivery. Under the second and third aims, we will apply the self-trackable liposome system on experimental animals, assess the antitumor effects, and quantify the enhanced drug delivery with CEST MRI. These aims are expected to result in a translatable nanotechnology to obtain tumor-targeted prodrug delivery in CD suicide gene therapy that can be monitored by non-invasive CEST MRI. The innovation of this proposed research lies in a "non-labeled" approach to tag nanoparticles based on the drugs they carry. The proposed research is significant, because it is expected to shift the paradigm of the tagging strategy for MR imaging of nanoparticle-mediated drug delivery from metallic agents to bioorganic drug analogues. Ultimately, such a new multifunctional nanoparticle system has the potential to boost the development of an image-guided nanoparticle system for gene and drug delivery, either as an 'effect enhancer' for existing therapies or as an initiator of new therapies