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，迫切需要构建具有成像能力的纳米颗粒，以便可以用医学成像方式监测和量化递送和释放过程。尽管已经有成功的临床前研究表明了这种监测的可能性，但对临床兼容的成像方法来监测纳米颗粒介导的药物传递和释放的需求与目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，这

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