Monitoring Prodrug Delivery in Suicide Gene Therapy Using CEST MRI

描述(申请人提供)：为了加速药物和基因输送的纳米技术的发展，人们非常希望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输送和释放的过程。尽管已经有成功的临床前研究表明了这种监测的可能性，但在监测纳米颗粒介导的药物传递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之间显然存在差距，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。为了弥补这一空白，生物有机分子最近被开发为可以通过化学交换饱和转移(CEST)磁共振技术检测的“非标记”示踪剂(即，非放射性，也不是顺磁或超顺磁)。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磁共振成像对比剂来标记纳米颗粒，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证明，这 应用的目的是在不需要额外的成像探针的情况下，开发一种灵敏的CEST MRI可跟踪脂质体系统来监测肿瘤靶向递送5-FC，从而预测胞嘧啶脱氨酶(CD)/5-FC基因治疗的疗效。中心假设是，5-FC携带的CEST信号可以直接用于检测5-FC脂质体，从而使CEST MRI能够监测和潜在地定量携带药物的纳米颗粒。在强大的初步数据的指导下，这一假设将通过三个具体目标进行验证：1)开发一种敏感的CEST MRI可跟踪脂质体包裹5-FC前药；2)评估脂质体介导的前药输送的抗肿瘤效果；以及3)利用CEST MRI监测脂质体介导的前药输送。在第一个目标下，我们将从已经证明具有足够CEST检测能力的脂质体配方入手，优化脂质体配方，以获得具有更高CEST敏感性和良好给药特性的系统。在第二个和第三个目标下，我们将在实验动物身上应用自跟踪脂质体系统，评估其抗肿瘤效果，并使用CEST MRI对增强的药物输送进行量化。这些目标有望导致一种可翻译的纳米技术，以在CD自杀基因治疗中获得肿瘤靶向前药物输送，可以通过非侵入性CEST MRI进行监测。这项拟议研究的创新之处在于一种基于纳米颗粒携带的药物来标记纳米颗粒的“非标记”方法。这项拟议的研究具有重要意义，因为它有望将纳米颗粒介导的药物释放的磁共振成像标记策略的范式从金属试剂转变为生物有机药物类似物。最终，这种新的多功能纳米颗粒系统有可能促进用于基因和药物输送的图像引导纳米颗粒系统的发展，无论是作为现有疗法的效果增强剂还是作为新疗法的发起人

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