Monitoring Prodrug Delivery in Suicide Gene Therapy Using CEST MRI

使用 CEST MRI 监测自杀基因治疗中的前药递送

• 批准号: 8510646
• 负责人: Guanshu Liu
• 金额: $ 19.05万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510646
• 关键词: Address; Amines; Animals; Blood Vessels; Cells; Characteristics; Chemical Dynamics; Chemicals; Clinical Trials; Colon; Colonic Neoplasms; Colorectal Cancer; Contrast Media; Cytosine deaminase; Data; Delayed-Action Preparations; Development; Dose; Drug Carriers; Drug Controls; Drug Delivery Systems; Drug Formulations; Encapsulated; Endocytosis; Enhancers; Ensure; Evolution; Flucytosine; Fluorescence Microscopy; Future; Gene Delivery; Gene-Directed Enzyme Prodrug Therapy; Goals; Image; Liposomes; Magnetic Resonance Imaging; Measures; Mediating; Medical Imaging; Methods; Mission; Monitor; Mus; Nanotechnology; Oncogenes; Pharmaceutical Preparations; Process; Prodrugs; Protons; Public Health; Radioactive; Reporting; Research; Rhodamine; Side; Signal Transduction; Suicide Gene Therapy; System; TNF gene; Techniques; Technology; Testing; Therapeutic Effect; Time; Tracer; Translating; Treatment Efficacy; Water; analog; base; chemical group; clinical application; fluorescence imaging; gene delivery system; gene therapy; imaging modality; imaging probe; improved; innovation; insight; nanoparticle; nanosized; neoplastic cell; new technology; non-invasive monitor; novel; preclinical study; subcutaneous; targeted delivery; tumor; tumor growth; tumor-specific gene delivery

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

描述（由申请人提供）：为了加速药物和基因输送的纳米技术的发展，高度希望使用具有成像功能的纳米颗粒，以便可以通过医学成像方式对传递和释放的过程进行监控和量化。尽管已经有成功的临床前研究表明了这种监测的可能性，但对临床兼容成像方法的需求显然存在差距，以监测纳米颗粒介导的药物输送和释放以及当前的纳米颗粒标记策略，这通常需要使用金属或放射性损伤药物。为了解决这一差距，最近已经开发了可以通过化学交换饱和转移（CEST）MRI技术检测到的生物有机分子（即未标记的”（即，不是放射性的，也不是顺磁性或超顺磁性）示踪剂。我们研究的长期目标是将生物有机药物或类似物用作标记纳米颗粒标记的MR成像对比剂，然后将这项新技术转化为临床应用。作为这样一个原则的初始演示， 应用旨在开发不需要其他成像探针，一种灵敏的CEST MRI TRACK-TRACK脂质体系统，以监测5-FC肿瘤的递送的递送，因此可以预测胞质脱氨酶（CD）/5-FC基因治疗的治疗作用。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，从而实现了用CEST MRI的监测和潜在对携带药物携带的纳米颗粒的定量。在强大的初步数据的指导下，该假设将通过三个特定目的进行检验：1）开发一种敏感的可疑MRI-Trackable脂质体，以封装5-FC的前药； 2）评估脂质体介导的前药的抗肿瘤作用； 3）使用CEST MRI监测脂质体介导的前药。在第一个目标下，从已经经过验证的脂质体配方开始，具有足够的CEST可检测性，我们将优化脂质体配方，以获得具有提高CEST敏感性的系统，并具有良好的药物输送特性。在第二和第三目的下，我们将在实验动物上应用可自行table的脂质体系统，评估抗肿瘤作用，并用CEST MRI量化增强的药物递送。预计这些目标将导致可翻译的纳米技术在CD自杀基因治疗中获得以肿瘤为目标的前药递送，该药物可以通过非侵入性CEST MRI来监测。这项提出的研究的创新在于一种基于其携带的药物标记纳米颗粒的“未标记”方法。拟议的研究很重要，因为预计将改变纳米颗粒介导的药物从金属剂到生物有机药物类似物的标记策略的范式。最终，这种新的多功能纳米颗粒系统有可能提高图像引导的基因和药物输送的纳米颗粒系统的开发，这是现有疗法的“效应增强剂”，或作为新疗法的启动

项目成果

One-Component Supramolecular Filament Hydrogels as Theranostic Label-Free Magnetic Resonance Imaging Agents.

• DOI: 10.1021/acsnano.6b07196
• 发表时间: 2017-01-24
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Lock LL;Li Y;Mao X;Chen H;Staedtke V;Bai R;Ma W;Lin R;Li Y;Liu G;Cui H
• 通讯作者: Cui H

Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.

• DOI: 10.7150/thno.15492
• 发表时间: 2016
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Liu H;Jablonska A;Li Y;Cao S;Liu D;Chen H;Van Zijl PC;Bulte JW;Janowski M;Walczak P;Liu G
• 通讯作者: Liu G