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）：为了加速用于药物和基因递送的纳米技术的发展，非常希望构建具有成像能力的纳米颗粒，使得递送和释放的过程可以用医学成像模式进行监测和量化。虽然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相容的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，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。为了解决这一差距，生物有机分子最近被开发为“非标记的”（即，非放射性，且非顺磁性或超顺磁性）示踪剂，其可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成像造影剂标记纳米颗粒，并随后将这项新技术转化为临床应用。作为对这一原则的初步论证， 本申请旨在开发一种灵敏的CEST MRI可跟踪脂质体系统，以监测5-FC的肿瘤靶向递送，从而预测胞嘧啶脱氨酶（CD）/5-FC基因疗法的治疗效果，而不需要额外的成像探针。中心假设是5-FC携带的CEST信号可直接用于检测5-FC包封脂质体，从而能够用CEST MRI监测和潜在定量载药纳米颗粒。在强有力的初步数据的指导下，将通过三个特定目的对该假设进行检验：1）开发一种敏感的CEST MRI可跟踪脂质体，包封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可检测性的脂质体制剂开始，我们将优化脂质体制剂以获得具有改善的CEST灵敏度以及有利的药物递送特性的系统。在第二和第三个目标下，我们将在实验动物上应用自跟踪脂质体系统，评估抗肿瘤作用，并使用CEST MRI量化增强的药物递送。这些目标预计将导致一种可翻译的纳米技术，以获得CD自杀基因治疗中的肿瘤靶向前药递送，该治疗可以通过非侵入性CEST MRI进行监测。这项研究的创新之处在于一种“非标记”的方法，根据纳米颗粒携带的药物对其进行标记。拟议的研究是有意义的，因为它有望将纳米颗粒介导的药物递送的MR成像的标记策略的范式从金属试剂转移到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递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”还是作为新疗法的启动剂。

项目成果

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

单分子超分子水凝胶作为无抑制标签的无磁共振成像剂。

• 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