Image-Guided Delivery and Image-Guided Evaluation of Target and Non-Target Tissue

目标和非目标组织的图像引导递送和图像引导评估

• 批准号: 7275071
• 负责人: VIKAS KUNDRA
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275071
• 关键词: Adenovirus Vector; Adenoviruses; Affect; Anatomy; Animal Model; Animals; Biopsy; Blood Vessels; Blood capillaries; Blood flow; CMV promoter; Capillary Permeability; Catheters; Chimera organism; Clinical; Coupled; Data; Detection; Diffuse; Disease; Distal; Effectiveness; Evaluation; Fluoroscopy; Gene Expression; Hemagglutinin; Human; Image; Immunologics; In Vitro; Injection of therapeutic agent; Internal Ribosome Entry Site; Interventional radiology; Invasive; Lesion; Light; Link; Liver; Malignant Neoplasms; Methods; Monitor; Needles; Neoplasms; Oryctolagus cuniculus; Penetration; Permeability; Pre-Clinical Model; Procedures; Radiopharmaceuticals; Receptor Gene; Reporter; Retroviridae; SSTR2 gene; Somatostatin Receptor; Spasm; Squamous cell carcinoma; Subfamily lentivirinae; Techniques; Technology; Therapeutic; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; United States Food and Drug Administration; Vascular Permeabilities; Vasoconstrictor Agents; Vasodilator Agents; base; capillary; clinically relevant; feeding; gene therapy; improved; in vivo; light scattering; non-invasive monitor; novel therapeutics; pre-clinical; promoter; receptor; residence; success; therapeutic gene; time use; tumor; vasoconstriction; vector

DESCRIPTION (provided by applicant): Interventional radiology offers excellent opportunities for image guided delivery of cancer therapeutics, including gene therapy; however, after delivery, it is uncertain to what degree the product is retained in the lesion for efficacy or to what degree the product is delivered to unattended targets, which may result in toxicity. The method of image guided delivery, such as direct tumor injection or intravascular injection, can affect residence time and the distribution of the therapeutic in the tumor. Although it may be advantageous for smaller lesions, direct injection is less suitable for larger or multiple lesions. During intravascular delivery, agents causing vasoconstriction of normal liver vasculature direct flow to the tumor. Blood flow will both deliver and wash out the therapeutic. Agents that increase flow to and within the tumor, decrease transit, and/or increase permeability may improve delivery and therefore therapeutic efficacy. Novel therapeutic approaches include gene therapy, for which the most common vector is adenovirus. A barrier to the success of gene therapy has been delivery to the target lesion and a lack of methods for in vivo monitoring of expression. Reporter technology can be used to follow gene expression. Using a combination of functional and anatomic imaging, we have demonstrated that reporter gene expression in tumors can be quantified in vivo, using a hemagglutinin A-somatostatin receptor gene chimera (HA-SSTR2). The HA domain allows for immunologic detection in vitro and ex vivo, including at biopsy, and the receptor portion allows for imaging in vivo using an FDA approved radiopharmaceutical. Thus, expression can be quantified in the tumor and non- target tissues in vivo and data can be confirmed ex vivo. Larger animals, such as rabbits harboring VX-2 squamous cell carcinomas, allow manipulations needed for both percutaneous injection and minimally invasive catheter-based delivery. In this preclinical model, we hypothesize that a) direct tumor injection will result in a greater amount of, but more heterogeneous gene expression; whereas, b) catheter based delivery will result in more uniform expression in the tumor that c) can be enhanced by manipulating the vasculature. Specific aims: Specific aims 1-4 will be performed by catheter based delivery in the presence of vasoconstrictors to direct flow to the tumor. 1. Evaluate the hypothesis that agents that agents that inhibit vascular flow can enhance gene expression. 2. Evaluate the hypothesis that vasodilatory agents can increase gene expression. 3. Evaluate the hypothesis that increased permeability agents can increase gene expression. 4. Evaluate the hypothesis that combining vasodilatory, permeability, and capillary blocking agents increases gene expression. 5. Evaluate the hypothesis that intratumoral delivery results in greater amount of local delivery (gene expression/tumor), but infra-arterial based delivery results in more uniform delivery (gene expression throughout tumor) to the tumor. This preclinical/translational proposal seeks to define clinically relevant, minimally invasive methods for delivering therapy that can be monitored by non-invasive imaging. The methods employed can be translated into clinical use for treating and monitoring a variety of diseases, particularly, cancer. The proposal seeks to find methods to improve delivery of therapeutics delivered locally using minimally invasive techniques for treating diseases such as cancer as well as a variety of other illnesses.

描述(申请人提供)：介入放射学为图像引导的癌症治疗方法，包括基因治疗提供了极好的机会；然而，在交付后，尚不确定产品在多大程度上保留在病变内以发挥疗效，或在多大程度上将产品交付给可能导致毒性的无人看管的靶标。肿瘤直接注射或血管内注射等影像引导给药方法会影响肿瘤的滞留时间和药物在肿瘤中的分布。虽然直接注射对于较小的病变可能是有利的，但对于较大或多个病变则不太适合。在血管内给药期间，引起正常肝血管收缩的药物直接流向肿瘤。血液流动既会传递治疗效果，也会冲走治疗效果。增加流向肿瘤和肿瘤内的流量、减少转运和/或增加渗透性的药物可能会改善给药效果，从而提高治疗效果。新的治疗方法包括基因治疗，其中最常见的载体是腺病毒。基因治疗成功的一个障碍是将基因输送到靶病变，以及缺乏体内监测表达的方法。报告技术可以用来跟踪基因表达。利用功能成像和解剖成像相结合的方法，我们已经证明了利用血凝素A-生长抑素受体基因嵌合体(HA-SSTR2)可以在体内定量报告基因在肿瘤中的表达。HA结构域允许在体外和体外进行免疫检测，包括在活检时，而受体部分允许使用FDA批准的放射性药物进行体内成像。因此，可以量化在体内肿瘤组织和非靶组织中的表达，并可以在体外证实数据。较大的动物，如患有VX-2鳞状细胞癌的兔子，允许进行经皮注射和微创导管注射所需的操作。在这个临床前模型中，我们假设a)直接注射肿瘤将导致更多的基因表达，但更多的异质性；而，b)基于导管的输送将导致在肿瘤中更均匀的表达，c)可以通过操纵血管系统来增强。特定目标：特定目标1-4将在血管收缩药存在的情况下通过导管递送，以引导血流至肿瘤。1.评估一种假说，即抑制血管流动的药物可以增强基因表达。2.评估血管扩张剂可以增加基因表达的假说。3.评估渗透性增强剂可以增加基因表达的假说。4.评估结合血管扩张剂、通透性和毛细血管阻滞剂可增加基因表达的假说。5.评估这样一种假设，即瘤内传递导致更多的局部传递(基因表达/肿瘤)，而动脉下传递导致更均匀的传递(整个肿瘤中的基因表达)。这项临床前/翻译建议旨在定义临床上相关的、微创的治疗方法，这些方法可以通过非侵入性成像进行监测。所采用的方法可以转化为临床使用，用于治疗和监测各种疾病，特别是癌症。该提案寻求找到方法，利用微创技术改善当地提供的治疗药物，以治疗癌症等疾病和各种其他疾病。