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

描述（由申请人提供）：介入放射学为癌症治疗（包括基因治疗）的图像引导输送提供了极好的机会;然而，输送后，不确定产品在多大程度上保留在病变中以获得疗效，或者产品在多大程度上输送到无人值守的靶点，这可能导致毒性。图像引导递送的方法，例如直接肿瘤注射或血管内注射，可以影响治疗剂在肿瘤中的停留时间和分布。尽管直接注射可能对较小的病变有利，但不太适合较大或多个病变。在血管内递送期间，引起正常肝脉管系统的血管收缩的药剂引导流向肿瘤。血液流动将输送和冲洗治疗剂。增加流向肿瘤和在肿瘤内的流动、减少转运和/或增加渗透性的药剂可以改善递送，从而改善治疗功效。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传递到靶病变和缺乏体内监测表达的方法。报告技术可用于跟踪基因表达。使用功能和解剖成像的组合，我们已经证明，报告基因在肿瘤中的表达可以在体内定量，使用血凝素A-生长抑素受体基因嵌合体（HA-SSTR 2）。HA结构域允许体外和离体免疫检测，包括在活组织检查时，并且受体部分允许使用FDA批准的放射性药物进行体内成像。因此，可以在体内定量肿瘤和非靶组织中的表达，并且可以离体确认数据。较大的动物，如携带VX-2鳞状细胞癌的兔子，允许经皮注射和微创导管输送所需的操作。在该临床前模型中，我们假设a）直接肿瘤注射将导致更大量但更异质的基因表达;而B）基于导管的递送将导致肿瘤中更均匀的表达，c）可以通过操纵脉管系统来增强。具体目标：具体目标1-4将在存在血管收缩剂的情况下通过基于导管的输送进行，以将血流引导至肿瘤。1.评估抑制血管血流的药物可以增强基因表达的假设。2.评估血管扩张剂可以增加基因表达的假设。3.评价渗透性增加剂可增加基因表达的假设。4.评估联合使用血管扩张剂、渗透剂和毛细血管阻断剂增加基因表达的假设。5.评价肿瘤内递送导致更大量的局部递送（基因表达/肿瘤），但基于动脉内的递送导致更均匀的递送（整个肿瘤的基因表达）至肿瘤的假设。该临床前/转化提案旨在定义临床相关的微创方法，用于提供可通过非侵入性成像监测的治疗。所采用的方法可以转化为临床用途，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来改善使用微创技术局部递送的治疗剂的递送，以治疗诸如癌症以及各种其他疾病的疾病。

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.