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: 7488804
• 负责人: VIKAS KUNDRA
• 金额: $ 15.4万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488804
• 关键词: Adenoviruses; Affect; Anatomy; Animals; Biopsy; Blood Vessels; Blood flow; Capillary Permeability; Catheters; Chimera organism; Clinical; Data; Detection; Disease; Evaluation; Gene Expression; Hemagglutinin; Image; Immunologics; In Vitro; Injection of therapeutic agent; Interventional radiology; Invasive; Lesion; Liver; Malignant Neoplasms; Methods; Monitor; Oryctolagus cuniculus; Permeability; Pre-Clinical Model; Radiopharmaceuticals; Receptor Gene; Reporter; Somatostatin Receptor; Squamous cell carcinoma; Techniques; Technology; Therapeutic; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; United States Food and Drug Administration; Vasoconstrictor Agents; base; clinically relevant; gene therapy; improved; in vivo; non-invasive monitor; novel therapeutics; pre-clinical; receptor; residence; success; 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（由申请人提供）：介入放射学为图像引导的癌症治疗（包括基因治疗）提供了极好的机会；然而，在递送后，不确定产品在多大程度上保留在病灶中以发挥功效，或者在多大程度上将产品递送到无人看管的目标，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。尽管直接注射对于较小的病变可能是有利的，但对于较大或多发的病变来说，直接注射不太适合。在血管内输送期间，引起正常肝血管系统血管收缩的药物直接流向肿瘤。血流会输送并冲走治疗剂。增加流向肿瘤和肿瘤内的流量、减少转运和/或增加渗透性的药剂可以改善递送并因此改善治疗效果。新的治疗方法包括基因治疗，最常见的载体是腺病毒。基因治疗成功的一个障碍是递送至目标病变并且缺乏体内表达监测方法。报告技术可用于追踪基因表达。通过结合功能和解剖成像，我们证明可以使用血凝素 A-生长抑素受体基因嵌合体 (HA-SSTR2) 在体内定量肿瘤中报告基因的表达。 HA 结构域允许进行体外和离体免疫检测，包括活检，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，例如携带 VX-2 鳞状细胞癌的兔子，可以进行经皮注射和微创导管输送所需的操作。在这个临床前模型中，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；然而，b)基于导管的递送将导致肿瘤中更均匀的表达，而c)可以通过操纵脉管系统来增强。具体目标：具体目标 1-4 将在血管收缩剂存在的情况下通过基于导管的输送来实现，以引导血流流向肿瘤。 1. 评估以下假设：抑制血管流动的药物可以增强基因表达。 2. 评估血管舒张剂可以增加基因表达的假设。 3. 评估增加渗透性的试剂可以增加基因表达的假设。 4. 评估联合使用血管舒张剂、通透性药物和毛细血管阻断剂可增加基因表达的假设。 5.评估这样的假设：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）到肿瘤。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，用于治疗和监测多种疾病，特别是癌症。该提案旨在寻找方法来改善使用微创技术在当地提供的治疗方法，以治疗癌症等疾病以及各种其他疾病。

项目成果

Perfusion CT assessment of tissue hemodynamics following hepatic arterial infusion of increasing doses of angiotensin II in a rabbit liver tumor model.

在兔肝肿瘤模型中肝动脉输注剂量增加的血管紧张素 II 后，灌注 CT 评估组织血流动力学。

• DOI: 10.1148/radiol.11101868
• 发表时间: 2011
• 期刊: Radiology
• 影响因子: 19.7
• 作者: Wright,KennethC;Ravoori,MuraliK;Dixon,KatherineA;Han,Lin;Singh,SheelaP;Liu,Ping;Gupta,Sanjay;Johnson,ValenE;Kan,Zuxing;Kundra,Vikas
• 通讯作者: Kundra,Vikas