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）：介入放射学为癌症治疗剂的图像指导提供了极好的机会，包括基因疗法；但是，交付后，尚不确定该产品在疗效的病变中保留了多大程度的程度，或将产品传递到无人值守的靶标，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，可能会影响停留时间和治疗性在肿瘤中的分布。尽管它可能对较小的病变有利，但直接注射量不太适合较大或多个病变。在血管内递送过程中，引起正常肝血管直接流向肿瘤的血管收缩的药物。血流将既可以输送并洗净治疗。增加流入肿瘤，减少过境和/或增加渗透率的药物可能会改善递送，从而改善治疗功效。新颖的治疗方法包括基因疗法，最常见的载体是腺病毒。基因疗法成功的障碍是传递到靶病变，并且缺乏体内表达监测的方法。记者技术可用于遵循基因表达。使用功能和解剖成像的组合，我们已经证明了肿瘤中的报告基因表达可以在体内使用血凝集素A--素蛋白抑素受体基因嵌合体（HA-SSTR2）进行定量。 HA结构域允许在体外和体内进行免疫学检测，包括活检，并且受体部分允许使用FDA认可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，并且可以证实数据。较大的动物，例如具有VX-2鳞状细胞癌的兔子，允许经皮注射和基于微创导管的递送所需的操纵。在这个临床前模型中，我们假设a）直接肿瘤注射将导致更多但更异质的基因表达；而b）基于导管的递送将在肿瘤中产生更均匀的表达，即通过操纵脉管系统可以增强c）。具体目的：特定的目标1-4将通过基于导管的递送在血管收缩的存在下直接流向肿瘤。 1。评估以下假设：抑制血管流量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。评估渗透率增加可以增加基因表达的假设。 4。评估以下假设：结合血管舒张，渗透性和毛细管阻断剂会增加基因表达。 5。评估肿瘤内递送会导致局部递送量增加（基因表达/肿瘤）的假设，但是基于基于动脉的肿瘤会导致肿瘤的递送更均匀（基因表达）。该临床前/翻译建议旨在定义临床上相关的，微创的方法，用于提供可以通过非侵入性成像监测的治疗方法。所采用的方法可以转化为治疗和监测各种疾病的临床用途，尤其是癌症。该提案旨在寻找使用最小侵入性技术来治疗癌症等疾病以及各种其他疾病的疾病的方法来改善本地交付的治疗疗法的方法。

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