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. ? ? ?
| Singh, Sheela P; Ravoori, Murali K; Dixon, Katherine A et al. (2016) Angiotensin II increases gene expression after selective intra-arterial adenovirus delivery in a rabbit model assessed using in vivo SSTR2-based reporter imaging. EJNMMI Res 6:25 |
| Wright, Kenneth C; Ravoori, Murali K; Dixon, Katherine A et al. (2011) Perfusion CT assessment of tissue hemodynamics following hepatic arterial infusion of increasing doses of angiotensin II in a rabbit liver tumor model. Radiology 260:718-26 |
| Singh, Sheela P; Yang, Dan; Ravoori, Murali et al. (2009) In vivo functional and anatomic imaging for assessment of in vivo gene transfer. Radiology 252:763-71 |
