Targeted Radionuclide Therapy Using a Wnt-Targeted Replicating Adenovirus Encoding the Na/I Symporter

Abstract

Purpose: The Na/I symporter (hNIS) promotes concentration of iodine in cells. In cancer gene therapy, this transgene has potential as a reporter gene for molecular imaging of viral biodistribution and as a therapeutic protein promoting 131 I-mediated radiotherapy. Here, we combined the imaging and therapeutic potential of hNIS in an oncolytic adenoviruses targeting colorectal cancer cells. Experimental Design: We generated an adenovirus (AdIP2) encoding hNIS and capable of selective replication in colorectal carcinoma cells. The selectivity of this virus was verified in vitro and in vivo. Its spread in tumors was monitored in vivo using singlephoton emission computed tomography/CT imaging upon 99m TcO 4 -injection and confirmed by immunohistochemistry. Metabolic radiotherapy was done through injection of therapeutic doses of 131 I -. Results:We showed in vitro and in vivo the selectivity of AdIP2 and that hNIS expression is restricted to the target cells. Imaging and immunohistochemical data showed that viral spread is limited and that the point of maximal hNIS expression is reached 48 hours after a single intratumoral injection. Administration of a single therapeutic dose of 131

Systemic Image-Guided Liver Cancer Radiovirotherapy Using Dendrimer-Coated Adenovirus Encoding the Sodium Iodide Symporter as Theranostic Gene

“…In order to overcome the limitation of therapeutic efficacy by the lack of iodide organification, in the present study we aimed at combining NIS-mediated radioiodine therapy with virus-mediated oncolysis. Synergies between oncolytic virotherapy and NIS-mediated radioiodine treatment have been reported previously (25)(26)(27)(28)(29). In a recent study, Haddad et al (30) used an oncolytic vaccinia virus encoding the human NIS gene for local and systemic therapy of pancreatic carcinoma in a murine xenograft model.…”

Mesenchymal Stem Cell–Mediated, Tumor Stroma–Targeted Radioiodine Therapy of Metastatic Colon Cancer Using the Sodium Iodide Symporter as Theranostic Gene

“…A large number of NIS-compatible radioactive tracers are available including 123 I for scintigraphy/SPECT and 124 I-and 18 F-tetrafluoroborate (30) for PET imaging. Finally, NIS transgene expression allows the delivery of a robust therapeutic effect through 131 I or 188 Re application (5,20,(31)(32)(33)(34)(35)(36). We have demonstrated the flexibility of this approach in studies using oncolytic viruses and nonviral nanoparticles equipped with the NIS gene to facilitate noninvasive in vivo vector biodistribution imaging as well as 131 I-based radiotherapy after systemic application (37,38).…”

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“…In vivo, intratumoural injections of miRNA were performed in a model of subcutaneous HT 29 tumour in athymic nude mice. Treatment significantly reduced tumour volume 79 . In another study, a replication-deficient adenovirus expressing p53 and a miRNA targeting the cyclin-dependent kinase inhibitor p 21(Adp53 ⁄ mIR-p21) have been engineered.…”