Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells

• Published in: Cancer gene therapy Vol. 17; no. 4; pp. 289 - 297
• Main Authors: Dembinski, J L, Spaeth, E L, Fueyo, J, Gomez-Manzano, C, Studeny, M, Andreeff, M, Marini, F C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2010; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Animals; Biomedical and Life Sciences; Biomedicine; Breast; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Breast Neoplasms - virology; Care and treatment; Cell Line, Tumor; Female; Gene Expression; Gene Therapy; Genetic aspects; Genetic Vectors - therapeutic use; Health aspects; Humans; Immunoenzyme Techniques; Melanoma, Experimental - genetics; Melanoma, Experimental - therapy; Melanoma, Experimental - virology; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - virology; Mice; Oncolytic Virotherapy; original-article; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Ovarian Neoplasms - virology; Ovaries; Physiological aspects; Solid tumors; Stem cell transplantation; Stem cells; Stroma; Survival Rate; Toxicity; Tumors; Virus Replication; Xenograft Model Antitumor Assays; gene delivery; fiber-modified adenovirus; MSC; ovarian cancer
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2009.67

The fiber-modified adenoviral vector Δ-24-RGD (D24RGD) offers vast therapeutic potential. Direct injection of D24RGD has been used to successfully target ovarian tumors in mice. However, systemic toxicity, especially in the liver, profoundly limits the efficacy of direct viral vector delivery. Mesenchymal stem cells (MSC) have the ability to function as a vector for targeted gene therapy because of their preferential engraftment into solid tumors and participation in tumor stroma formation. We show that MSC-guided delivery of D24RGD is specific and efficient and reduces the overall systemic toxicity in mice to negligible levels compared with D24RGD alone. In our model, we found efficient targeted delivery of MSC-D24RGD to both breast and ovarian cell lines. Furthermore, immunohistochemical staining for adenoviral hexon protein confirmed negligible levels of systemic toxicity in mice that were administered MSC-D24RGD compared with those that were administered D24RGD. These data suggest that delivery of D24RGD through MSC not only increases the targeted delivery efficiency, but also reduces the systemic exposure of the virus, thereby reducing overall systemic toxicity to the host and ultimately enhancing its value as an anti-tumor therapeutic candidate.