title: Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells.
abstract: The fiber-modified adenoviral vector Delta-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.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Dembinski
authors.forename: E L
authors.initials: EL
authors.lastname: Spaeth
authors.forename: J
authors.initials: J
authors.lastname: Fueyo
authors.forename: C
authors.initials: C
authors.lastname: Gomez-Manzano
authors.forename: M
authors.initials: M
authors.lastname: Studeny
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.forename: F C
authors.initials: FC
authors.lastname: Marini
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy / Q000821:virology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000821:virology*; D051379:Mice; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D015996:Survival Rate; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays