Pharmacokinetic study of neural stem cell-based cell carrier for oncolytic virotherapy: targeted delivery of the therapeutic payload in an orthotopic brain tumor model.

Abstract

Oncolytic virotherapy is a promising novel therapy for glioblastoma that needs to be optimized before introduced to clinic. The targeting of conditionally replicating adenoviruses (CRAds) can be improved by relying on the tumor-tropic properties of neural stem cells (NSCs). Here, we report the characterization of an FDA approved NSC, HB1.F3-CD, as a cell carrier for CRAd-S-pk7, a glioma-tropic oncolytic adenovirus. We show that NSCs replicate and release infectious CRAd-S-pk7 progeny capable of lysing glioma cell lines. Moreover, ex-vivo-loaded NSCs, injected intracranially in nude mice bearing human glioma xenografts (i) retained their tumor tropism, (ii) continued to replicate CRAd-S-pk7 for more than a week after reaching the tumor site and (iii) successfully handed off CRAd-S-pk7 to glioma cells in vivo. Delivery via carrier cells reduced non-specific adenovirus distribution in the mouse brain. Moreover, we assessed biodistribution of loaded NSCs after intracranial injection in animal models semi-permissive to adenovirus replication, the Syrian hamster and cotton rat. NSCs did not migrate to distant organs and high levels of CRAd-S-pk7 DNA were observed only in the injected hemisphere. In conclusion, this optimized carrier system, with high efficiency of adenovirus delivery and minimal systemic toxicity, poses considerable advantages for anti-glioma oncolytic virotherapy.

• Authors: B Thaci, A U Ahmed, I V Ulasov, A L Tobias, Y Han, K S Aboody, M S Lesniak
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 19 Issue 6 Pg. 431-42 (Jun 2012) ISSN: 1476-5500 [Electronic] England
• PMID: 22555507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adenovirus E1A Proteins
• Recombinant Proteins
• Green Fluorescent Proteins
• Luciferases, Firefly

Topics

• Adenoviridae (genetics, physiology)
• Adenovirus E1A Proteins (biosynthesis, genetics)
• Animals
• Brain (pathology, virology)
• Brain Neoplasms (therapy)
• Cell Line
• Cell Survival
• Cricetinae
• Disease Models, Animal
• Glioma (therapy)
• Green Fluorescent Proteins (biosynthesis)
• Humans
• Luciferases, Firefly (biosynthesis)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neural Stem Cells (transplantation)
• Oncolytic Virotherapy (methods)
• Oncolytic Viruses (genetics, physiology)
• Organisms, Genetically Modified
• Recombinant Proteins (biosynthesis)
• Sigmodontinae
• Viral Load
• Virus Replication