title: 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.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Thaci
authors.forename: A U
authors.initials: AU
authors.lastname: Ahmed
authors.forename: I V
authors.initials: IV
authors.lastname: Ulasov
authors.forename: A L
authors.initials: AL
authors.lastname: Tobias
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: K S
authors.initials: KS
authors.lastname: Aboody
authors.forename: M S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D001932:Brain Neoplasms / Q000628:therapy*; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004195:Disease Models, Animal; D005910:Glioma / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells / Q000637:transplantation*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D030781:Organisms, Genetically Modified; D011994:Recombinant Proteins / Q000096:biosynthesis; D016205:Sigmodontinae; D019562:Viral Load; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D049409:Luciferases, Firefly