Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas.
Delta24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Delta24-RGD to human gliomas. To assess cellular events, green fluorescent protein-labeled hMSCs carrying Delta24-RGD (hMSC-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Delta24 selectively localized to glioma xenografts and released Delta24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Delta24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Delta24-treated animals compared with controls (P < 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta24-treated animals (P < 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Delta24 selectively localize to human gliomas and are capable of delivering and releasing Delta24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.
Yong
Raymund L
RL
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Shinojima
Naoki
N
Fueyo
Juan
J
Gumin
Joy
J
Vecil
Giacomo G
GG
Marini
Frank C
FC
Bogler
Oliver
O
Andreeff
Michael
M
Lang
Frederick F
FF
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology / Q000821:virology; D001932:Brain Neoplasms / Q000628:therapy* / Q000821:virology; D005909:Glioblastoma / Q000628:therapy* / Q000821:virology; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000821:virology*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides; D050130:Oncolytic Virotherapy / Q000379:methods*; D014161:Transduction, Genetic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid