TY - JOUR
T1 - Widespread gene transfer to malignant gliomas with In vitro-to-In vivo correlation
AU - Negron, Karina
AU - Khalasawi, Namir
AU - Lu, Billy
AU - Ho, Chi Ying
AU - Lee, Jason
AU - Shenoy, Siddharth
AU - Mao, Hai Quan
AU - Wang, Tza Huei
AU - Hanes, Justin
AU - Suk, Jung Soo
N1 - Funding Information:
The funding was provided by the National Institutes of Health ( R01CA164789 , R01EB020147 , R01CA197111 , R01CA220841 , R01CA204968 , and P30EY001765 ), Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship F31 (K.N.) and W.W. Smith Charitable Trust (J.S.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/6/10
Y1 - 2019/6/10
N2 - Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymer-based DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great importance as the highly invasive glioma cells infiltrated into normal brain tissue are responsible for tumor recurrence. Of note, the transgene expression within the orthotopic tumor tissue occurred preferentially in glioma cells over microglial cells. We also show that three-dimensional (3D) multicellular spheroids established with malignant glioma cells, unlike conventional two-dimensional (2D) cell cultures, serve as an excellent in vitro model reliably predicting gene vector behaviors in vivo. Briefly, DNA-NP possessing greater surface PEG coverage exhibited more uniform and higher-level transgene expression both in the 3D model and in vivo, whereas the trend was opposite in 2D culture. The finding here alerts that gene transfer studies based primarily on 2D cultures should be interpreted with caution and underscores the relevance of 3D models for screening newly engineered gene vectors prior to their in vivo evaluation.
AB - Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymer-based DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great importance as the highly invasive glioma cells infiltrated into normal brain tissue are responsible for tumor recurrence. Of note, the transgene expression within the orthotopic tumor tissue occurred preferentially in glioma cells over microglial cells. We also show that three-dimensional (3D) multicellular spheroids established with malignant glioma cells, unlike conventional two-dimensional (2D) cell cultures, serve as an excellent in vitro model reliably predicting gene vector behaviors in vivo. Briefly, DNA-NP possessing greater surface PEG coverage exhibited more uniform and higher-level transgene expression both in the 3D model and in vivo, whereas the trend was opposite in 2D culture. The finding here alerts that gene transfer studies based primarily on 2D cultures should be interpreted with caution and underscores the relevance of 3D models for screening newly engineered gene vectors prior to their in vivo evaluation.
KW - Convection enhanced delivery
KW - Malignant gliomas
KW - Synthetic gene vectors
KW - Tumor spheroids
KW - Volume of transgene expression
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U2 - 10.1016/j.jconrel.2019.04.010
DO - 10.1016/j.jconrel.2019.04.010
M3 - Article
C2 - 30978431
AN - SCOPUS:85064259399
SN - 0168-3659
VL - 303
SP - 1
EP - 11
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -