TY - JOUR
T1 - siRNA Nanoparticle Suppresses Drug-Resistant Gene and Prolongs Survival in an Orthotopic Glioblastoma Xenograft Mouse Model
AU - Wang, Kui
AU - Kievit, Forrest M.
AU - Chiarelli, Peter A.
AU - Stephen, Zachary R.
AU - Lin, Guanyou
AU - Silber, John R.
AU - Ellenbogen, Richard G.
AU - Zhang, Miqin
N1 - Funding Information:
This work was partially supported by National Institutes of Health Grants (NIH/NCI R01CA161953 and NIH/NIBIB R01EB026890). K.W. acknowledges the support of the College of Engineering Dean's Fellowship (the Scott Fellowship and the Marsh Fellowship) from the University of Washington. F.M.K. acknowledges support from an American Brain Tumor Association fellowship in honor of Susan Kramer. P.A.C. and Z.R.S. acknowledge the support through NCI training grant T32CA138312. The authors would like to acknowledge the use of resources at the Department of Pathology's cell analysis facility at the University of Washington. They acknowledge the Department of Pathology at the University of Washington on conducting H&E and Perls’ Prussian blue staining. The authors acknowledge the use of the equipment on NP characterization in Nanoengineering & Science Institute and Molecular Engineering & Science Institute supported by NSF (grant NNCI‐1542101), and Department of Chemistry at the University of Washington. The authors also thank Shelby J. Hatzinger for laboratory assistance.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
PY - 2021/2/3
Y1 - 2021/2/3
N2 - Temozolomide (TMZ) is the standard-of-care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug-resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here, the development of an iron oxide nanoparticle (NP) system for targeted delivery of small interfering RNAs to suppress the TMZ-resistance gene (MGMT) is reported. The NPs are able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ result in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.
AB - Temozolomide (TMZ) is the standard-of-care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug-resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here, the development of an iron oxide nanoparticle (NP) system for targeted delivery of small interfering RNAs to suppress the TMZ-resistance gene (MGMT) is reported. The NPs are able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ result in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.
KW - O -methylguanine-DNA methyltransferase
KW - brain tumors
KW - drug-resistances
KW - glioblastoma stem cells
KW - nanoparticles
KW - small interfering RNA deliveries
KW - treatment resistances
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U2 - 10.1002/adfm.202007166
DO - 10.1002/adfm.202007166
M3 - Article
C2 - 33708035
AN - SCOPUS:85096740775
SN - 1616-301X
VL - 31
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 6
M1 - 2007166
ER -