Abstract
Glioblastoma is one of the most aggressive types of brain tumor. Epidermal growth factor receptors (EGFRs) are overexpressed in glioma, and EGFR amplifications and mutations lead to rapid proliferation and invasion. EGFR-targeted therapy might be an effective treatment for glioma. Gefitinib (Ge) is an EGFR tyrosine kinase inhibitor (TKI), and Golgi phosphoprotein 3 (GOLPH3) expression is associated with worse glioma prognosis. Downregulation of GOLPH3 could promote EGFR degradation. Here, an angiopep-2 (A2)-modified cationic lipid-poly (lactic-co-glycolic acid) (PLGA) nanoparticle (A2-N) was developed that can release Ge and GOLPH3 siRNA (siGOLPH3) upon entering glioma cells and therefore acts as a combinatorial anti-tumor therapy. The in vitro and in vivo studies proved that A2-N/Ge/siGOLPH3 successfully crossed the blood-brain barrier (BBB) and targeted glioma. Released siGOLPH3 effectively silenced GOLPH3 mRNA expression and further promoted EGFR and p-EGFR degradation. Released Ge also markedly inhibited EGFR signaling. This combined EGFR-targeted action achieved remarkable anti-glioma effects and could be a safe and effective treatment for glioma.
Key messages
-
Angiopep-2-modified cationic lipid polymer can penetrate the BBB.
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Gefitinib can inhibit EGFR signaling and block the autophosphorylation of critical tyrosine residues on EGFR.
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GOLPH3 siRNA can be transfected into glioma and downregulate GLOPH3 expression.
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A2-N/Ge/siGOLPH3 can inhibit glioma growth.
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Change history
03 January 2020
The correct affiliation no 2 is presented in this paper.
Abbreviations
- A2:
-
angiopep2
- ATP:
-
adenosine triphosphate
- BBB:
-
blood-brain barrier
- CLs:
-
cationic liposomes
- CLSM:
-
confocal laser scan microscopy
- DAPI:
-
4′, 6-diamidino-2-phenylindole dihydrochloride
- DMSO:
-
dimethyl sulfoxide
- DMEM:
-
Dulbecco’s Modified Eagle’s Medium
- DOTAP:
-
1, 2-Dioleoyl-3-trimethylammonium-propane
- DSPE-PEG-MAL:
-
2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethyleneglycol)]
- EB:
-
Ethidium Bromide
- EdU:
-
5-Ethynyl-2'-deoxyuridine
- EGFR:
-
epidermal growth factor receptor
- EGFRvIII:
-
epidermal growth factor receptor variant typeIII
- EPR:
-
enhanced permeability and retention
- FBS:
-
fetal bovine serum
- GBM:
-
glioblastoma multiforme
- Ge:
-
gefitinib
- GOLPH3:
-
golgi phosphoprotein 3
- H&E:
-
hematoxylin-eosin
- i.v.:
-
intravenous injection
- MAbs:
-
monoclonal antibodies
- LRP-1:
-
low-density lipoprotein receptor-related protein-1
- N:
-
nanoparticle
- NCsiRNA:
-
nonsense siRNA
- n.s.:
-
nonesense
- OD:
-
optical density
- PBS:
-
phosphate buffer saline
- PLGA:
-
poly (D, L-lactic-co-glycolic acid)
- qRT-PCR:
-
quantitative real-time polymerase chain reaction
- RMT:
-
receptor mediated transcytosis
- RNAi:
-
RNA interference
- siGOLPH3:
-
GOLPH3 siRNA
- siRNA:
-
small interfering RNA
- TCGA:
-
The Cancer Genome Atlas
- TEM:
-
transmission electron microscopy
- TKIs:
-
tyrosine kinase inhibitors
- WB:
-
western blot
- Wls:
-
wntless
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Funding
This work was financially supported by National Natural Science Foundation of China (Grant No. 81772665), Jiangsu Province, Key Research & Development Plan of Jiangsu Province (No. BE2016646), Jiangsu provincial Commission of Health and Family Planning (Grant No. Q201608), Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX18_2197), and Six Talents Peak Foundation of Jiangsu Province (No. 2018-WSW-071).
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This study was performed according to the guidelines for the Care and Use of Laboratory Animals and the animal experimental protocols were approved by Xuzhou Medical University of China Animal Care and Use Committee.
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Chengkun Ye, Bomin Pan, Haoyue Xu. These authors contributed to this paper equally.
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Ye, C., Pan, B., Xu, H. et al. Co-delivery of GOLPH3 siRNA and gefitinib by cationic lipid-PLGA nanoparticles improves EGFR-targeted therapy for glioma. J Mol Med 97, 1575–1588 (2019). https://doi.org/10.1007/s00109-019-01843-4
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DOI: https://doi.org/10.1007/s00109-019-01843-4