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Co-delivery of GOLPH3 siRNA and gefitinib by cationic lipid-PLGA nanoparticles improves EGFR-targeted therapy for glioma

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A Correction to this article was published on 03 January 2020

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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.

  • Gefitinib can inhibit EGFR signaling and block the autophosphorylation of critical tyrosine residues on EGFR.

  • GOLPH3 siRNA can be transfected into glioma and downregulate GLOPH3 expression.

  • 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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Authors and Affiliations

  1. Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Chengkun Ye, Bomin Pan, Haoyue Xu, Zongren Zhao, Jiawei Shen, Rutong Yu & Hongmei Liu

  2. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China

    Chengkun Ye, Bomin Pan, Haoyue Xu, Zongren Zhao, Jiawei Shen, Rutong Yu & Hongmei Liu

  3. Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China

    Jun Lu

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  1. Chengkun Ye
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Correspondence to Hongmei Liu.

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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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The authors declare that they have no competing interests.

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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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