Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells.
OBJECTIVE
Among heterogeneous glioblastoma multiforme (GBM) cells, glioblastoma stem cells (GSCs) is a subpopulation having a critical role in tumor initiation and therapy resistance. Thus targeting GSCs would be an essential step to completely eradicate this lethal disease. MicroRNA-1 (miR-1) expression is deregulated in GBM patients and restoration of miR-1 by viral-vector in GBM cells has been demonstrated to inhibit tumor initiation and attenuate cell migration. Here, we show that a transferrin-targeting non-invasive nanoparticle delivery system (Tf-NP) can efficiently deliver miR-1 to GBM patient-derived GSC-enriched sphere cultures (GBM spheres).


METHODS
Delivery efficiency of the transferrin- targeting non-invasive nanoparticle was investigated by flow cytometry and further confirmed by confocal microscopy. The levels of miR-1 and its target molecules in GBM spheres were measured by qRT-PCR and immunoblotting. Migration capacity of Tf-NP-miR-1 treated GBM spheres were evaluated by transwell migration assay.


RESULTS
Tf-NPmiR- 1 treatment resulted in an over 200-fold increase of mature miR-1 compared to free miR-1 and Tf-NP-miR negative control (Tf-NP-miR-NC). Transferrin-mediated NP delivery resulted in a 3-fold higher delivery efficiency compared to NP without transferrin modification. Tf-NP-miR-1 treatment on GBM spheres significantly inhibited migration of GBM spheres by 30-50% with associated decline of MET and EGFR expression. Our data supported that Tf-NP could be used as an efficient and effective delivery system which has high potential to benefit the development of miR-based therapeutics for GBM treatment.
Xinmei
X
Wang
Xiaomeng
X
Huang
Zhaogang
Z
Yang
Daniel
D
Gallego-Perez
Junyu
J
Ma
Xi
X
Zhao
Jing
J
Xie
Ichiro
I
Nakano
1012 Smith Lab, 174 West 18th Ave. The Ohio State University, Columbus, OH 43210, USA. lee.31@osu.edu.
L James
LJ
Lee
D001932:Brain Neoplasms; D002465:Cell Movement; D002470:Cell Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma; D006801:Humans; D035683:MicroRNAs / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D053758:Nanoparticles / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D013234:Stem Cells; D014162:Transfection / Q000379:methods; D014168:Transferrin / Q000737:chemistry*; D014407:Tumor Cells, Cultured
C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D011990:Receptors, Transferrin; D014168:Transferrin; D011094:Polyethyleneimine; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met