Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells

Xinmei Wang, Xiaomeng Huang, Zhaogang Yang, Daniel Gallego-Perez, Junyu Ma, Xi Zhao, Jing Xie, Ichiro Nakano, L. James Lee

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberA09
Pages (from-to)839-846
Number of pages8
JournalCurrent Pharmaceutical Biotechnology
Volume15
Issue number9
StatePublished - Jan 1 2015
Externally publishedYes

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Glioblastoma
Transferrin
MicroRNAs
Nanoparticles
Stem Cells
Neoplasms
Therapeutics
Immunoblotting
Confocal Microscopy
Cell Movement
Flow Cytometry

Keywords

  • Cancer initiating cells
  • Cancer stem cells
  • Glioma stem cells
  • Targeted delivery
  • Transferrin-conjugated nanoparticles

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

Cite this

Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells. / Wang, Xinmei; Huang, Xiaomeng; Yang, Zhaogang; Gallego-Perez, Daniel; Ma, Junyu; Zhao, Xi; Xie, Jing; Nakano, Ichiro; James Lee, L.

In: Current Pharmaceutical Biotechnology, Vol. 15, No. 9, A09, 01.01.2015, p. 839-846.

Research output: Contribution to journalArticle

Wang, X, Huang, X, Yang, Z, Gallego-Perez, D, Ma, J, Zhao, X, Xie, J, Nakano, I & James Lee, L 2015, 'Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells', Current Pharmaceutical Biotechnology, vol. 15, no. 9, A09, pp. 839-846.
Wang, Xinmei ; Huang, Xiaomeng ; Yang, Zhaogang ; Gallego-Perez, Daniel ; Ma, Junyu ; Zhao, Xi ; Xie, Jing ; Nakano, Ichiro ; James Lee, L. / Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells. In: Current Pharmaceutical Biotechnology. 2015 ; Vol. 15, No. 9. pp. 839-846.
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AU - Wang, Xinmei

AU - Huang, Xiaomeng

AU - Yang, Zhaogang

AU - Gallego-Perez, Daniel

AU - Ma, Junyu

AU - Zhao, Xi

AU - Xie, Jing

AU - Nakano, Ichiro

AU - James Lee, L.

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N2 - 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.

AB - 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.

KW - Cancer initiating cells

KW - Cancer stem cells

KW - Glioma stem cells

KW - Targeted delivery

KW - Transferrin-conjugated nanoparticles

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