Induction Therapy of Retinoic Acid with a Temozolomide-Loaded Gold Nanoparticle-Associated Ultrasound Effect on Glioblastoma Cancer Stem-Like Colonies

Siaka Fadera, Pin Yuan Chen, Hao Li Liu*, I. Chi Lee*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations


Glioblastoma multiforme (GBM) is the most aggressive glioma. The treatment response is always low, and the condition is typically rapidly fatal. The undifferentiated and self-renewal characteristics of cancer stem cells (CSCs) have been reported, and their potential contribution may cause tumor initiation, recurrence, metastasis, and therapeutic resistance. In particular, glioblastoma stem-like cells exhibit highly invasive properties and drug resistance, serving as a model for the development of novel therapeutic strategies. Induction therapy provides an alternative therapeutic strategy to eliminate the stem cell properties of CSCs and enhance therapeutic sensitivity. The differentiated cells may lose their self-renewal ability, downregulate stem cell-related genes and drug resistance genes, and enhance anticancer drug sensitivity. Therefore, the purpose of this study is to establish a niche for glioblastoma stem-like cell selection as a platform and facilitate the assessment of differentiation therapy on GBM cancer stem-like colonies by retinoic acid (RA) with temozolomide (TMZ)-loaded gold nanoparticles (GNPs) associated with low-intensity ultrasound (LIUS). Herein, a hyaluronic acid-based material system was used to isolate GBM cancer stem-like colonies. Colony formation, size determination, stem cell-related marker expression, and GBM cancer stem-like cell marker expression with the culture period were identified. The effect of TMZ on GBM stem-like colonies on HA-based material systems was also determined, and the results revealed that drug resistance was highly enhanced in GBM colonies compared with that in the control cell population. In addition, GBM colonies also exhibited a significant increase in breast cancer resistance protein expression, which is consistent with the drug resistance effect. Furthermore, several factors, including LIUS, RA, and GNPs, were used to determine the possibility of induction therapy. RA with TMZ-loaded GNP-associated LIUS stimulation exhibited a significant and synergistic effect on the differentiation effect and drug sensitivity enhancement. The GBM cancer stem-like colony system presents an opportunity for the development of new therapeutic strategies, and this study provides an alternative differentiation therapy for malignant tumors.

Original languageEnglish
Pages (from-to)32845-32855
Number of pages11
JournalACS Applied Materials and Interfaces
Issue number28
StatePublished - 21 07 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.


  • TMZ-loaded gold nanoparticles
  • drug resistance
  • glioblastoma cancer stem-like colony
  • induction therapy
  • low-intensity ultrasound
  • retinoic acid


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