Transferrin modified gsh sensitive hyaluronic acid derivative micelle to deliver hsp90 inhibitors to enhance the therapeutic efficacy of brain cancers

Ayane Debele Tilahun, Ping Ching Wu, Yu Feng Wei, Jian Ying Chuang, Kwang Yu Chang, Jui Hung Tsai, Wen Pin Su

Research output: Contribution to journalArticlepeer-review

Abstract

Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence micros-copy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cyto-toxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was sim-ultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accu-mulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histo-logical analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.

Original languageEnglish
Article number2375
JournalCancers
Volume13
Issue number10
DOIs
Publication statusPublished - 2021 May 2

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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