TY - JOUR
T1 - Transferrin modified gsh sensitive hyaluronic acid derivative micelle to deliver hsp90 inhibitors to enhance the therapeutic efficacy of brain cancers
AU - Debele, Tilahun Ayane
AU - Wu, Ping Ching
AU - Wei, Yu Feng
AU - Chuang, Jian Ying
AU - Chang, Kwang Yu
AU - Tsai, Jui Hung
AU - Su, Wen Pin
N1 - Funding Information:
Funding: This research was funded by the Ministry of Science and Technology, Taiwan; grant number: MOST 108-2811-B-006-501, MOST 108-2811-B-006-525, MOST 106-2314-B-006-074-MY3, MOST 109-2314-B-006-078, MOST 110-2811-B-006 -501 and MOST 109-2314-B-006-084-MY3; National Cheng Kung University Hospital, grant number: 10703056 and 10804005; and E-DA hospital, grant number: NCKUEDA10610 for financial support.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/2
Y1 - 2021/5/2
N2 - 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.
AB - 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.
KW - Brain cancer
KW - GSH-sensitive micelle
KW - Hyaluronic acid
KW - Poly(lactic-co-glycolic) acid
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UR - http://www.scopus.com/inward/citedby.url?scp=85105748804&partnerID=8YFLogxK
U2 - 10.3390/cancers13102375
DO - 10.3390/cancers13102375
M3 - Article
AN - SCOPUS:85105748804
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 10
M1 - 2375
ER -
