TY - JOUR
T1 - Bioreduction-ruptured nanogel for switch on/off release of Bcl2 siRNA in breast tumor therapy
AU - Li, Huipeng
AU - Yang, Xue
AU - Gao, Fang
AU - Qian, Chenggen
AU - Li, Chenzi
AU - Oupicky, David
AU - Sun, Minjie
N1 - Funding Information:
This work was financially supported by the National Science and Technology Major Projec t ( 2017YFA0205400 ), the National Natural Science Foundation of China (No. 81373983 and 81573377 ), The Jiangsu Fund for Distinguished Youth ( BK20170028 ) and the Natural Science Foundation (No. BK20141352 ). The authors also acknowledged Dr. Maoshen Jie (Roquette Ltd., Shanghai, China) for his kind help in providing dextrin.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/12/28
Y1 - 2018/12/28
N2 - In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin. Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro. Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity, moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
AB - In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin. Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro. Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity, moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
KW - Bioreduction-rupture
KW - Lysosomal escape
KW - PEI-1.8 kDa
KW - Reduction-sensitive
KW - siRNA delivery
KW - siRNA switch on/off controlled release
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U2 - 10.1016/j.jconrel.2018.02.036
DO - 10.1016/j.jconrel.2018.02.036
M3 - Article
C2 - 29499219
AN - SCOPUS:85053658611
VL - 292
SP - 78
EP - 90
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -