Doxorubicin-polyglycerol-nanodiamond conjugates disrupt STAT3/IL-6-mediated reciprocal activation loop between glioblastoma cells and astrocytes

被引：26

作者：

Chen, Zhuo ^{[1
,2
,9
]}

Yuan, Shen-Jun ^{[9
]}

Li, Ke ^{[3
]}

Zhang, Quan ^{[4
]}

Li, Tong-Fei ^{[1
,9
]}

An, Hui-Chao ^{[1
,9
]}

Xu, Hua-Zhen ^{[1
,9
]}

Yue, Yuan ^{[1
,9
]}

Han, Min ^{[5
]}

Xu, Yong-Hong ^{[6
]}

Komatsu, Naoki ^{[7
]}

Zhao, Li ^{[8
]}

Chen, Xiao ^{[1
,9
]}

机构：

[1] Wuhan Univ, Sch Basic Med Sci, Dept Pharmacol, Donghu Ave 185, Wuhan 430072, Peoples R China

[2] Hubei Univ Med, Sch Basic Med Sci, Dept Pathol, Hubei Key Lab Embryon Stem Cell Res, Shiyan 442000, Peoples R China

[3] Wuhan Univ, Ctr Lab Teaching, Sch Basic Med, Donghu Ave 185, Wuhan 430072, Peoples R China

[4] Wuhan Univ, Sch Basic Med Sci, Dept Anat & Embryol, Donghu Ave 185, Wuhan 430072, Peoples R China

[5] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Nephrol, Wuhan 430030, Peoples R China

[6] Wuhan Univ, Inst Ophthalmol Res, Dept Ophthalmol, Renmin Hosp, Wuhan 430060, Peoples R China

[7] Kyoto Univ, Grad Sch Human & Environm Studies, Sakyo Ku, Kyoto 6068501, Japan

[8] Soochow Univ, State Key Lab Radiat Med & Protect, Sch Radiat Med & Protect, Sch Radiol & Interdisciplinary Sci RAD X,Collabor, Suzhou 215123, Jiangsu, Peoples R China

[9] Hubei Prov Key Lab Developmentally Originated Dis, Wuhan 43007, Peoples R China

来源：

JOURNAL OF CONTROLLED RELEASE | 2020年 / 320卷

基金：

中国国家自然科学基金;

关键词：

Doxorubicin-polyglycerol-nanodiamond conjugates; Glioblastoma; Astrocytes; Reciprocal activation; STAT3; IL-6; REACTIVE ASTROCYTES; DRUG-DELIVERY; STAT3; INHIBITION; RESISTANCE; IL-6;

D O I：

10.1016/j.jconrel.2020.01.044

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Astrocytes are key stromal components in glioblastoma (GBM) and have complex interactions with the GBM cells (GBC) promoting the survival, progression and therapy resistance of GBM. In this study, we first demonstrated the existence of a reciprocal activation loop mediated by the STAT3/IL-6 signaling between GBC and astrocytes. This loop of reciprocity was found to be initiated by the constitutive activity of STAT3 and downstream expression of IL-6 in the GBC. GBC-derived IL-6 activated STAT3 and thereby upregulated IL-6 expression in the astrocytes. Astrocyte-derived IL-6 acted back on the GBC causing further activation of STAT3 and leading to enhanced downstream events that promote proliferation, migration, invasion and apoptosis resistance of the GBC. Next, we showed that doxorubicin-polyglycerol-nanodiamond conjugates (Nano-DOX), which could be delivered via GBM-associated macrophages, suppressed STAT3 activity in the GBC reducing their IL-6 output to the astrocytes and thereby abolished the astrocytes' feedback activation of the GBC. Moreover, Nano-DOX also suppressed stimulated activation of STAT3 and IL-6 induced by temozolomide, a first-line anti-GBM chemotherapy, resistance to which critically involves STAT3 activation. In conclusion, Nano-DOX could disrupt the STAT3/IL-6-mediated reciprocal activation loop between the GBC and astrocytes. Nano-DOX also provides a novel approach to therapeutic modulation of the GBM microenvironment.

引用

页码：469 / 483

页数：15