A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer

作者全名："Liu, Fan; Xiang, Qinyanqiu; Luo, Yuanli; Luo, Ying; Luo, Wenpei; Xie, Qirong; Fan, Jingdong; Ran, Haitao; Wang, Zhigang; Sun, Yang"

作者地址："[Liu, Fan; Luo, Yuanli; Xie, Qirong; Fan, Jingdong; Ran, Haitao; Wang, Zhigang; Sun, Yang] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Liu, Fan; Luo, Ying; Luo, Wenpei] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China; [Liu, Fan; Luo, Ying; Luo, Wenpei] Chongqing Med Univ, State Key Lab Ultrasound Med & Engn, Chongqing 400010, Peoples R China; [Xiang, Qinyanqiu] Chongqing Med Univ, Dept Radiol, Affiliated Hosp 1, Chongqing 400010, Peoples R China"

通信作者："Sun, Y (通讯作者)，Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000994288400001

JCR分区：Q1

影响因子：10.6

年份：2023

卷号：21

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Nanopharmaceutical; Oxidative stress; Spontaneous cascade effect; STAT3; Contrast agent; Pancreatic cancer

摘要："Background Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies. Results A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst -(SiO2@ MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2- GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released -Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (center dot OH), which together with the subsequent release of GAL from SiO2 increases ROS. The ""overwhelming"" ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/ STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the -O-2 and -Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively. Conclusion This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery."

基金机构："National Natural Science Foundation of China [81871369]; Innovation Leaders Program of Chongqing Talents [CQYC20210303225]; Senior Medical Talents Program of Chongqing for Young and Middleaged [2020-219]; Program for Youth Innovation in Future Medicine, Chongqing Medical University; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University"

基金资助正文："This study was financially supported by the National Natural Science Foundation of China (Grant No. 81871369), the Innovation Leaders Program of Chongqing Talents (Grant No. CQYC20210303225), Senior Medical Talents Program of Chongqing for Young and Middleaged (2020-219), Program for Youth Innovation in Future Medicine, Chongqing Medical University, and Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University"