Bioinspired Lipoproteins of Furoxans-Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy Resistance

作者全名："Sun, Maoyuan; Xie, Honglei; Zhang, Wenli; Li, Xianlu; Jiang, Zhan; Liang, Yiyu; Zhao, Guanjian; Huang, Ning; Mao, Jinning; Liu, Guodong; Zhang, Zhiwen"

作者地址："[Sun, Maoyuan; Zhao, Guanjian; Huang, Ning; Liu, Guodong] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400016, Peoples R China; [Xie, Honglei] Shandong First Med Univ & Shandong Acad Med Sci, Sch Pharmaceut Sci, Inst Pharmacol, 619 Changcheng Rd, Tai An 271016, Shandong, Peoples R China; [Zhang, Wenli] Chongqing Med Univ, Affiliated Hosp 2, Dept Radiol, Chongqing 400016, Peoples R China; [Li, Xianlu; Liang, Yiyu; Zhang, Zhiwen] Fudan Univ, Sch Pharm, Minist Educ, Shanghai 201203, Peoples R China; [Li, Xianlu; Liang, Yiyu; Zhang, Zhiwen] Fudan Univ, Key Lab Smart Drug Delivery, Minist Educ, Shanghai 201203, Peoples R China; [Jiang, Zhan] Chongqing Gen Hosp, Dept Oncol, Chongqing 400016, Peoples R China; [Mao, Jinning] Chongqing Med Univ, Affiliated Hosp 2, Hlth Management Ctr, Chongqing 400016, Peoples R China"

通信作者："Liu, GD (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400016, Peoples R China.; Zhang, ZW (通讯作者)，Fudan Univ, Sch Pharm, Minist Educ, Shanghai 201203, Peoples R China.; Zhang, ZW (通讯作者)，Fudan Univ, Key Lab Smart Drug Delivery, Minist Educ, Shanghai 201203, Peoples R China.; Mao, JN (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Hlth Management Ctr, Chongqing 400016, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:001112638500001

JCR分区：Q1

影响因子：14.3

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：DNA repair; glioblastoma; lipoprotein; peroxynitrite; radiotherapy resistance

摘要："Radiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio-sensitizer and a CCL5 peptide-modified bioinspired lipoprotein system of NG (C-LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C-LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO-) upon X-ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261-induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance. Inspired by the aberrant upregulation of DNA-repairing RAD51, scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide donor conjugate of furoxans-gemcitabine (NG) is rationally synthesized and a CCL5-modified bioinspired lipoprotein system of C-LNG is designed, which preferentially targets the orthotopic GBM tumors and profoundly circumvents the radiotherapy resistance.image"

基金机构："National Key Research and Development Program of China; National Natural Science Foundation of China [32271461, 32071385]; Chongqing Talents: Youth Top-notch Talent Project [cstc2022ycjh-bgzxm0167]; Chongqing Scientific and Health Joint Medical Research Project [2020GDRC021]; Natural Science Foundation of Chongqing [2022NSCQ-MSX0872, cstc2021jcyj-msxmX0036]; China postdoctoral science fund [2022MD723750]; Second Affiliated Hospital of Chongqing Medical University; YLS [2023-079]; Chongqing Medical University Laboratory Animal Center; Chongqing Medical University [IACUC-CQMU-2023-0096]; [2022YFE012727]; [2022YFC2304303]"

基金资助正文："M.S., H.X., and W.Z. contributed equally to this work. This work was financially supported by the National Key Research and Development Program of China (2022YFE012727 and 2022YFC2304303), the National Natural Science Foundation of China (32271461 and 32071385), Chongqing Talents: Youth Top-notch Talent Project (cstc2022ycjh-bgzxm0167), Chongqing Scientific and Health Joint Medical Research Project (2020GDRC021), the Natural Science Foundation of Chongqing (2022NSCQ-MSX0872 and cstc2021jcyj-msxmX0036) and China postdoctoral science fund (2022MD723750). All specimens of patients were obtained with written informed consent and standard research protocol approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University (Approved No. YLS 2023-079). The animal experiments were performed in the Chongqing Medical University Laboratory Animal Center and the protocols were approved by the Animal Ethics Committee of the Chongqing Medical University (Approved No. IACUC-CQMU-2023-0096)"