Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy

作者全名："Jiang, Weixi; Chen, Li; Guo, Xun; Cheng, Chen; Luo, Yuanli; Wang, Jingxue; Wang, Junrui; Liu, Yang; Cao, Yang; Li, Pan; Wang, Zhigang; Ran, Haitao; Zhou, Zhiyi; Ren, Jianli"

作者地址："[Jiang, Weixi; Guo, Xun; Cheng, Chen; Luo, Yuanli; Wang, Jingxue; Cao, Yang; Li, Pan; Wang, Zhigang; Ran, Haitao; Ren, Jianli] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Jiang, Weixi; Guo, Xun; Cheng, Chen; Luo, Yuanli; Wang, Jingxue; Cao, Yang; Li, Pan; Wang, Zhigang; Ran, Haitao; Ren, Jianli] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Chen, Li] Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, Chongqing 400010, Peoples R China; [Wang, Junrui] Chongqing Med Univ, Affiliated Hosp 2, Dept Radiol, Chongqing 400010, Peoples R China; [Liu, Yang] Chongqing Med Univ, Affiliated Hosp 2, Dept Gynecol & Obstet, Chongqing 400010, Peoples R China; [Zhou, Zhiyi] Univ Chinese Acad Sci, Dept Gen Practice, Chongqing Gen Hosp, Chongqing 401147, Peoples R China"

通信作者："Ren, JL (通讯作者)，Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing 400010, Peoples R China.; Ren, JL (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：THERANOSTICS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000777626900030

JCR分区：Q1

影响因子：12.4

年份：2022

卷号：12

期号：6

开始页：2987

结束页：3006

文献类型：Article

关键词：ER stress; cell-nucleus penetration; immunogenic cell death; ATP-responsive drug release; multidrug resistance

摘要："Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells. Methods: In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin ((DOX)-D-P) were used to prepare a theranostic nanocomposite (Ag-TF@(DOX)-D-P), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration. Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe3+ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@(DOX)-D-P has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance. Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level."

基金机构："National Natural Science Foundation of China [81873901, 82171946]; basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission [cstc2019jcyj-zdxmX0020]; High-level Medical Reserved Personnel Training Project of Chongqing, Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [KR2019G001]; Chongqing Science and Health Joint Medical Research Project-Young and Middle-Aged High-Level Talent Project [2020GDRC 011]"

基金资助正文："Weixi Jiang and Li Chen contributed equally to this work. The authors are sincerely grateful for the financial support from the National Natural Science Foundation of China (Grant No. 81873901, 82171946) , the basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission (Grant No. cstc2019jcyj-zdxmX0020) , High-level Medical Reserved Personnel Training Project of Chongqing, Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (KR2019G001) , and the Chongqing Science and Health Joint Medical Research Project-Young and Middle-Aged High-Level Talent Project (2020GDRC 011) ."