Catcher in the rel: Nanoparticles-antibody conjugate as NF-κB nuclear translocation blocker

被引:15
作者
Chen, Yi-Ping [1 ,2 ]
Chen, Chien-Tsu [3 ]
Liu, Tsang-Pai [4 ,5 ]
Chien, Fan-Ching [6 ]
Wu, Si-Han [1 ,2 ]
Chen, Peilin [7 ]
Mou, Chung-Yuan [1 ,8 ]
机构
[1] Taipei Med Univ, Grad Inst Nanomed & Med Engn, Taipei 110, Taiwan
[2] Taipei Med Univ, Int PhD Program Biomed Engn, Coll Biomed Engn, Taipei 110, Taiwan
[3] Taipei Med Univ, Coll Med, Dept Biochem & Mol Cell Biol, Taipei 110, Taiwan
[4] Mackay Jr Coll Med Nursing & Management, Taipei 112, Taiwan
[5] Mackay Mem Hosp, Dept Surg, Taipei 104, Taiwan
[6] Natl Cent Univ, Dept Opt & Photon, Chungli 320, Taiwan
[7] Acad Sinica, Res Ctr Appl Sci, Taipei 115, Taiwan
[8] Natl Taiwan Univ, Dept Chem, Taipei 106, Taiwan
关键词
NF-kappa B; Antibody therapy; TAT peptide; Mesoporous silica nanoparticles; Size hindrance; TARGETED DRUG-DELIVERY; SQUAMOUS-CELL CARCINOMA; HUMAN HEAD; TRANSCRIPTION FACTORS; CANCER; ALPHA; LOCALIZATION; ACTIVATION; INFLAMMATION; PREVENTION;
D O I
10.1016/j.biomaterials.2020.119997
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Transcription factor complex NF-kappa B (p65/p50) is localized to the cytoplasm by its inhibitor I kappa B alpha. Upon activation, the Rel proteins p65/p50 are released from I kappa B alpha and transported through nuclear pore to affect many gene expressions. While inhibitions of up or down stream signal pathways are often ineffective due to crosstalks and compensations, direct blocking of the Rel proteins p65/p50 has long been proposed as a potential target for cancer therapy. In this work, a nanoparticle/antibody complex targeting NF-kappa B is employed to catch the Rel protein p65 in perinuclear region and thus blocking the translocation near the nuclear pore gate. TAT peptide conjugated on mesoporous silica nanoparticles (MSN) help non-endocytosis cell-membrane transducing and converge toward perinuclear region, where the p65 specific antibody performed the targeting and catching against active NF-kappa B p65 effectively. The size of the p65 bound nanoparticle becomes too big to enter nucleus. Simultaneous treatment of mice with the hybrid MSN and doxorubicin conferred a significant therapeutic effect against 4T1 tumor-bearing mice. The new approach of anti-body therapy targeting on transcription factor with "nucleus focusing" and "size exclusion blocking" effects of the antibody-conjugated nanoparticle is general and may be applicable to modulating other transcription factors.
引用
收藏
页数:11
相关论文
共 48 条
[1]   Transcription factor NF-κB -: A sensor for smoke and stress signals [J].
Ahn, KS ;
Aggarwal, BB .
NATURAL PRODUCTS AND MOLECULAR THERAPY, 2005, 1056 :218-233
[2]   Cigarette smoke condensate activates nuclear transcription factor-κB through phosphorylation and degradation of IκBα:: correlation with induction of cyclooxygenase-2 [J].
Anto, RJ ;
Mukhopadhyay, A ;
Shishodia, S ;
Gairola, CG ;
Aggarwal, BB .
CARCINOGENESIS, 2002, 23 (09) :1511-1518
[3]   Nuclear factor-kappa B and cancer: its role in prevention and therapy [J].
Bharti, AC ;
Aggarwal, BB .
BIOCHEMICAL PHARMACOLOGY, 2002, 64 (5-6) :883-888
[4]   Targeting transcription factors for therapeutic benefit [J].
Brennan, Paul ;
Donev, Rossen ;
Hewamana, Saman .
MOLECULAR BIOSYSTEMS, 2008, 4 (09) :909-919
[5]   Quantitative Analysis of Tat Peptide Binding to Import Carriers Reveals Unconventional Nuclear Transport Properties [J].
Cardarelli, Francesco ;
Serresi, Michela ;
Albanese, Alberto ;
Bizzarri, Ranieri ;
Beltram, Fabio .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (14) :12292-12299
[6]   Nanomachines and Other Caps on Mesoporous Silica Nanoparticles for Drug Delivery [J].
Chen, Wei ;
Glackin, Carlotta A. ;
Horwitz, Marcus A. ;
Zink, Jeffrey I. .
ACCOUNTS OF CHEMICAL RESEARCH, 2019, 52 (06) :1531-1542
[7]   Impacts of Cross-Linkers on Biological Effects of Mesoporous Silica Nanoparticles [J].
Chen, Yi-Ping ;
Wu, Si-Han ;
Chen, I-Chih ;
Chen, Chien-Tsu .
ACS APPLIED MATERIALS & INTERFACES, 2017, 9 (11) :10254-10265
[8]   Nucleus-Targeted Drug Delivery: Theoretical Optimization of Nanoparticles Decoration for Enhanced Intracellular Active Transport [J].
Cohen, Ohad ;
Granek, Rony .
NANO LETTERS, 2014, 14 (05) :2515-2521
[9]   Regulation of nuclear localization during signaling [J].
Cyert, MS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (24) :20805-20808
[10]  
Duffey DC, 1999, CANCER RES, V59, P3468