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Biosynthesized tumor acidity and MMP dual-responsive plant toxin gelonin for robust cancer therapy.
Ding, Guo-Bin; Cao, Huiyan; Zhu, Chenchen; Chen, Fangyuan; Ye, Jiaqi; Li, Bin-Chun; Yang, Peng; Stauber, Roland H; Qiao, Mingqiang; Li, Zhuoyu.
Afiliación
  • Ding GB; Institutes of Biomedical Sciences/School of Life Sciences, Inner Mongolia University, Hohhot 010070, China. ding@imu.edu.cn.
  • Cao H; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Zhu C; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Chen F; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Ye J; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Li BC; Institutes of Biomedical Sciences/School of Life Sciences, Inner Mongolia University, Hohhot 010070, China. ding@imu.edu.cn.
  • Yang P; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Stauber RH; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Qiao M; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China. qmq@sxu.edu.cn.
  • Li Z; Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany.
Biomater Sci ; 12(2): 346-360, 2024 Jan 16.
Article en En | MEDLINE | ID: mdl-38099814
ABSTRACT
Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity via inhibiting intracellular protein synthesis. However, gelonin lacks a translocation domain, and thus its poor cellular uptake leads to low outcomes of antitumor response. Here, tumor acidity and matrix metalloproteinase (MMP) dual-responsive functional gelonin (Trx-PVGLIG-pHLIP-gelonin, TPpG), composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), an MMP-responsive motif PVGLIG hexapeptide and gelonin, was innovatively proposed and biologically synthesized by a gene recombination technique. TPpG exhibited good thermal and serum stability, showed MMP responsiveness and could enter tumor cells under weakly acidic conditions, especially for MMP2-overexpressing HT1080 cells. Compared to low MMP2-expressing MCF-7 cells, TPpG displayed enhanced in vitro antitumor efficacy to HT1080 cells at pH 6.5 as determined by different methods. Likewise, TPpG was much more effective in triggering cell apoptosis and inhibiting protein synthesis in HT1080 cells than in MCF-7 cells. Intriguingly, with enhanced stability and pH/MMP dual responsiveness, TPpG notably inhibited subcutaneous HT1080 xenograft growth in mice and no noticeable off-target side effect was observed. This ingeniously designed strategy aims at providing new perspectives for the development of a smart platform that can intelligently respond to a tumor microenvironment for efficient protein delivery.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biomater Sci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biomater Sci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido