1. Targeted iron nanoparticles with platinum-(IV) prodrugs and anti-EZH2 siRNA show great synergy in combating drug resistance in vitro and in vivo
- Author
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Bengang Xing, Dayong Jin, Ping'an Ma, Kerong Deng, Binbin Ding, Chang Yu, Ziyong Cheng, Xinyang Zhang, Jun Lin, Xiaoran Deng, and School of Physical and Mathematical Sciences
- Subjects
0301 basic medicine ,Materials science ,Organoplatinum Compounds ,endocrine system diseases ,Iron ,Biophysics ,Cisplatin Resistant ,Antineoplastic Agents ,Apoptosis ,Bioengineering ,Drug resistance ,Pharmacology ,Biomaterials ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Chemistry [Science] ,medicine ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Prodrugs ,RNA, Small Interfering ,Cytotoxicity ,Platinum ,Cisplatin ,Iron Nanoparticles ,Prodrug ,030104 developmental biology ,Cell killing ,Drug Resistance, Neoplasm ,Mechanics of Materials ,030220 oncology & carcinogenesis ,Cancer cell ,Ceramics and Composites ,Nanoparticles ,Nanocarriers ,medicine.drug - Abstract
Resistance to platinum agents is challenging in cancer treatment with platinum drugs. Such resistant cells prevent effective platinum accumulation intracellular and alter cellular adaptations to survive from cytotoxicity by regulating corresponding proteins expression. Ideal therapeutics should combine resolution to these pump and non-pump relevant resistance of cancer cells to achieve high efficacy and low side effect. Fe3O4 nanocarrier loaded with drugs could enter cells in a more efficient endocytosis manner which circumvents pump-relevant drug resistance. EZH2 protein which was previously found to be over-expressed in drug-resistant cancer cells was reported to be involved in platinum drug resistance and play a vital role in anti-apoptosis pathways. Here, we report Fe3O4 nanoparticles loaded with siEZH2 (siRNA), a platinum prodrug in +4 oxidation state (cis, cis, trans-diamminedichlorodisuccinato-platinum-(IV), namely Pt(IV)) and luteinizing hormone-releasing hormone (LHRH) targeting polypeptides. Results show that targeted nanoparticles loading with siEZH2 synergize with Pt(IV) and result in similar cell killing performance to A2780/DDP cells (cisplatin resistant) compared with non-siEZH2 loaded nanoparticles to A2780 cells (cisplatin sensitive). Thus, this Fe3O4@PEI-Pt(IV)-PEG-LHRH@siEZH2 nanoparticles reverse the cisplatin resistance from the pump and non-pump relevant aspects, fully taking advantage of nanocarrier system.
- Published
- 2018