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 the 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 which are over-expressed on the surface of various cancer cells. 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.

在使用铂类药物治疗癌症中，对铂类药物的耐药性具有挑战性。这样的抗性细胞通过调节相应的蛋白质表达来防止有效的铂在细胞内积累，并改变细胞的适应性，使其免受细胞毒性的影响。理想的治疗方法应兼具对癌细胞的泵浦性和与泵浦无关的抵抗力，以实现高功效和低副作用。载有药物的Fe ₃ O ₄纳米载体可以更有效的内吞作用进入细胞，从而避免了与泵相关的耐药性。据报道，先前发现在耐药癌细胞中过表达的EZH2蛋白与铂类药物耐药有关，并且在抗凋亡途径中起着至关重要的作用。在这里，我们报告Fe ₃装有siEZH2（siRNA），+ 4氧化态的铂前药（顺式，顺式，反式-二氨基二氯二琥珀酸铂（IV），即Pt（IV））和促黄体生成激素释放激素（LHRH）的多肽的O ₄纳米颗粒在各种癌细胞表面过度表达。结果显示，与未装载siEZH2的纳米颗粒对A2780细胞（对顺铂敏感）相比，装载有siEZH2的靶向纳米颗粒与Pt（IV）协同作用，并导致与A2780 / DDP细胞相似的细胞杀伤性能（顺铂耐药）。因此，这种Fe ₃ O ₄ @ PEI-Pt（IV）-PEG-LHRH @ siEZH2纳米颗粒从泵浦和非泵浦相关方面逆转了顺铂耐药性，充分利用了纳米载体系统的优势。