Reversal of Cisplatin Resistance in Ovarian Cancer by the Multitargeted Nanodrug Delivery System Tf-Mn-MOF@Nira@CDDP,ACS Applied Materials & Interfaces

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Reversal of Cisplatin Resistance in Ovarian Cancer by the Multitargeted Nanodrug Delivery System Tf-Mn-MOF@Nira@CDDP
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2023-05-23 , DOI: 10.1021/acsami.3c05374
Yuan Liu ₁ , Yiru Wang ₁ , Xue Guan ₂ , Qiong Wu ₃ , Mengjun Zhang ₁ , Ping Cui ₁ , Can Wang ₁ , Xiuwei Chen ₁ , Xianwei Meng ₃ , Tengchuang Ma ₄

Affiliation

Cisplatin (CDDP) is a widely used chemotherapeutic drug with proven efficacy for treating tumors. However, its use has been associated with severe side effects and eventually leads to drug resistance, thus limiting its clinical application in patients with ovarian cancer (OC). Herein, we aimed to investigate the success rate of reversing cisplatin resistance using a synthetic, multitargeted nanodrug delivery system comprising a Mn-based metal–organic framework (Mn-MOF) containing niraparib (Nira) and CDDP alongside transferrin (Tf) conjugated to the surface (Tf-Mn-MOF@Nira@CDDP; MNCT). Our results revealed that MNCT can target the tumor site, consume glutathione (GSH), which is highly expressed in drug-resistant cells, and then decompose to release the encapsulated Nira and CDDP. Nira and CDDP play a synergistic role in increasing DNA damage and apoptosis, exhibiting excellent antiproliferation, migration, and invasion activities. In addition, MNCT significantly inhibited tumor growth in tumor-bearing mice and exhibited excellent biocompatibility without side effects. Furthermore, it depleted GSH, downregulated multidrug-resistant transporter protein (MDR) expression, and upregulated tumor suppressor protein phosphatase and tensin homolog (PTEN) expression, consequently reducing DNA damage repair and reversing cisplatin resistance. These results indicate that multitargeted nanodrug delivery systems can provide a promising clinical approach to overcoming cisplatin resistance. This study provides an experimental basis for further investigation into multitargeted nanodrug delivery systems to reverse cisplatin resistance in patients with OC.

中文翻译：

多靶点纳米药物递送系统 Tf-Mn-MOF@Nira@CDDP 逆转卵巢癌顺铂耐药性

顺铂 (CDDP) 是一种广泛使用的化疗药物，已被证明对治疗肿瘤有效。然而，它的使用与严重的副作用有关，并最终导致耐药性，从而限制了它在卵巢癌 (OC) 患者中的临床应用。在此，我们旨在研究使用合成的多靶点纳米药物递送系统逆转顺铂耐药的成功率，该系统包含含有尼拉帕尼（Nira）和 CDDP 以及转铁蛋白（Tf）的锰基金属有机骨架（Mn-MOF）表面（Tf-Mn-MOF@Nira@CDDP；MNCT）。我们的研究结果表明，MNCT 可以靶向肿瘤部位，消耗在耐药细胞中高表达的谷胱甘肽 (GSH)，然后分解释放包裹的 Nira 和 CDDP。Nira 和 CDDP 在增加 DNA 损伤和细胞凋亡方面发挥协同作用，表现出优异的抗增殖、迁移和侵袭活性。此外，MNCT 显着抑制了荷瘤小鼠的肿瘤生长，并表现出良好的生物相容性且无副作用。此外，它耗尽了 GSH，下调了多药耐药转运蛋白（MDR ) 表达，并上调肿瘤抑制蛋白磷酸酶和张力蛋白同源物 ( PTEN ) 表达，从而减少 DNA 损伤修复和逆转顺铂耐药。这些结果表明，多靶点纳米药物递送系统可以提供一种有前途的临床方法来克服顺铂耐药性。该研究为进一步研究多靶点纳米药物递送系统以逆转 OC 患者的顺铂耐药性提供了实验基础。

更新日期：2023-05-23

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