The transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2) is considered as
the master regulator of antioxidant and cytoprotective gene expressions. Moreover, it plays a
pivotal role in cancer progression. Nrf2 mediates the adaptive response which contributes to the
resistance to chemotherapeutic pro‐oxidant drugs, such as cisplatin (CDDP), in various tumors,
including bladder cancers. For this reason, Nrf2 could be a promising target to overcome
chemoresistance. There are several known Nrf2 pharmacological inhibitors; however, most of
them are not specific. The use of a specific small interfering RNA (siRNA) targeting the Nrf2 gene
(siNrf2) loaded into nanovehicles is an attractive alternative, since it can increase specificity. This
study aimed to evaluate the biological activity of siNrf2 loaded on guanidine‐terminated
carbosilane dendrimers (GCDs) in overcoming CDDP resistance in bladder cancer cells with a
high level of Nrf2. Parameters such as viability, proliferation, apoptosis, migration, and oxidative
stress level were taken into account. Results demonstrated that siNrf2‐GCD treatment sensitized
CDDP‐resistant cells to CDDP treatment. Moreover, data obtained by treating the non‐cancerous
human kidney HK‐2 cell line strongly suggest a good safety profile of the carbosilane dendrimers
loaded with siNrf2. In conclusion, we suggest that siNrf2‐GCD is a promising drug delivery
system for gene therapy to be used in vivo; and it may represent an important tool in the therapy
of CDDP‐resistant cancer.



中文翻译：

---

载有靶向Nrf2的siRNA的碳硅烷树状大分子作为克服膀胱癌细胞中顺铂化学耐药性的工具

转录因子核因子红系2相关因子2（Nrf2）被认为是
抗氧化剂和细胞保护性基因表达的主要调节剂。此外，它
在癌症进展中起关键作用。Nrf2介导适应性反应，有助于
在
包括膀胱癌在内的多种肿瘤中抵抗化学疗法的抗氧化剂药物，例如顺铂（CDDP）。因此，Nrf2可能是克服
化学耐药性的有希望的靶标。有几种已知的Nrf2药理抑制剂。但是，大多数
都不是特定的。使用靶向
加载到纳米载体中的Nrf2基因（siNrf2）的特定小干扰RNA（siRNA）是一种有吸引力的选择，因为它可以提高特异性。这个
这项研究旨在评估负载在胍基
碳硅烷树枝状大分子（GCD）上的siNrf2在克服
高Nrf2水平的膀胱癌细胞对CDDP的抵抗中的生物学活性。考虑了诸如生存力，增殖，凋亡，迁移和氧化
应激水平的参数。结果表明，siNrf2-GCD处理可使
CDDP耐药细胞对CDDP处理敏感。此外，通过治疗非癌性
人肾HK-2细胞系获得的数据强烈表明，
载有siNrf2的碳硅烷树状聚合物具有良好的安全性。总之，我们建议siNrf2-GCD是
用于体内基因治疗的有前途的药物递送系统。它可能代表治疗中的重要工具
CDDP耐药癌症。