Background

5-Fluorouracil (5-FU) is a good anti-cancer drug, but its prolonged use results in overexpression of certain enzymes like thymidylate synthase and causes multidrug resistance in cancer cells. Many studies proven that a combination of curcumin (CUR) and 5-FU can overcome the above difficulties. It was in this direction that a novel material that could reversibly bind with drug molecules was designed and developed to overcome drug resistance.

Methods

ZIF-8 was surface modified with nitro groups (NZIF-8); 5-FU was encapsulated in the NZIF-8 through one pot method. Nitro groups on the surface of NZIF-8 enable coating of curcumin loaded chitosan, thereby forming CUR-loaded chitosan-coated 5-FU encapsulated NZIF-8 (CUR-loaded CS-coated 5-FU@NZIF-8). The drug loading and in vitro drug release studies were conducted using UV–Visible spectrophotometry at 266 nm for 5-FU and 425 nm for CUR, respectively.

Results

The nanocarrier exhibited an average size of 60 nm and was highly stable as indicated by thermogravimetric studies. The residual positive charge imparted by the amino groups on chitosan enabled enhanced cellular uptake and maybe responsible for the enhanced cytotoxicity of 5-FU + CUR combination in MCF-7 breast cancer cells (83.2%) compared to that of individual drug treatment without the nanocarrier (67.7%).

Conclusion

The study demonstrates the capability of CUR-loaded CS-coated 5-FU@NZIF-8 for combination therapy to overcome drug resistance. The results obtained from MTT assay suggest the potential applicability of the present material in the sustained delivery of simultaneous drugs. This approach can further improve efficacy as well as the cost effectiveness of chemotherapy.

Graphical Abstract

Schematic representation of combination therapy using CUR-loaded CS-coated 5-FU@NZIF-8

Highlights

• A dual drug delivery system was used in which CUR-loaded chitosan-coated 5-FU encapsulated nitro modified ZIF-8 was synthesized for combination therapy.

• The surface of ZIF-8 was modified with nitro groups which enables effective coating of chitosan.

• In a tumor environment, which is acidic in nature, chitosan swells thereby CUR releases quickly, while due to chitosan coating the encapsulated 5-FU releases slowly.

• The positively charged amino group on the surface of chitosan helps for targeted delivery since tumor cell surface is negatively charged.

中文翻译：

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用于组合癌症治疗的负载姜黄素的壳聚糖包被的 5-氟尿嘧啶封装的纳米沸石咪唑酯框架

背景

5-氟尿嘧啶（5-FU）是一种很好的抗癌药物，但长期使用会导致某些酶（如胸苷酸合成酶）过度表达，并导致癌细胞产生多药耐药性。许多研究证明姜黄素（CUR）和5-FU的组合可以克服上述困难。正是沿着这个方向，设计和开发了一种可以与药物分子可逆结合的新型材料来克服耐药性。

方法

ZIF-8经过硝基表面修饰（NZIF-8）；通过一锅法将5-FU封装在NZIF-8中。NZIF-8表面的硝基使姜黄素负载壳聚糖包被，从而形成CUR负载壳聚糖包被5-FU封装NZIF-8（CUR负载CS包被5-FU@NZIF-8）。5-FU 的载药量和体外药物释放研究分别使用紫外可见分光光度法在 266 nm 处进行，CUR 则在 425 nm 处进行。

结果

热重研究表明，纳米载体的平均尺寸为 60 nm，并且高度稳定。与没有纳米载体的单独药物治疗相比，壳聚糖上的氨基赋予的残留正电荷能够增强细胞摄取，并且可能是 MCF-7 乳腺癌细胞中 5-FU + CUR 组合的细胞毒性增强的原因 (83.2%) （67.7%）。

结论

该研究证明了负载 CUR 的 CS 包被的 5-FU@NZIF-8 用于联合治疗克服耐药性的能力。MTT 测定获得的结果表明本材料在同时药物持续递送中的潜在适用性。这种方法可以进一步提高化疗的疗效和成本效益。

图形概要

使用 CUR 负载 CS 包被的 5-FU@NZIF-8 进行联合治疗的示意图

强调

• 使用双药物递送系统，其中合成了负载 CUR 的壳聚糖包被的 5-FU 封装的硝基修饰 ZIF-8 用于联合治疗。

• ZIF-8 的表面经过硝基修饰，能够有效包覆壳聚糖。

• 在本质上呈酸性的肿瘤环境中，壳聚糖膨胀，从而使 CUR 快速释放，而由于壳聚糖涂层，封装的 5-FU 释放缓慢。

• 由于肿瘤细胞表面带负电荷，壳聚糖表面带正电荷的氨基有助于靶向递送。