pH响应铜掺杂介孔硅纳米催化剂增强肿瘤化疗-化学动力学联合治疗的研究

doi:10.15541/jim20230151

无机材料学报 ›› 2024, Vol. 39 ›› Issue (1): 90-98.DOI: 10.15541/jim20230151

pH响应铜掺杂介孔硅纳米催化剂增强肿瘤化疗-化学动力学联合治疗的研究

何倩(), 唐婉兰, 韩秉锟, 魏佳元, 吕文轩, 唐昭敏()

西南石油大学新能源与材料学院, 成都 610500

收稿日期:2023-03-23 修回日期:2023-04-24 出版日期:2024-01-20 网络出版日期:2023-09-12
通讯作者: 唐昭敏, 高级实验师. E-mail: tl8687@163.com
作者简介:何倩(1999-), 女, 硕士研究生. E-mail: 1084518887@qq.com
基金资助:
国家自然科学基金(51803174);四川省玄武岩纤维复合材料开发及应用工程技术研究中心开放基金(2022SCXWYXWFC002)

pH Responsive Copper-Doped Mesoporous Silica Nanocatalyst for Enhanced Chemo-Chemodynamic Tumor Therapy

HE Qian(), TANG Wanlan, HAN Bingkun, WEI Jiayuan, LÜ Wenxuan, TANG Zhaomin()

School of New Energy and Materials, Southwest Petroleum University, Chengdu 610500, China

Received:2023-03-23 Revised:2023-04-24 Published:2024-01-20 Online:2023-09-12
Contact: TANG Zhaomin, senior experimentalist. E-mail: tl8687@163.com
About author:HE Qian (1999-), female, Master candidate. E-mail: 1084518887@qq.com
Supported by:
National Natural Science Foundation of China(51803174);Foundation of Sichuan Engineering Technology Research Center of Basalt Fiber Composite Development and Application of Southwest Petroleum University(2022SCXWYXWFC002)

摘要/Abstract

摘要：

化学动力学疗法(CDT)利用肿瘤细胞内源性H₂O₂与芬顿催化剂反应生成高毒性的羟基自由基(•OH), 从而杀死肿瘤细胞, 但内源性H₂O₂不足和纳米粒子转运效率较低导致抗癌效果不理想。本研究制备了一种分散性良好、尺寸较小的铜掺杂介孔二氧化硅(Cu-MSN), 负载化疗药物阿霉素(DOX)和抗坏血酸盐(AA)后, 表面经叶酸(FA)和二甲基马来酸酐(DMMA)改性的壳聚糖(FA-CS-DMMA)以及羧甲基壳聚糖(CMC)包裹, 得到pH响应型靶向纳米催化剂FA-CS-DMMA/CMC@Cu-MSN@DOX/AA(缩写为FCDC@Cu-MSN@DA)。扫描电镜显示纳米粒子FCDC@Cu-MSN@DA粒径约为100 nm。体外48 h内Cu²⁺释放量可达80%, 药物DOX释放达到57.3%。释放的AA经自氧化后产生H₂O₂, 诱导Cu²⁺发生类芬顿反应, 从而增强CDT。细胞实验证明, FCDC@Cu-MSN@DA联合化疗药物表现出优异的抗肿瘤活性, 说明该多功能纳米催化剂在癌症治疗中具有潜在应用前景。

关键词: 癌症治疗, 铜离子, 过氧化氢, 纳米催化剂, 化学动力学疗法

Abstract:

Chemodynamic therapy (CDT) uses endogenous H₂O₂ of tumor cells to react with Fenton catalysts to generate highly toxic hydroxyl radical (•OH), thereby killing cancer cells. However, the insufficient endogenous H₂O₂ and low transport efficiency of nanoparticles result in unsatisfactory anticancer efficacy. Here, we successfully synthesized a Cu²⁺ doped mesoporous silica nanoparticles (Cu-MSN) with excellent dispersity and small size. After loaded with doxorubicin (DOX) and ascorbate (AA), Cu-MSN was coated with folic acid (FA), dimethyl maleic anhydride (DMMA) modified chitosan (FA-CS-DMMA) and carboxymethyl chitosan (CMC) to obtain a pH responsive targeted nanocatalyst FCDC@Cu-MSN@DA. SEM images showed that particle size of FCDC@Cu-MSN@DA was about 100 nm. After 48 h in vitro, cumulative amount of Cu²⁺release reached 80% and DOX release was about 57.3% in the acidic environment. After oxidation of AA, the produced exogenous H₂O₂ induced Cu²⁺to catalytic the Fenton-like reaction, which enhanced the therapeutic effect of tumor chemodynamic therapy (CDT). Cell experiments in vitro demonstrated that FCDC@Cu-MSN@DA exhibited excellent anticancer ability in the combination of CDT and chemotherapy. This multifunctional nanocatalyst has great potential application in cancer therapy in the future.

Key words: tumor therapy, copper iron, hydrogen peroxide, nanocatalyst, chemodynamic therapy

中图分类号:

TQ174

何倩, 唐婉兰, 韩秉锟, 魏佳元, 吕文轩, 唐昭敏. pH响应铜掺杂介孔硅纳米催化剂增强肿瘤化疗-化学动力学联合治疗的研究[J]. 无机材料学报, 2024, 39(1): 90-98.

HE Qian, TANG Wanlan, HAN Bingkun, WEI Jiayuan, LÜ Wenxuan, TANG Zhaomin. pH Responsive Copper-Doped Mesoporous Silica Nanocatalyst for Enhanced Chemo-Chemodynamic Tumor Therapy[J]. Journal of Inorganic Materials, 2024, 39(1): 90-98.

图/表 8

图1 FCDC@Cu-MSN@DA纳米催化剂的制备及增强放大CDT与化疗协同作用的示意图

Fig. 1 Schematic illustration of synthetic procedure and mechanism for enhanced chemo-CDT of nanocatalyst FCDC@Cu-MSN@DA MSN: Mesoporous silica; DOX: Doxorubicin; AA: Ascorbic acid; FA: Folic acid; CS: Chitosan; DMMA: Dimethyl maleic anhydride; CMC: Carboxymethyl chitosan; CDT: Chemodynamic therapy

图2 Cu-MSN和FCDC@Cu-MSN@DA的表征

Fig. 2 Characterization of Cu-MSN and FCDC@Cu-MSN@DA (A, B) SEM images of Cu-MSN (A) and FCDC@Cu-MSN@DA (B); (C, D) Size distributions of Cu-MSN (C) and FCDC@Cu-MSN@DA (D); (E) Elemental (N, O, Si, and Cu) mappings of Cu-MSN; (F) XPS full survey of Cu-MSN; (G) High resolution XPS analysis on Cu2p of Cu-MSN; Colorful figures are available on website

图3 FCDC@Cu-MSN@DA的pH响应特性表征

Fig. 3 pH response of FCDC@Cu-MSN@DA (A) Zeta potential of Cu-MSN and FCDC@Cu-MSN@DA in pH 7.4, 6.5 and 5.0 solutions; (B-D) DOX (B), Cu2+ (C) and AA (D) released from FCDC@Cu-MSN@DA in different pH buffer solutions

图4 不同催化反应时间的FCDC@Cu-MSN@DA的电子自旋共振能谱(A), Cu-MSN和FCDC@Cu-MSN@DA的电子自旋共振能谱(B)

Fig. 4 ESR signals of FCDC@Cu-MSN@DA for different time (A), ESR spectra of Cu-MSN and FCDC@Cu-MSN@DA (B)

图5 FCDC@Cu-MSN@DA化学动力学性能

Fig. 5 Chemodynamic property of FCDC@Cu-MSN@DA (A) Absorbance of oxidized TMB after treatment with FCDC@Cu-MSN@DA (1 mg/mL) and H2O2 (100 μmol/L) in different pH solutions (pH 3.0, 4.0, 5.0, 6.5, and 7.4); (B) UV-Vis absorption spectra of TMB (oxTMB) catalyzed by (1) TMB+Cu-MSN+H2O2, (2) TMB+FCDC@Cu-MSN@DA, (3) TMB+AA, (4) TMB+H2O2, and (5) TMB in ABS solution (pH 5.0) Insets in (A) and (B) show the corresponding color changes under each pH; TMB: 3,3,5,5-Tetramethylbenzidine; ABS: Acetate buffer solution; Colorful figures are available on website

图6 A549、MCF-7 和4T1三种癌细胞吞噬Cu-MSN@DA和FCDC@Cu-MSN@DA的激光共聚焦显微照片

Fig. 6 Laser scanning confocal microscopic images of A549, MCF-7 and 4T1 cancer cells incubated with Cu-MSN@DA and FCDC@Cu-MSN@DA for 5 h DAPI: a staining to show cell neuclei; Actin: a staining to show cell plasm, especially the protein actin; DOX: a staining to show doxolubinson, an anticancer medicine

图7 不同样品处理4T1细胞后产生ROS的荧光照片

Fig. 7 Fluorescence images of generation of radical oxigen epecies (ROS) by 4T1 cells incubated with different samples G(1): PBS; G(2): DOX; G(3): FCDC@Cu-MSN@D; G(4): FCDC@Cu-MSN@A; G(5): CDC@Cu-MSN@DA; G(6): FCDC@Cu-MSN@DA

图8 FCDC@Cu-MSN@DA对4T1细胞的化疗-化学动力学协同治疗效果

Fig. 8 Effect of chemo-chemodynamic therapy on 4T1 cells by FCDC@Cu-MSN@DA (A, B) Cell viablity of normal cells (endothelial cell, EC) (A) and cancer cells (4T1 cells) (B) after incubation with different concentrations of Cu-MSN and FCFC@Cu-MSN@DA for 24 h; (C) Cell viability of 4T1 cells incubated with various formulations for 24 h; (D) Semi-quantitative analysis of live/dead cells; (E) Live/dead cell staining images of 4T1 cells after different treatments: G(1): Phosphate buffered saline (PBS); G(2): DOX; G(3): FCDC@Cu-MSN@D; G(4): FCDC@Cu-MSN@A; G(5): CDC@Cu-MSN@DA; G(6): FCDC@Cu-MSN@DA; Colorful figures are available on website

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pH响应铜掺杂介孔硅纳米催化剂增强肿瘤化疗-化学动力学联合治疗的研究

pH Responsive Copper-Doped Mesoporous Silica Nanocatalyst for Enhanced Chemo-Chemodynamic Tumor Therapy

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