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

doi:10.15541/jim20230151

Abstract

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

CLC Number:

TQ174

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.

Figures/Tables 8

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

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

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

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

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

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

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

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

References 31

[1]	LI Z L, WU H, ZHU J Q, et al. Novel strategy for optimized nanocatalytic tumor therapy: from an updated view. Small Science, 2022, 2(7):2200024. DOI URL
[2]	YANG B W, CHEN Y, SHI J L. Nanocatalytic medicine. Advanced Materials, 2019, 31(39):e1901778.
[3]	WU A, ZHU M, ZHU Y. Copper-incorporated calcium silicate nanorods composite hydrogels for tumor therapy and skin wound healing. Journal of Inorganic Materials, 2022, 37(11):1203. DOI
[4]	ZHU L P, DAI Y L, GAO L Z, et al. Tumor microenvironment- modulated nanozymes for NIR-II-triggered hyperthermia-enhanced photo-nanocatalytic therapy via disrupting ROS homeostasis. International Journal of Nanomedicine, 2021, 16: 4559.
[5]	TANG Z M, ZHAO P R, WANG H, et al. Biomedicine meets Fenton chemistry. Chemical Reviews, 2021, 121: 1981. DOI URL
[6]	BIAN Y L, LIU B, LIANG S, et al. Cu-based MOFs decorated dendritic mesoporous silica as tumor microenvironment responsive nanoreactor for enhanced tumor multimodal therapy. Chemical Engineering Journal, 2022, 435(2):135046. DOI URL
[7]	ZHANG W J, ZHAO X Y, LÜ J W, et al. Progresses on hollow periodic mesoporous organosilicas: preparation and application in tumor therapy. Journal of Inorganic Materials, 2022, 37(11):1192. DOI
[8]	LIU Y, WANG Y H, SONG S Y, et al. Cancer therapeutic strategies based on metal ions. Chemical Science, 2021, 12(37):12234. DOI PMID
[9]	SUN Q Q, WANG Z, LIU B, et al. Recent advances on endogenous/exogenous stimuli-triggered nanoplatforms for enhanced chemodynamic therapy. Coordination Chemistry Reviews, 2022, 451: 214267.
[10]	WANG Z, LIU B, SUN Q Q, et al. Fusiform-like copper(II) based metal-organic framework through relief hypoxia and GSH-depletion co-enhanced starvation and chemodynamic synergetic cancer therapy. ACS Applied Materials & Interfaces, 2020, 12(15):17254.
[11]	SHENOY N, CREAGAN E, WITZIG T, et al. Ascorbic acid in cancer treatment: let the phoenix fly. Cancer Cell, 2018, 34(5):700. DOI PMID
[12]	DOSKEY C M, BURANASUDJA V, WAGNER B A, et al. Tumor cells have decreased ability to metabolize H₂O₂: implications for pharmacological ascorbate in cancer therapy. Redox Biology, 2016, 10: 274.
[13]	YANG B W, SHI J L. Ascorbate tumor chemotherapy by an iron- engineered nanomedicine catalyzed tumor-specific pro-oxidation. Journal of the American Chemical Society, 2020, 142(52):21775. DOI URL
[14]	AI Y J, SUN H, GAO Z X, et al. Dual enzyme mimics based on metal-ligand cross-linking strategy for accelerating ascorbate oxidation and enhancing tumor therapy. Advanced Functional Materials, 2021, 31(40):2103581. DOI URL
[15]	WU M Q, DING Y M, LI L L. Recent progress in the augmentation of reactive species with nanoplatforms for cancer therapy. Nanoscale, 2019, 11: 19658.
[16]	FANG C, DENG Z, CAO G, et al. Co-ferrocene MOF/glucose oxidase as cascade nanozyme for effective tumor therapy. Advanced Functional Materials, 2020, 30: 1910058.
[17]	ZHANG C Y, YAN L, WANG X, et al. Tumor microenvironment-responsive Cu₂(OH)PO₄ nanocrystals for selective and controllable radiosentization via the X-ray-triggered Fenton-like reaction. Nano Letters, 2019, 19(3):1749. DOI URL
[18]	DONG S M, DONG Y S, JIA T, et al. GSH depleted nanozymes with hyperthermia-enhanced dual enzyme-mimic activities for tumor nanocatalytic therapy. Advanced Materials, 2020, 32(42):e2002439.
[19]	CHEN T, ZENG W W, LIU Y Q, et al. Cu-doped polypyrrole with multi-catalytic activities for sono-enhanced nanocatalytic tumor therapy. Small, 2022, 18(29):2270152. DOI URL
[20]	NIU J X, SUN S, LIU P F, et al. Copper-based nanozymes: properties and applications in biomedicine. Journal of Inorganic Materials, 2023, 38(5):489. DOI
[21]	XU W J, WANG Y P, HOU G H, et al. Tumor microenvironment responsive hollow nanoplatform for triple amplification of oxidative stress to enhance cuproptosis-based synergistic cancer therapy. Advanced Healthcare Materials, 2023, doi.org/10.1002/adhm.202202949.
[22]	XU W J, QIAN J M, HOU G H, et al. A hollow amorphous bimetal organic framework for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy via disrupting intracellular redox homeostasis and copper/iron metabolisms. Advanced Functional Materials, 2022, 32(40):2205013. DOI URL
[23]	SHAO L J, HU T S, FAN X Y, et al. Intelligent nanoplatform with multitherapeutic modalities for synergistic cancer therapy. ACS Applied Materials & Interfaces, 2022, 14(11):13122.
[24]	MIAO Y L, QIU Y D, YANG W J, et al. Charge reversible and bio-degradable nanocarriers showing dual pH-/reduction-sensitive disinte-gration for rapid site-specific drug delivery. Colloids and Surfaces B: Biointerfaces, 2018, 169: 313.
[25]	TESTA U, PELOSI E, CASTELLI G. New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug. Hematology/Oncology and Stem Cell Therapy, 2021, 14(3):179. DOI PMID
[26]	LEVINE M, VIOLET P C. Data Triumph at C. Cancer cell, 2017, 31(4):467. DOI PMID
[27]	WANG Y W, CHEN J J, TIAN Z F, et al. Potassium ferrate-loaded porphyrin-based (VI) metal-organic frameworks for combined photodymanic and chemodynamic tumor therapy. Journal of Inorganic Materials, 2021, 36(12):1305. DOI
[28]	WU W C, YU L D, JIANG Q Z, et al. Enhanced tumor-specific disulfiram chemotherapy by in situ Cu²⁺ chelation-initiated nontoxicity-to-toxicity transition. Journal of The American Chemical Society, 2019, 141(29):11531. DOI URL
[29]	CHENG L C, MA H, SHAO M K, et al. Synthesis of folate-chitosan nanoparticles loaded with ligustrazine to target folate receptor positive cancer cells. Molecular Medicine Reports, 2017, 16(2):1101. DOI URL
[30]	HONG J Y, SUN Z H, LI Y J, et al. Folate-modified annonaceous acetogenins nanosuspensions and their improved antitumor efficacy. International Journal of Nanomedicine, 2017, 12(1):5053. DOI PMID
[31]	ZHANG L Z, YANG A J, RUAN C P, et al. Copper-nitrogen- coordinated carbon dots: transformable phototheranostics from precise PTT/PDT to post-treatment imaging-guided PDT for residual tumor cells. ACS Applied Materials & Interfaces, 2023, 15 (2): 325.