| Background: Breast cancer is the most common malignant tumor in women.Drug resistance,recurrence and metastasis are increasingly more serious.How to further improve the treatment effect is facing major challenges,and new treatment strategies need to be developed.In recent years,studies have found that silver nanoparticles have strong anti-cancer properties without drug resistance.More importantly,the combination of silver nanoparticles and chemotherapeutic drug can produce a synergistic anti-cancer effect,so they have attracted the attention of researchers.As a photothermal conversion medium with great development potential,silver nanotriangles(Ag NTs)also have good photothermal properties due to their anisotropy and special geometric shapes.It is reported in the literature that hyperthermia can be complementary to chemotherapy to reduce toxicity and increase therapeutic efficacy.Taking full advantages of the above two synergies will help to greatly improve the therapeutic effect of breast cancer.Nucleolin is overexpressed in the cytoplasm of cancer cells and transferred to the cell membrane,and the expression is stable.Aptamer AS1411 can specifically bind to nucleolin on the surface of cancer cells and can be used as an effective ligand for Ag NTs to actively target breast cancer cells.Objective: To screen out the chemotherapeutic drug with high-efficiency and broad-spectrum synergistic anti-breast cancer effect with Ag NTs,and to explore their synergistic mechanism.The AS1411 targeted drug-loaded Ag NTs composites will be constructed to study the effect of combined photothermal-chemotherapy on breast cancer.Methods: The chitosan-coated Ag NTs were synthesized and characterized by transmission electron microscopy,followed by X-ray diffraction and ultraviolet-visible spectroscopy,etc.The anti-cancer effects of Ag NTs combined with five chemotherapeutic drugs(cyclophosphamide,gemcitabine,5-fluorouracil,oxaliplatin and doxorubicin)on a variety of breast cancer cell lines(MDA-MB-231,MCF-7 and 4T1)were studied.The drug with the most broad-spectrum and strongest synergistic activity was screened out,and used for subsequent research.The effects of the combination of the nanomaterials and chemotherapeutic drug on the level of intracellular reactive oxygen species and cell apoptosis were detected using flow cytometry.The drug-loaded AS1411-modified Ag NTs(AS1411-Ag NTs)were constructed,their drug loading and drug release were examined by ultraviolet spectrophotometry,and then the cell uptake was observed using dark-field microscopy.MTT assay was utilized to assess the anti-cancer effect of photothermotherapy combined with chemotherapy of the composite on MDA-MB-231 breast cancer cells.Results: The synthesized Ag NTs were triangular in shape,with a mean edge length of 126 nm,and were face-centered cubic crystal structures.The four characteristic ultraviolet absorption peaks were located at 333 nm,410 nm,509 nm and 786 nm.The synergistic anti-breast cancer effect of Ag NTs plus cyclophosphamide or gemcitabine was found to be cell type-specific,while 5-fluorouracil,oxaliplatin and doxorubicin displayed synergistic effects with Ag NTs on viabilities of all breast cancer cell lines tested,and doxorubicin was the strongest in general.The combination of Ag NTs and doxorubicin could significantly elevate the intracellular reactive oxygen species level and induce cell apoptosis,and the synergic effect could be greatly reversed by reactive oxygen species scavenger.The Ag NTs displayed excellent photothermal performance,with a photothermal conversion efficiency of 50.6%.The ultraviolet-visible absorption spectrum suggested that AS1411 was successfully connected to Ag NTs.The AS1411 modification could increase the uptake of Ag NTs by MDA-MB-231 breast cancer cells,which reached the peak level at 12 h incubation time.The drug release of drug-loaded AS1411-Ag NTs was p H and temperature-sensitive,and the combined photothermal-chemotherapy could significantly kill breast cancer cells.Conclusions: The combination of Ag NTs and doxorubicin exhibits a highly effective and broad-spectrum synergistic anti-breast cancer effect,which is proved to mainly result from reactive oxygen species-mediated cell apoptosis.Drug-loaded AS1411-Ag NTs can efficiently target and kill breast cancer cells through Ag NTs-chemotherapy synergy and photothermal-chemotherapy synergy.This study provides new methods and ideas for the treatment of breast cancer. |
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