| Objective: In this work,a redox-stimuli responsive multifunctional mesoporous upconversion nanoparticles-based drug controlled release system was developed.The physicochemical properties,in vitro/vivo anti-tumor effect and in vivo imaging were investigated to study the synergetic therapy guided by UCL/MR/PAT imaging.Methods:(1)Core-shell mUCNPs were prepared in the process of high temperature thermal decomposition,which were characterized through spectrofluorimetry,X-ray photoelectron spectroscopy(XPS),X ray diffraction(XRD),dynamic light scattering(DLS),transmission electron microscopy(TEM),N2 adsorption-desorption.mUCNPs were modified with The disulfide bond,and linked to CuS and HA.The m UCNPs@DOX/CuS/HA was characterized through ultraviolet spectrophotometry,spectrofluorimetry,fourier transform infrared spectroscopy(FT-IR),dynamic light scattering(DLS),transmission electron microscopy(TEM).Drug loading and drug release were measured by HPLC.(2)Study of anti-tumor activity and targeting: The effects of the system on the cell viability were investigated by SRB with MCF-7 cells.The uptake of the cells was investigated by laser confocal microscopy and flow cytometry.The effects of the system on the cell cycle and cell apoptosis were also investigated with MCF-7cells.(3)Pharmacokinetic study: SD rats were used as the animal model to carry out pharmacokinetic experiments,and the drug concentration of the plasma was determined by HPLC.The chamber model was fitted with PK Solver software and the pharmacokinetic parameters were calculated.(4)Pharmacodynamics and in vivo imaging studies: S180 tumor-bearing mice used as animal models,the toxicity and tumor inhibition of the diagnosis and treatment system were investigated by changes of tumor relative volume and HE staining.The UCL/MR/PAT imaging and targeting effect were also studied.Results: The results showed that the mesoporous layer of NaGdF4 could improve the upconversion luminescence intensity.mUCNPs remained hexagonal structure.The adsorption capacity of mUCNPs was proved by nitrogen adsorptionand desorption experiments.Ultraviolet spectroscopy,FT-IR and TGA results showed that CuS and HA were successfully modified on the surface of mUCNPs,with mean size of 60 nm.The photothermal and thermal stability were proved.In addition,the drug carriers have the ability of MR imaging,showing good stability.DOX was released at largest amount at pH 5.0 in the presence of laser and10 mM GSH,which could be accelerated by the photothermal effect,indicating that the drug delivery system could response to tumor cell microenvironment.The results of cell cytotoxicity test showed that mUCNPs@CuS/HA had good biocompatibility.When combining chemotherapy with hyperthermia,mUCNPs@DOX/ CuS/HA showed a strong cytotoxic effect under 980 nm laser irradiation,revealing excellent antitumor effect.The results of cellular uptake showed that the accumulation of mUCNPs@DOX/CuS/HA was the highest in MCF-7 cells.By investigating the effects of the diagnosis and treatment systems on cell cycle and apoptosis,it was further demonstrated that synergetic chemo-thermotherapy.The pharmacokinetic results of mUCNPs@DOX/CuS/HA in vivo showed that mUCNPs@DOX/CuS/HA prolonged the time of drug in vivo and slowed the clearance of the drug.When combined with 980 nm laser,mUCNPs@DOX/CuS/HA showed synergetic chemo-thermotherapy effect,revealing strong anti-tumor capacity.The changes of body weight and HE staining showed that the drug delivery system had almost no toxic and side effects on normal tissues and organs.In addition,In vivo imaging results showed that mUCNPs@DOX/CuS/HA reached a maximum imaging capacity and targeting effect at the tumor site at 2 h after injection.Conclusions: We have succeeded in developing multifunctional tumor-targeted and redox-stimuli responsive drug delivery system(mUCNPs@DOX/CuS/HA)for UCL/MR/PAT guided synergetic chemo-thermotherapy and real-time assessment of tumor therapeutic effect. |
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