Mn Doped Mesoporous Silica Nanoparticles For Dual-modal Imaging Guided Chemical-photothermal Combination Therapy In Melanoma

Objective: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate.Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease.In this study,we fabricated a multifunctional drug delivery system that incorporates dacarbazine(DTIC)and indocyanine green(ICG)into manganese-doped mesoporous silica nanoparticles(MSN(Mn))coupled with magnetic resonance imaging(MRI)and photothermal imaging(PI),for achieving the superior antitumor effect of combined chemo-photothermal therapy.Methods: firstly,mesoporous silica(MSN)was synthesized by hydrothermal reaction to modify manganese ion,and MSN(Mn),was obtained by encapsulating photothermal agent indocyanine green(ICG)and chemotherapeutic drug dacarbazine(DTIC)at a certain mass ratio.Finally,MSN(Mn)-ICG/DTIC,was obtained.The size and morphology of MSN nanoparticles and MSN(Mn)nanoparticles were characterized by particle size analyzer transmission electron microscope and inductively coupled plasma mass spectrometry(ICP-MS).The drug loading and entrapment efficiency of nanoparticles were measured and calculated by ultraviolet spectrophotometer,and the mixed oxidation state was determined by X-ray photoelectron spectroscopy(XPS).The formation of biological complex of synthetic particles was further confirmed by Fourier transform infrared spectroscopy.Thermal imaging effect,photothermal effect and thermal stability of nanoparticles were studied by thermal imager.The use of MRI imaging system to explore it can be used as a contrast agent to achieve magnetic resonance imaging effect.In vitro experiment:MTT colorimetric assay was used to determine the toxicity of blank nanoparticles MSN(Mn)on human normal epidermal cells Ha Ca T cells and the killing effect of drug-loaded nanoparticles on melanoma cells A375.In vivo experiment: the mouse melanoma model was randomly divided into 5 groups: PBS+Laser,MSN(Mn)-ICG/DTIC only,MSN(Mn)-ICG+Laser,DTIC only and MSN(Mn)-ICG/DTIC+Laser.The changes of tumor size and body weight were recorded every day and observed continuously for 2 weeks.On the 14 th day,the mice were examined by skin ultrasound,and then the mice were killed.The solid tumor was dissected completely and histopathological examination was performed.Results: The as-synthesized MSN(Mn)were characterized as mesoporous spherical nanoparticles with 125.57±5.96 nm.MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25±2.20 %and 50.00±3.24 %,and 32.68±2.10% of DTIC was released respectively.Manganese doping content could reach up to 65.09±2.55 wt%,providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 m M-1s-1.And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells.Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro.Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.