Study On Gambogic Acid-loaded Mesoporous Nanoparticles For Chemotherapy-photothermal Synergistic Therapy Of Breast Cancer

Objective:Breast cancer（BC）is the most common cancer in women and poses a serious threat to women’s health.It seriously affects the therapeutic effect of breast cancer.At present,the existing traditional treatment methods still have many challenges,including poor selectivity,toxic and side effects.The rapid development of novel drug delivery systems based on nano-platform and the comprehensive application of multiple therapeutic methods bring hope for improving the therapeutic effect of breast cancer.This study prepared gambogic acid-loaded mesoporous polydopamine nanoparticles（GA@MPDA）for combined chemotherapy and photothermal therapy of BC.And the anti-tumor effect and mechanism of GA@MPDA on breast cancer were systematically studied at the cellular and animal levels.Methods:Firstly,MPDA was prepared by the one-pot method,and GA@MPDA was obtained by mixing GA and MPDA with mild stirring for 24 h at room temperature.The successful preparation of GA@MPDA was established by ultraviolet-visible spectrophotometry and Fourier Transform Infrared Spectroscopy.The particle size and structure of GA@MPDA were investigated by dynamic light scattering（DLS）and Transmission Electron Microscopy（TEM）.The photothermal effect in vitro was investigated by recording the temperature change of GA@MPDA solution after laser irradiation for 10 min.Secondly,the anti-tumor effects on 4T1 cells were studied through quantitative and qualitative analysis of cell uptake,reactive oxygen species（ROS）level,mitochondrial membrane potential（MMP）,intracellular Ca²⁺concentration,cell apoptosis and cytotoxicity,respectively.Finally,the in vivo photothermal effect,biological distribution,antitumor effect,biological safety and molecular mechanism were explored on a mouse breast cancer model.Results:MPDA and GA@MPDA nanoparticles with average particle sizes of186.821±16.171 nm and 323.306±2.121 nm were successfully prepared,which have good photothermal properties in vitro and in vivo.MPDA could promote the drug uptake of 4T1 cells,and GA@MPDA showed significant anti-tumor activity with laser irradiation,which promoted cell apoptosis,increased intracellular ROS as well as calcium ion concentration,and reduced MMP.Furthermore,MPDA could accumulate at the tumor site and reached its peak about 6 h after injection in vivo.GA@MPDA combined with laser irradiation showed a remarkable therapeutic effect on breast cancer with a tumor inhibition rate of 83.01%.Nanoparticles have good biosafety and low toxicity.GA@MPDA can promote Immunogenic cell death（ICD）and induce immunity in mice after laser irradiation.Conclusion:In summary,a simple preparation method of GA@MPDA nanoparticles was designed in this paper,which has a strong photothermal effect and antitumor activity.Experimental results showed that the combination of chemotherapy and photothermal therapy based on GA@MDPA had a good therapeutic effect on breast cancer,which could induce immunity in mice and promote ICD.In addition,GA@MDPA also had high biosafety,indicating that nanoparticles have a certain clinical application value.