Radiosensitization Effect Of A Novel Gadolinium-based Nanoparticle-AGuIX On NSCLC Cell Lines

Radiotherapy is a major treatment regimen for cancer patients.The resistance of human non-small cell lung cancer tumors to radiation is an important challenge in the treatment of NSCLC.However,the radiation dose deliverable to the tumors is often limited by the possibility of collateral damages to surrounding healthy tissues.So it is very important to find an effective radiosensitizer.A new efficient type of gadolinium-based nanoparticle:AGuIX has recently been developed for MRI-guided radiotherapy(RT)and has been proven to act as efficient radiosensitizer.It has been established that the amplification of radiation effects by AGuIX nanoparticles appears due to the emission of low energy photoelectrons and Auger electron interactions.We demonstrated that AGuIX nanoparticles exacerbate radiation-induced DNA DSBs damage and reduces DNA repair in non-small cell lung cancer cell H1299.And we observed that pretreatment of AGuIX nanoparticles prior to radiation therapy significantly aggravated tumor cell damage and had a significant improvement in tumor growth suppression in the H1299 xenograft nude mouse model.Our research paves the way for the radiosensitization mechanism of AGuIX nanoparticles,and provides scientific basis for AGuIX nanoparticles as a radiosensitizing drug.Purpose:To clarify the radiosensitization of AGuIX nanoparticles on non-small cell lung cancer H1299 in vitro and in vivo.Studying preliminarily on the radiosensitization mechanism of AGuIX nanoparticles in H1299.Methods:The cells were assigned to four groups as following:Control,AGuIX nanoparticles,Radiation and AGuIX nanoparticles combined Radiation.Clonogenic assay for cell proliferation and flow cytometry for determination of apoptosis were used to examine radiosensitization of AGuIX nanoparticles to H1299 cell line.Flow cytometry was used to determine the effect of AGuIX nanoparticles on the cell cycle of H1299.Immunofluorescence assays and Comet assays were used to observe DNA damage repair.Furthermore,we used western blotting assay to examine the protein expression of DNA damage repair related proteins.Tumor growth and DNA damage in tumor tissues were observed in nude mice in different treated groups in vivo.Results:AGuIX nanoparticles was discovered to have radiosensitization in H1299 through clonogenic survival assays,and flow cytometry detected more apoptosis cells utilizing radiation combined AGuIX nanoparticles.Pretreatment of AGuIX nanoparticles before radiation delayed arrest of G2/M phase cells of H1299 compared to using radiation alone in the cell cycle assay by flow cytometry.There was significant difference in average yH2AX foci number after irradiation with or without AGuIX nanoparticles,which in AGuIX nanoparticles combined radiation group was significantly more than in individual radiation group.Comet assays demonstrated that AGuIX nanoparticles exacerbates radiation-induced DNA damage,and reduces DNA damage repair.As in vivo experiments,remarkable suppression of tumor growth and DNA damage in tumor tissues were discovered in the combination treatment group of AGuIX nanoparticles and radiation,which is statistically significantly greater than any treatment alone.Conclusions:Our data implied that AGuIX nanoparticles is a novel radiosensitizer to non-small cell lung cancer The radiosensitization mechanism of AGuIX nanoparticles involves aggravated DNA damage and reduced DNA damage repair,and the concrete signal pathways remain to be studied.Anyhow,our study provides the proof-of-concept for future development of AGuIX nanoparticles as a new radiosensitizing agent against cancer cells.