| Background:The incidence of cervical cancer ranks the fourth among female tumors and the first among female reproductive system tumors,which seriously endangers women’s life and health.Compared with pathological diagnosis,there is still a bottleneck in preoperative imaging diagnosis,and the diagnostic accuracy is generally not high.On the other hand,as the main treatment of cervical cancer,synchronous chemoradiotherapy plays an important role in the prevention and control of cervical cancer.However,the toxicity and side effects of traditional chemoradiotherapy are serious.How to further improve the efficacy,reduce the toxicity and improve the quality of life of patients is another major clinical problem in the field of cervical cancer prevention and treatment.In recent decades,the rapid development of nanotechnology has contributed to the overall progress of medicine.Nanoparticles have natural tumor targeting and unique pharmacokinetic characteristics,which have made great achievements in the field of diagnosis and treatment of malignant tumors.Inorganic nanoparticles,usually composed of metal elements,can be used as effective radiosensitizers and imaging sensitizers for cervical cancer imaging evaluation and radiotherapy,so as to realize the integration of cervical cancer diagnosis and treatment.Objective:Bi@Bi2S3-PEG heterojunction nanomaterials were prepared.The sensitization function of cervical cancer radiotherapy guided by computed tomography（CT）/photoacoustic dualmode imaging was verified and the related regulatory mechanism was explored.Methods:Bi@Bi2S3-PEG heterojunction nanoparticles were synthesized and characterized by Xray diffraction（XRD）pattern,transmission electron microscope（TEM）image,EDS and mapping,X-ray photoelectron spectroscopy（XPS）energy spectrum,dynamic light scattering（DLS）dynamic light scattering and zeta potential.The photocurrent response was detected by electrochemical test,and the species of reactive oxygen species was detected by electron spin resonance（ESR）.In vitro cell experiments,the cytotoxicity of Bi@Bi2S3-PEG heterojunction nanomaterials was detected by CCK-8 cell proliferation assay.The uptake of Bi@Bi2S3-PEG heterojunction nanoparticles by Hela cells was observed by confocal microscopy.Plate cell cloning assay was used to detect cell proliferation,cell apoptosis was detected by flow cytometry,DNA double-strand damage was detected by γ-H2AX,intracellular reactive oxygen species（ROS）production was detected by H2DCF-DA,immunofluorescence imaging of calreticulin（CRT）and high-mobility group box B1（HMGB1）was used to detect immunogenic death of tumor cells.In vivo treatment experiments,tumor volume and weight were compared to evaluate the effect of radiotherapy sensitization and anti-tumor,H&E staining to evaluate the destruction of tissue structure,TUNEL staining to detect tumor tissue apoptosis,CD8 and Foxp3 tissue immunofluorescence to detect cytotoxic T lymphocyte（CTL）and Treg cell infiltration.Finally,the in vitro CT/photoacoustic dual-mode imaging performance of the materials was tested using the small animal live CT imager and the ultrahigh resolution multi-mode ultrasonic photoacoustic imaging system for small animals.After injecting the materials into the tail vein,the enrichment in the tumor,the dual-mode imaging performance of the tumor and the biosafety effect in vivo were tested.Results:1.Bi@Bi2S3-PEG heterojunction nanoparticles were successfully prepared,and the Bi@Bi2S3 nanomaterial was spherical with a size of about 80nm and an average water and particle size of 132nm.After surface modification of PEG,the water and particle size increased to about 292nm,and the zeta potential was-9.37mV.It has good dispersion.The photochemical test and ESR showed that the heterojunction nanoparticles had good photoelectrical response and produced highly reactive OH under X-ray irradiation.2.Bi@Bi2S3-PEG heterojunction nanomaterials have good biological safety,in combination with low dose radiation（2gy）effectively restrain cervical cancer cell proliferation,through increasing tumor cell DNA damage and improve the level of reactive oxygen species in the cell,promote apoptosis and immunogenicity death,activate the antitumor immune response.3.Bi@Bi2S3-PEG heterojunction nanomaterials CT/photoacoustic signal had good linear relationship with concentration,after tail vein injection,at around 8～12h material in the tumor site has the largest concentration,24h basic back to the front of the injection rate.Conclusion:Bi@Bi2S3-PEG heterojunction nanomaterials can effectively promote the apoptosis of cervical cancer,inducing tumor cells immunogenicity death activate anti-tumor immune response,collaborative kill tumor radiotherapy sensitization,combined CT/photoacoustic imaging sensitization,double modal integrates cervical cancer diagnosis and treatment. |
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