Structure Changes Of Blood-brain Barrier And Chemotherapeutic Drugs Permeability In Lung Cancer Brain Metastases

Objective:Lung cancer is one of the most common malignant tumors and remains the leading cause of cancer-related lethality in the world.Most patients will eventually succumb to tumor metastasis,especially brain metastasis.There are few effective chemotherapeutic options because of the presence of blood-brain barrier(BBB).However,the study about the characteristics of the BBB in brain metastases and normal brain is also sparse.Our aim is to identify the difference of the barrier structure between normal brain and lung cancer brain metastasis.Meanwhile,we will study the distribution of clinical routine chemotherapeutic drugs in normal brain,brain metastasis and peripheral tumor.Methods:We used intraparenchymal and subcutaneous implantation of mouse lung cancer cells models.To verify and monitor the formation of lung cancer brain metastasis,in vivo bioluminescent imaging technical was used.The blood-brain barrier permeability of brain metastases were measured using fluorescent tracers of both low and high molecular sizes.Transmission electron microscope combined immuofluorescence and immuohistochemical were used to observe the structure of the barrier in normal brain and lung cancer brain metastasis.Liquid chromatography tandem mass spectrometry analysis was used to analysis the distribution of the chemotherapy drugs in normal brains,brain metastases and peripheral tumors.Results:Average bioluminescence of the imaged mice exhibited exponential growth over time.From day 4,the fluorescence of low molecular tracer could observe in brain metastasis,and after day 6,both high and low molecular tracers could penetrate,what’s more,the fluorescence couldn’t be observed in normal brain.The results show that the brain metastasis exhibited increased blood-brain-barrier permeability compared to normal brain and the permeability was changed over time.From the transmission electron microscope of the brain metastasis,we found that blood vessels at the central of the tumors were abnormal.Compared with normal brain,the endothelial cells in the metastatic lesions were damaged,the basement membranes were thicker and the interendothelial tight junctions were open.The immuofluorescence combined immuohistochemical displayed that the new vessels inside brain tumor were lack of astrocytes.Liquid chromatography tandem mass spectrometry analysis showed that the concentrations of paclitaxel,pemetrexed and gemcitabine were higher in peripheral tumor than in brain metastasis,and gemcitabine were more easily to penetrate to the metastasis.Conclusion:The lung cancer brain metastasis has a disrupted blood-brain barrier,and the permeability of the BBB was associated with the size of the tumor.The levels of chemotherapeutic drugs in brain metastasis were higher than that in normal brain.