The Structure of Blood–tumor Barrier and Distribution of Chemotherapeutic Drugs in Non-small Cell Lung Cancer Brain Metastases

Abstract

\n Background: Brain metastasis is an important cause increasing the mortality of non-small cell lung cancer (NSCLC) patients. In brain metastasis, blood-brain barrier (BBB) is frequently impaired, while blood-tumor barrier (BTB) formed and leading to poor effects of chemotherapy. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. Methods: Bioluminescent image was used to confirm the formation of brain metastases of transplanted lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The content of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues was assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS).Results: Brain metastasis exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine and paclitaxel showed higher permeability in brain metastatic lesions.Conclusions: Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.