Abstract
Glioblastoma is the most common and highly malignant brain tumor in adults. New targeted therapeutic approaches are imperative. EGFRvIII has appealing therapeutic targets using monoclonal antibodies. Thus, endeavors toward developing new mAbs therapies for GBM capable of targeting the tumor EGFRvIII biomarker must prevail to improve the patient's prognosis. Here, we isolated and characterized an anti-EGFRvIII vNAR from a non-immune freshwater stingray mixed library, termed vNAR R426. The vNAR R426 and pEGFRvIII interaction was demonstrated by molecular docking and molecular dynamics, and the recognition of EGFRvIII in vitro was further confirmed by cell immunofluorescence staining. Moreover, the vNAR R426 was shown to be an effective cisplatin drug carrier in the U87-MG glioma cell line. The cisplatin-coupled vNAR demonstrated highly significant differences when compared to free CDDP at 72 h. Notably, the cisplatin-vNAR carrier achieved better efficacy in the U87-MG cell line. Thus, we described the vNAR R426 internalization by receptor-mediated endocytosis and the subsequent COPI-mediated nuclear translocation of EGFRvIII and highlighted the importance of this shuttle mechanism to enhance the targeted delivery of cisplatin within the glioma cell's nucleus and improved cytotoxic effect. In conclusion, vNAR R426 could be a potential therapeutic carrier for EGFRvIII-targeted glioblastoma and cancer therapies.
Keywords:
EGFRvIII; Potamotrygon spp.; drug carrier; glioblastoma; modelling and molecular dynamics simulation; targeted drug delivery; variable new antigen receptor (vNAR).