Preoperative Administration Of A Biomimetic Platelet Nanodrug Enhances Postoperative Drug Delivery For Glioblastoma

Background:The postoperative thrombus attached to the damaged blood vessels severely obstructs macromolecular drugs from crossing the damaged blood-brain barrier(BBB)and targeting residual glioma cells around surgical margins,leading to glioblastoma(GBM)recurrence.To address this phenomenon,a thrombus-bypassing,BBB-crossing,and surgical margin-targeted nanodrug is needed.Methods:Electron electron microscopy(TEM)and dynamic light scattering instrument(DLS)were used to observe the morphology of platelet biomimetic nanodrugs and detect their size and surface potential;Western blot experiment was used to detect key proteins on the membrane;Fluorescence microscopy,flow cytometry,and CCK-8 experiments were used to detect their adhesion effect on a simulated postoperative environment,targeting ability,and killing ability of glioma cells.The GBM resection model was established to detect the targeting ability on surgical margins and tumor inhibition ability of nanodrugs in vivo.The mechanism of action of nanodrugs was studied by immunohistochemistry;The safety of nanodrugs was evaluated by HE staining.Results:We synthesized a platelet membrane-coated nanodrug(PM-HDOX)with a small particle size,negative surface potential,high stability,and preserved platelet membrane proteins,including CD62P and GPVI proteins.In vitro experiments,we found that PM-HDOX can target damaged vascular endothelial cells and IV collagen of the subendothelial matrix and has the ability to target and kill CD44-expressing GBM cells.In GBM resection models,PM-HDOX with preoperative administration demonstrated significantly enhanced BBB-crossing and surgical margin-targeted efficacy.In particular,the PM-HDOX intensities around the surgical margins of the preoperative administration group were more than twice that of the postoperative administration group,which is due to bypassing the thrombus formed in the broken BBB.In the antitumor experiment,the preoperative administration of PM-HDOX significantly inhibited the growth of postoperative residual tumors and prolonged the median survival time of mice.Meanwhile,PM-HDOX is also biosafe.Conclusion:Preoperative administration of a biomimetic platelet nanodrug can serve as an ideal and efficient drug delivery strategy for residual GBM after surgery.