HGG-05. GLUCOSE CONJUGATION FOR THE SPECIFIC TARGETING AND TREATMENT OF GLIOBLASTOMA

Abstract

Abstract BACKGROUND Malignant brain tumors, such as Glioblastoma (GBM), are a major challenge in oncology with a dismal prognosis. This can be in part explained by the inability to deliver more effective drugs, as Doxorubicin (DOX), into the brain because of resistance mechanisms. Malignant tumors as GBM also show an elevated glycolytic rate through glucose transporters and GLUT1 is reported to be the main mediator of BBB glucose uptake. For these reasons, we have developed an innovative approach able to increase drug efficiency and selectivity, by conjugating the anticancer agents DOX to glucose. METHODS Two glycoconjugates (EB73 and EB74) were synthesized, using an oxime-based linkers between position 6 of glucose and carbonyl group of DOX, and characterized for absorbance, fluorescence and binding affinity to ctDNA. The cytotoxic effect of EB73 and EB74 was evaluated in two GBM cell lines (A172 and T98G). These cells were also used to study the effect of glucose deprivation on GLUT1 and breast cancer resistance protein (BCRP) expression. Moreover, cellular uptake of the glicoconjugates was evaluate in an in vitro BBB model and by immunofluorescence (IF) in GBM cells. RESULTS Our results indicated that EB73 and EB74 maintained Ka binding constants comparable to DOX, confirming that functionalization with glucose did not alter DOX intercalation capability and fluorescence. The cytotoxicity results demonstrated that EB74 has the major effect in A172 and T98G DOX-resistant cells starting from 24h of treatment. Moreover, glucose deprivation showed a GLUT1 overexpression and BCRP downregulation in both cell lines improving EB74 efficacy. BBB in vitro model and IF experiments revealed that only EB74 is able to accumulate in cells nuclei as conventional DOX CONCLUSION In conclusion, these results indicated that glycoconjugation of DOX and glucose deprivation may be helpful instruments to increase drugs uptake and effectiveness in aggressive and chemoresistant tumor cells.