DDEL-11SELECTIVE TARGETING OF GLIOBLASTOMA USING FOLATE-DECORATED NANO-PARTICULATE CYTOCHROME C DRUG CONSTRUCTS

Abstract

DDEL-11. SELECTIVE TARGETING OF GLIOBLASTOMA USING FOLATE-DECORATED NANO-PARTICULATE CYTOCHROME C DRUG CONSTRUCTS Josue Davila1, Kimberleve Rolon Reyes1, Moraima Morales Cruz2, Michael Inyushin1, Yuriy Kucheryavykh1, Kai Griebenow2, and Lilia Kucheryavykh1; UniversidadCentraldel Caribe,Bayamon,Puerto Rico; University of Puerto Rico, Rio Piedras, Puerto Rico BACKGROUND: Glioblastoma (GBM) is one of the most malignant forms of brain cancers due to resistance to chemoand radiotherapy, mostly caused by enhanced resistance to apoptosis. We propose the development of targeted apoptosis-inducing drugs for glioblastomatreatment andapprobationof these drugs in glioblastoma cell lines and animal model. We developed nano-sized protein particles containing cytochrome C (NPs). For targeted delivery of the drug specifically to GBM cells we decorated the drug nano-particles with the ligand folic acid (FA). Many GBMs express Proton Coupled Folate Transporters that provide selective internalization of the designed NPs. Protein drug stability problems were countered by covalently decorating the constructs with glycans. RESULTS: Confocal imaging revealed the specific up-take of FITC tagged FA-NPs by GL261 cells, but not by primary cultured astrocytes. Examination of live brain slices encompassing glioblastoma tumor showed some non-specific accumulation of NPs in healthy tissue in two hours after application of FA-NPs, but 20-times less compared to the tumorarea.NPs, used invitro inconcentration of100 mg/ml,havenocytotoxic effect in astrocytes but cause 40% death in tumor cells. The use of NPs in combination with LY294002 (PI3K/AKT blocker), 50 mM, caused 90% death in tumor cells. In vivo TUNEL investigation of tumors generated in C57Bl/6 mice by implantation of GL261 cells revealed the strong signs of apoptosis after three days of in-site administration of NPs through the microosmotic pumps without the evident signs of apoptosis in healthy tissue. In CONCLUSION: We can state that the designed NPs demonstrate good specificity for GL261 cells, effectively cause the apoptosis in these cells when used in combination with LY294002, and give a good baseline for the development of efficient methods for treating GBM. Acknowledgement: NIH Grant Numbers 1SC2GM102040-01A1, SC2GM095410-01A1, 8G12MD007583-27, R25GM110513, Title V grant number P031S130068. Neuro-Oncology 17:v73–v77, 2015. doi:10.1093/neuonc/nov212.11 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.