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Selective targeting of glioblastoma using folate-decorated nano-particulate cytochrome c drug constructs

Y.V. Kucheryavykh1, J. Davila¹, M. Morales Cruz2, K. Rolon Reyes¹, M. Inyushin1, K. Griebenow2, L. Kucheryavykh¹.

¹Univ. Central del Caribe, Bayamón, PR; 2University of Puerto Rico, Rio Piedras, PR

We developed new targeted apoptosis-inducing drugs for glioblastoma (GBM) treatment and probed these drugs in GBM cell lines and animal model. Nano-sized protein particles containing cytochrome c (NPs) were decorated with the ligand folic acid (FA) for targeted delivery of the drug. 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.

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 tumor area. NPs, used in vitro in concentration of 100 µg/ml, have no cytotoxic effect in astrocytes but cause 40% death in tumor cells. The use of NPs in combination with LY294002 (PI3K/AKT blocker), 50µM, 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 micro-osmotic 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.

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