Engineered extracellular vesicles for nose-to-brain co-delivery of chlorotoxin and curcumin for treatment of glioblastoma.

AIM: Extracellular vesicles (EVs) were developed as a co-delivery carrier of curcumin and chlorotoxin (CTX) into the brain.

MATERIALS &

METHODS

CTX was linked to the surface of EVs by genetic engineering. Curcumin was loaded onto CTX-linked EVs (CTX-EV) by hydrophobic interaction. Dynamic light scattering, flow cytometry, and cytotoxicity assay were performed in vitro characterization. The therapeutic effect was evaluated in the glioblastoma animal models.

RESULTS

The size and zeta-potential of curcumin-loaded CTX-EV (CTX-EV/Cur) were around 295 nm and -35 mV. The curcumin delivery efficiency of CTX-EV/Cur was higher than that of curcumin alone or Unmod-EV/Cur, suggesting that CTX facilitated the cellular uptake of CTX-EV/Cur. Cytotoxicity assay showed that the viability of C6 glioblastoma cells was decreased by CTX-EV compared with Unmod-EV. The results suggest that CTX has an anti-tumor effect. Finally, anti-tumor therapeutic effects of CTX-EV/Cur were evaluated in glioblastoma animal models after intranasal administration. We found that CTX-EV/Cur enhanced expression of the programmed cell death protein 4 (PDCD4) gene and induced apoptosis in the tumor compared with the other groups. In addition, the tumor size was effectively decreased by CTX-EV/Cur.

CONCLUSION

The results suggest that CTX is not only an anti-tumor drug, but also a targeting ligand for enhanced cellular uptake. Therefore, enhanced therapeutic effects of CTX-EV/Cur may be due to synergistic effects of CTX and curcumin. Combined delivery of curcumin and CTX using CTX-EVs may be useful for treatment of glioblastoma.