Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC delivery vehicle (EDVTM) is a nanocell which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase 1 trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein (SK-N-BE(2), high; SH-SY-5Y, low) were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin or non-doxorubicin loaded EGFREDVTM. In 3D-tumor spheroids, imaging and Fluorescence Life-time Microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox treated animals compared to control, doxorubicin or non-EGFR EDVTMDox. There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin or non-EGFR EDVTMDox. Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2F34XS9
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