期刊
MOLECULAR CANCER THERAPEUTICS
卷 17, 期 5, 页码 1012-1023出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-0738
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资金
- Balnaves Foundation
- NHMRC [APP1119152]
- Cancer Institute NSW Fellowship
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology [CE140100036]
- NHMRC Program [APP1091261]
- Cancer Council New South Wales Program [PG16-01]
- EnGeneIC Foundation
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 Dream Vector (EDV (TM)) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDV (TM) ((EDV)-E-EGFR (TM)(Dox)) 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. (EDV)-E-EGFR (TM)(Dox) induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded (EDV)-E-EGFR (TM). In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that (EDV)-E-EGFR (TM)(Dox) had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFRtargeted EDV (TM)(Dox), 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 (EDV)-E-EGFR (TM)(Dox)-treated animals compared to control, doxorubicin, or non-EGFR EDV (TM)(Dox). There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV (TM)(Dox). Moreover, overall survival was increased in neuroblastoma mice treated with (EDV)-E-EGFR (TM)(Dox) (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVs (TM) offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. (C) 2018 AACR.
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