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Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2018 May; Vol. 17 (5), pp. 1012-1023. Date of Electronic Publication: 2018 Feb 28. - Publication Year :
- 2018
-
Abstract
- 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 <superscript>TM</superscript> ) 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 <superscript>TM</superscript> ( <superscript>EGFR</superscript> EDV <superscript>TM</superscript> <subscript>Dox</subscript> ) 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. <superscript>EGFR</superscript> EDV <superscript>TM</superscript> <subscript>Dox</subscript> induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded <superscript>EGFR</superscript> EDV <superscript>TM</superscript> In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that <superscript>EGFR</superscript> EDV <superscript>TM</superscript> <subscript>Dox</subscript> had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDV <superscript>TM</superscript> <subscript>Dox</subscript> , 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 <superscript>EGFR</superscript> EDV <superscript>TM</superscript> <subscript>Dox</subscript> -treated animals compared to control, doxorubicin, or non-EGFR EDV <superscript>TM</superscript> <subscript>Dox</subscript> There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV <superscript>TM</superscript> <subscript>Dox</subscript> Moreover, overall survival was increased in neuroblastoma mice treated with <superscript>EGFR</superscript> EDV <superscript>TM</superscript> <subscript>Dox</subscript> ( P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVs <superscript>TM</superscript> offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther; 17(5); 1012-23. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Animals
Antibiotics, Antineoplastic administration & dosage
Apoptosis drug effects
Cell Line, Tumor
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Humans
Male
Mice, SCID
Neuroblastoma metabolism
Neuroblastoma pathology
Doxorubicin administration & dosage
Drug Delivery Systems methods
Neuroblastoma drug therapy
Xenograft Model Antitumor Assays
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 17
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 29491149
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-17-0738