Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma

• Published in: Molecular cancer therapeutics Vol. 17; no. 5; pp. 1012 - 1023
• Main Authors: Sagnella, Sharon M, Trieu, Jennifer, Brahmbhatt, Himanshu, MacDiarmid, Jennifer A, MacMillan, Alex, Whan, Renee M, Fife, Christopher M, McCarroll, Joshua A, Gifford, Andrew J, Ziegler, David S, Kavallaris, Maria
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2018
• Subjects: Adults; Animal models; Animals; Antibiotics, Antineoplastic - administration & dosage; Apoptosis; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Chemotherapy; Clinical trials; Disease control; Doxorubicin; Doxorubicin - administration & dosage; Drug delivery systems; Drug Delivery Systems - methods; Drug resistance; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Fluorescence; Humans; Male; Medical treatment; Mice; Mice, SCID; Microscopy; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; Pediatrics; Penetration; Proteins; Spheroids; Toxicity; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0738

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 ) 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 ( EDV ) 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 induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EDV In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EDV had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDV , 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 -treated animals compared to control, doxorubicin, or non-EGFR EDV There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV Moreover, overall survival was increased in neuroblastoma mice treated with EDV ( < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVs offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. .