Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma
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 D...
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Published in | Molecular cancer therapeutics Vol. 17; no. 5; pp. 1012 - 1023 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Association for Cancer Research Inc
01.05.2018
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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
) 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.
. |
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AbstractList | 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.
. 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 (EDVTM) 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 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 three-dimensional 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. Mol Cancer Ther; 17(5); 1012–23. ©2018 AACR. |
Author | Whan, Renee M Gifford, Andrew J Brahmbhatt, Himanshu McCarroll, Joshua A MacMillan, Alex Fife, Christopher M MacDiarmid, Jennifer A Kavallaris, Maria Sagnella, Sharon M Trieu, Jennifer Ziegler, David S |
Author_xml | – sequence: 1 givenname: Sharon M surname: Sagnella fullname: Sagnella, Sharon M organization: EnGeneIC Ltd., Sydney, New South Wales, Australia – sequence: 2 givenname: Jennifer surname: Trieu fullname: Trieu, Jennifer organization: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, University of New South Wales Sydney, New South Wales, Australia – sequence: 3 givenname: Himanshu surname: Brahmbhatt fullname: Brahmbhatt, Himanshu organization: EnGeneIC Ltd., Sydney, New South Wales, Australia – sequence: 4 givenname: Jennifer A surname: MacDiarmid fullname: MacDiarmid, Jennifer A organization: EnGeneIC Ltd., Sydney, New South Wales, Australia – sequence: 5 givenname: Alex surname: MacMillan fullname: MacMillan, Alex organization: Biomedical Imaging Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia – sequence: 6 givenname: Renee M surname: Whan fullname: Whan, Renee M organization: Biomedical Imaging Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia – sequence: 7 givenname: Christopher M surname: Fife fullname: Fife, Christopher M organization: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, University of New South Wales Sydney, New South Wales, Australia – sequence: 8 givenname: Joshua A surname: McCarroll fullname: McCarroll, Joshua A organization: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, University of New South Wales Sydney, New South Wales, Australia – sequence: 9 givenname: Andrew J surname: Gifford fullname: Gifford, Andrew J organization: Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia – sequence: 10 givenname: David S surname: Ziegler fullname: Ziegler, David S organization: Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia – sequence: 11 givenname: Maria surname: Kavallaris fullname: Kavallaris, Maria email: m.kavallaris@ccia.unsw.edu.au organization: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, University of New South Wales Sydney, New South Wales, Australia |
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References | MacDiarmid (2022060800571592400_bib4) 2007; 6 Digman (2022060800571592400_bib15) 2008; 94 Pecot (2022060800571592400_bib3) 2011; 11 Oeffinger (2022060800571592400_bib17) 2004; 2 Sagnella (2022060800571592400_bib18) 2014; 10 Ha (2022060800571592400_bib5) 2016; 6 Sagnella (2022060800571592400_bib14) 2014; 15 MacDiarmid (2022060800571592400_bib7) 2016; 11 Byrne (2022060800571592400_bib11) 2014; 33 Armenian (2022060800571592400_bib2) 2015 Shusterman (2022060800571592400_bib16) 2010; 28 McCarroll (2022060800571592400_bib13) 2015; 6 Boyer (2022060800571592400_bib12) 2013; 10 Whittle (2022060800571592400_bib9) 2015; 22 Ratner (2022060800571592400_bib1) 2016; 80 MacDiarmid (2022060800571592400_bib6) 2007; 11 Byrne (2022060800571592400_bib10) 2016; 1372 Solomon (2022060800571592400_bib8) 2015; 10 |
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SubjectTerms | 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 |
Title | Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma |
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