Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles

J. M. Warram, A. G. Sorace, R. Saini, A. V. Borovjagin, K. Hoyt, K. R. Zinn

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

One of the major limitations of cancer gene therapy using recombinant human adenovirus (Ad) is rapid Ad inactivation from systemic delivery. To eliminate this, biotin-coated ultrasound contrast agents, or microbubbles (MBs), were streptavidin-coupled with biotinylated antibodies to three distinct tumor vasculature-associated receptors (α V Β 3 integrin, P-selectin and vascular endothelial growth factor receptor-2) for systemic targeting of a previously generated vector Ad5/3-Id1-SEAP-Id1-mCherry. This cancer-specific, dual-reporter vector was loaded in the targeted MBs and confirmed by confocal microscopy. MB loading capacity was estimated by functional assays as 4.720.2 plaque forming unit (PFU) per MB. Non-loaded (free) Ad particles were effectively inactivated by treatment with human complement. The Ad-loaded, targeted-MBs were injected systemically in mice bearing MDA-MB-231 tumors (Grp 1) and compared with two control groups: Ad-loaded, non-targeted MBs (Grp 2) and free Ad (Grp 3) administered under the same conditions. Two days after administration the blood levels of secreted embryonic alkaline phosphatase (SEAP) reporter in Grp 1 mice (16.1 ng ml-1 2.5) were significantly higher (P<0.05) than those in Grp 2 (9.75 ng ml-1 1.5) or Grp 3 (4.26 ng ml-1 2.5) animals. The targeted Ad delivery was also confirmed by fluorescence imaging. Thus, Ad delivery by targeted MBs holds potential as a safe and effective system for systemic Ad delivery for the purpose of cancer screening.

Original languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalCancer Gene Therapy
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Microbubbles
Adenoviridae
Breast Neoplasms
Alkaline Phosphatase
Human Adenoviruses
Vascular Endothelial Growth Factor Receptor-2
Neoplasms
P-Selectin
Streptavidin
Neoplasm Genes
Optical Imaging
Biotin
Early Detection of Cancer
Confocal Microscopy
Integrins
Genetic Therapy
Contrast Media
Control Groups
Antibodies

Keywords

  • adenovirus
  • detection
  • fluorescence
  • microbubble

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

Warram, J. M., Sorace, A. G., Saini, R., Borovjagin, A. V., Hoyt, K., & Zinn, K. R. (2012). Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles. Cancer Gene Therapy, 19(8), 545-552. https://doi.org/10.1038/cgt.2012.29

Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles. / Warram, J. M.; Sorace, A. G.; Saini, R.; Borovjagin, A. V.; Hoyt, K.; Zinn, K. R.

In: Cancer Gene Therapy, Vol. 19, No. 8, 01.08.2012, p. 545-552.

Research output: Contribution to journalArticle

Warram, JM, Sorace, AG, Saini, R, Borovjagin, AV, Hoyt, K & Zinn, KR 2012, 'Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles', Cancer Gene Therapy, vol. 19, no. 8, pp. 545-552. https://doi.org/10.1038/cgt.2012.29
Warram, J. M. ; Sorace, A. G. ; Saini, R. ; Borovjagin, A. V. ; Hoyt, K. ; Zinn, K. R. / Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles. In: Cancer Gene Therapy. 2012 ; Vol. 19, No. 8. pp. 545-552.
@article{5fc678f080684faebdcf39127d3fbb90,
title = "Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles",
abstract = "One of the major limitations of cancer gene therapy using recombinant human adenovirus (Ad) is rapid Ad inactivation from systemic delivery. To eliminate this, biotin-coated ultrasound contrast agents, or microbubbles (MBs), were streptavidin-coupled with biotinylated antibodies to three distinct tumor vasculature-associated receptors (α V Β 3 integrin, P-selectin and vascular endothelial growth factor receptor-2) for systemic targeting of a previously generated vector Ad5/3-Id1-SEAP-Id1-mCherry. This cancer-specific, dual-reporter vector was loaded in the targeted MBs and confirmed by confocal microscopy. MB loading capacity was estimated by functional assays as 4.720.2 plaque forming unit (PFU) per MB. Non-loaded (free) Ad particles were effectively inactivated by treatment with human complement. The Ad-loaded, targeted-MBs were injected systemically in mice bearing MDA-MB-231 tumors (Grp 1) and compared with two control groups: Ad-loaded, non-targeted MBs (Grp 2) and free Ad (Grp 3) administered under the same conditions. Two days after administration the blood levels of secreted embryonic alkaline phosphatase (SEAP) reporter in Grp 1 mice (16.1 ng ml-1 2.5) were significantly higher (P<0.05) than those in Grp 2 (9.75 ng ml-1 1.5) or Grp 3 (4.26 ng ml-1 2.5) animals. The targeted Ad delivery was also confirmed by fluorescence imaging. Thus, Ad delivery by targeted MBs holds potential as a safe and effective system for systemic Ad delivery for the purpose of cancer screening.",
keywords = "adenovirus, detection, fluorescence, microbubble",
author = "Warram, {J. M.} and Sorace, {A. G.} and R. Saini and Borovjagin, {A. V.} and K. Hoyt and Zinn, {K. R.}",
year = "2012",
month = "8",
day = "1",
doi = "10.1038/cgt.2012.29",
language = "English (US)",
volume = "19",
pages = "545--552",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles

AU - Warram, J. M.

AU - Sorace, A. G.

AU - Saini, R.

AU - Borovjagin, A. V.

AU - Hoyt, K.

AU - Zinn, K. R.

PY - 2012/8/1

Y1 - 2012/8/1

N2 - One of the major limitations of cancer gene therapy using recombinant human adenovirus (Ad) is rapid Ad inactivation from systemic delivery. To eliminate this, biotin-coated ultrasound contrast agents, or microbubbles (MBs), were streptavidin-coupled with biotinylated antibodies to three distinct tumor vasculature-associated receptors (α V Β 3 integrin, P-selectin and vascular endothelial growth factor receptor-2) for systemic targeting of a previously generated vector Ad5/3-Id1-SEAP-Id1-mCherry. This cancer-specific, dual-reporter vector was loaded in the targeted MBs and confirmed by confocal microscopy. MB loading capacity was estimated by functional assays as 4.720.2 plaque forming unit (PFU) per MB. Non-loaded (free) Ad particles were effectively inactivated by treatment with human complement. The Ad-loaded, targeted-MBs were injected systemically in mice bearing MDA-MB-231 tumors (Grp 1) and compared with two control groups: Ad-loaded, non-targeted MBs (Grp 2) and free Ad (Grp 3) administered under the same conditions. Two days after administration the blood levels of secreted embryonic alkaline phosphatase (SEAP) reporter in Grp 1 mice (16.1 ng ml-1 2.5) were significantly higher (P<0.05) than those in Grp 2 (9.75 ng ml-1 1.5) or Grp 3 (4.26 ng ml-1 2.5) animals. The targeted Ad delivery was also confirmed by fluorescence imaging. Thus, Ad delivery by targeted MBs holds potential as a safe and effective system for systemic Ad delivery for the purpose of cancer screening.

AB - One of the major limitations of cancer gene therapy using recombinant human adenovirus (Ad) is rapid Ad inactivation from systemic delivery. To eliminate this, biotin-coated ultrasound contrast agents, or microbubbles (MBs), were streptavidin-coupled with biotinylated antibodies to three distinct tumor vasculature-associated receptors (α V Β 3 integrin, P-selectin and vascular endothelial growth factor receptor-2) for systemic targeting of a previously generated vector Ad5/3-Id1-SEAP-Id1-mCherry. This cancer-specific, dual-reporter vector was loaded in the targeted MBs and confirmed by confocal microscopy. MB loading capacity was estimated by functional assays as 4.720.2 plaque forming unit (PFU) per MB. Non-loaded (free) Ad particles were effectively inactivated by treatment with human complement. The Ad-loaded, targeted-MBs were injected systemically in mice bearing MDA-MB-231 tumors (Grp 1) and compared with two control groups: Ad-loaded, non-targeted MBs (Grp 2) and free Ad (Grp 3) administered under the same conditions. Two days after administration the blood levels of secreted embryonic alkaline phosphatase (SEAP) reporter in Grp 1 mice (16.1 ng ml-1 2.5) were significantly higher (P<0.05) than those in Grp 2 (9.75 ng ml-1 1.5) or Grp 3 (4.26 ng ml-1 2.5) animals. The targeted Ad delivery was also confirmed by fluorescence imaging. Thus, Ad delivery by targeted MBs holds potential as a safe and effective system for systemic Ad delivery for the purpose of cancer screening.

KW - adenovirus

KW - detection

KW - fluorescence

KW - microbubble

UR - http://www.scopus.com/inward/record.url?scp=84864143864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864143864&partnerID=8YFLogxK

U2 - 10.1038/cgt.2012.29

DO - 10.1038/cgt.2012.29

M3 - Article

VL - 19

SP - 545

EP - 552

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 8

ER -