Comparative Study of Subcutaneous and Orthotopic Mouse Models of Prostate Cancer

Vascular Perfusion, Vasculature Density, Hypoxic Burden and BB2r-Targeting Efficacy

Wenting Zhang, Wei Fan, Satyanarayana Rachagani, Zhengyuan Zhou, Subodh M Lele, Surinder K. Batra, Jered C Garrison

Research output: Contribution to journalArticle

Abstract

The gastrin-releasing peptide receptor (BB2r) is overexpressed in a variety of cancers including prostate cancer. As a consequence, the development of BB2r-targeted diagnostic/therapeutic radiopharmaceuticals has been widely explored. Both subcutaneous and orthotopic mouse models have been extensively used in BB2r-targeted agent development, but side-by-side studies examining how biological parameters (tumor perfusion efficacy, hypoxic burden and microvasculature density) impact BB2r-targeted agent delivery has not been reported. Herein, we examine these biological parameters using subcutaneous and orthotopic PC-3 xenografts. Using a dual isotope biodistribution study, tumor perfusion was accessed using [99mTc]NaTcO4 and BB2r-targeted uptake evaluated by utilization of a novel 177Lu-labeled conjugate ([177Lu]Lu-DOTA-SP714). Immunofluorescence, immunohistochemistry and autoradiography were utilized to examine the tumor vascular density, hypoxic burden and microdistribution of the BB2r-targeted agent. Our studies demonstrated that compared to the subcutaneous model the PC-3 orthotopic tumors had significantly higher levels of perfusion that led to higher BB2r-targeted uptake and lower levels of hypoxia burden. It is anticipated that our results will allow researchers to better understand the biological variables affecting drug delivery and assist them in more clearly interpreting their results in this common prostate cancer mouse model.

Original languageEnglish (US)
Number of pages1
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Jul 31 2019

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Blood Vessels
Prostatic Neoplasms
Perfusion
Neoplasms
Bombesin Receptors
Radiopharmaceuticals
Microvessels
Autoradiography
Heterografts
Isotopes
Fluorescent Antibody Technique
Immunohistochemistry
Research Personnel
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

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title = "Comparative Study of Subcutaneous and Orthotopic Mouse Models of Prostate Cancer: Vascular Perfusion, Vasculature Density, Hypoxic Burden and BB2r-Targeting Efficacy",
abstract = "The gastrin-releasing peptide receptor (BB2r) is overexpressed in a variety of cancers including prostate cancer. As a consequence, the development of BB2r-targeted diagnostic/therapeutic radiopharmaceuticals has been widely explored. Both subcutaneous and orthotopic mouse models have been extensively used in BB2r-targeted agent development, but side-by-side studies examining how biological parameters (tumor perfusion efficacy, hypoxic burden and microvasculature density) impact BB2r-targeted agent delivery has not been reported. Herein, we examine these biological parameters using subcutaneous and orthotopic PC-3 xenografts. Using a dual isotope biodistribution study, tumor perfusion was accessed using [99mTc]NaTcO4 and BB2r-targeted uptake evaluated by utilization of a novel 177Lu-labeled conjugate ([177Lu]Lu-DOTA-SP714). Immunofluorescence, immunohistochemistry and autoradiography were utilized to examine the tumor vascular density, hypoxic burden and microdistribution of the BB2r-targeted agent. Our studies demonstrated that compared to the subcutaneous model the PC-3 orthotopic tumors had significantly higher levels of perfusion that led to higher BB2r-targeted uptake and lower levels of hypoxia burden. It is anticipated that our results will allow researchers to better understand the biological variables affecting drug delivery and assist them in more clearly interpreting their results in this common prostate cancer mouse model.",
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AU - Batra, Surinder K.

AU - Garrison, Jered C

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