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 [ 99m Tc]NaTcO 4 and BB2r-targeted uptake evaluated by utilization of a novel 177 Lu-labeled conjugate ([ 177 Lu]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.

The past, present, and future of breast cancer models for nanomedicine development

“…While the subcutaneous transplantation of breast cancer cells to generate breast tumors is technically straightforward, subsequent tumors lack a representative tumor stroma and fail to fully recapitulate expected metastatic patterns [130] , [131] . In contrast, orthotopic breast cancer models represent a more faithful recapitulation of human tumorigenesis [132] , [133] , [134] . The generation of orthotopic breast cancer models via the injection of breast cancer cells inside the natural cavity of the mammary ducts (intraductal) provides for the histological and molecular features of the clinical setting, high implantation rates, and effective spontaneous metastasis [125] , [130] .…”

FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer

“…OT models are considered to reproduce the tumor microenvironment, which is thought to be more clinically relevant than SC models, and emulate important biological features of cancer progression, angiogenesis, metastasis, therapeutic sensitivity and drug resistance. The differences between SC and OT models might be associated with different tumor microenvironments [ 73 , 74 ]. However, the detailed mechanisms are still unclear.…”

Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells

“…Our model was developed using data collected from orthotopic lung tumor model rather than subcutaneous models. Orthotopic models are considered more clinically relevant than subcutaneous models [ 51 , 52 ]. However, the potential high aggressiveness of orthotopic tumor models [ 53 ] may cause most of animals to die before tumor volume reaches the linear growth phase.…”