Evaluation of targeting αVβ3 in breast cancers using RGD peptide-based agents

Anders Josefsson; Angel G Cortez; Jing Yu; Sunipa Majumdar; Abhinav Bhise; Robert F Hobbs; Jessie R Nedrow

doi:10.1016/j.nucmedbio.2024.108880

Evaluation of targeting α_Vβ₃ in breast cancers using RGD peptide-based agents

Nucl Med Biol. 2024 Jan-Feb:128-129:108880. doi: 10.1016/j.nucmedbio.2024.108880. Epub 2024 Feb 6.

Authors

Anders Josefsson¹, Angel G Cortez², Jing Yu³, Sunipa Majumdar³, Abhinav Bhise¹, Robert F Hobbs⁴, Jessie R Nedrow⁵

Affiliations

¹ Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: nedrowj@upmc.edu.

PMID: 38330637
DOI: 10.1016/j.nucmedbio.2024.108880

Abstract

Patients with HER2-positive and triple negative breast cancer (TNBC) are associated with increased risk to develop metastatic disease including reoccurring disease that is resistant to standard and targeted therapies. The α_Vβ₃ has been implicated in BC including metastatic disease. The aims of this study were to investigate the potential of α_Vβ₃-targeted peptides to deliver radioactive payloads to BC tumors expressing α_Vβ₃ on the tumor cells or limited to the tumors' neovascular. Additionally, we aimed to assess the pharmacokinetic profile of the targeted α-particle therapy (TAT) agent [²²⁵Ac]Ac-DOTA-cRGDfK dimer peptide and the in vivo generated decay daughters. The expression of α_Vβ₃ in a HER2-positive and a TNBC cell line were evaluated using western blot analysis. The pharmacokinetics of [¹¹¹In]In-DOTA-cRGDfK dimer, a surrogate for the TAT-agent, was evaluated in subcutaneous mouse tumor models. The pharmacokinetic of the TAT-agent [²²⁵Ac]Ac-DOTA-cRGDfK dimer and its decay daughters were evaluated in healthy mice. Selective uptake of [¹¹¹In]In-DOTA-cRGDfK dimer was shown in subcutaneous tumor models using α_Vβ₃-positive tumor cells as well as α_Vβ₃-negative tumor cells where the expression is limited to the neovasculature. Pharmacokinetic studies demonstrated rapid accumulation in the tumors with clearance from non-target organs. Dosimetric analysis of [²²⁵Ac]Ac-DOTA-cRGDfK dimer showed the highest radiation absorbed dose to the kidneys, which included the contributions from the free in vivo generated decay daughters. This study shows the potential of delivering radioactive payloads to BC tumors that have α_Vβ₃ expression on the tumor cells as well as limited expression to the neovascular of the tumor. Furthermore, this work determines the radiation absorbed doses to normal organs/tissues and identified key organs that act as suppliers and receivers of the actinium-225 free in vivo generated α-particle-emitting decay daughters.

Keywords: Actinium-225; Bismuth-213; Dosimetry; Francium-221; Pharmacokinetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Integrin alphaVbeta3 / metabolism
Mice
Oligopeptides / pharmacokinetics
Peptides
Triple Negative Breast Neoplasms*

Substances

arginyl-glycyl-aspartic acid
Oligopeptides
Peptides
Integrin alphaVbeta3