Ultrasound-Based Molecular Imaging of Tumors with PTPmu Biomarker-Targeted Nanobubble Contrast Agents.

Mette L Johansen,Reshani Perera,Susann M Brady-Kalnay,Xinning Wang,Eric Abenojar,Jason Vincent,Agata A Exner

doi:10.3390/ijms22041983

Abstract

Ultrasound imaging is a widely used, readily accessible and safe imaging modality. Molecularly-targeted microbubble- and nanobubble-based contrast agents used in conjunction with ultrasound imaging expand the utility of this modality by specifically targeting and detecting biomarkers associated with different pathologies including cancer. In this study, nanobubbles directed to a cancer biomarker derived from the Receptor Protein Tyrosine Phosphatase mu, PTPmu, were evaluated alongside non-targeted nanobubbles using contrast enhanced ultrasound both in vitro and in vivo in mice. In vitro resonant mass and clinical ultrasound measurements showed gas-core, lipid-shelled nanobubbles conjugated to either a PTPmu-directed peptide or a Scrambled control peptide were equivalent. Mice with heterotopic human tumors expressing the PTPmu-biomarker were injected with PTPmu-targeted or control nanobubbles and dynamic contrast-enhanced ultrasound was performed. Tumor enhancement was more rapid and greater with PTPmu-targeted nanobubbles compared to the non-targeted control nanobubbles. Peak tumor enhancement by the PTPmu-targeted nanobubbles occurred within five minutes of contrast injection and was more than 35% higher than the Scrambled nanobubble signal for the subsequent two minutes. At later time points, the signal in tumors remained higher with PTPmu-targeted nanobubbles demonstrating that PTPmu-targeted nanobubbles recognize tumors using molecular ultrasound imaging and may be useful for diagnostic and therapeutic purposes.

Highlights

The use of ultrasound (US) imaging for diagnostic purposes has grown considerably in recent years due to its wide availability, its adaptability, its safety profile and high sensitivity [1,2]
It is possible that the combination of real time image acquisition and the nature of the NBs used in US allowed the detection of the PTPμ-biomarker in the kidneys of these tumor-bearing mice
It is possible that specific interactions of both fluorophore-peptides and gadolinium-chelate-peptides with kidney are obscured by the clearance of either excess agent or agent that has bound and released from tumor

Summary

Introduction

The use of ultrasound (US) imaging for diagnostic purposes has grown considerably in recent years due to its wide availability, its adaptability, its safety profile and high sensitivity [1,2]. Ultrasound contrast agents (UCAs) are used to enhance US imaging and can be adapted for therapeutic and theranostic uses [2,3,4,6,7,8]. Approved applications in the United States include the use of UCAs to examine liver lesions and for voiding urosonography [4,6], applications that underscore the advantages of being able to dynamically image fluid flow. Contrast enhanced US (CEUS) can be used to distinguish between different types of malignant and benign lesions based on the patterns of phase enhancement (reviewed in [4,6]), and may provide a cost-effective alternative to the more standard use of MRI. MBs have shown preclinical utility in imaging kidney lesions and in assessing perfusion in recently transplanted kidneys [4,6]

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