1H/31P polarization transfer at 9.4 Tesla for improved specificity of detecting phosphomonoesters and phosphodiesters in breast tumor models.

Jannie P Wijnen,Tiffany R Greenwood,Kristine Glunde,Wybe J M Van Der Kemp,Lu Jiang,Dennis W J Klomp,Andrea Motta

doi:10.1371/journal.pone.0102256

Abstract

PurposeTo assess the ability of a polarization transfer (PT) magnetic resonance spectroscopy (MRS) technique to improve the detection of the individual phospholipid metabolites phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE) in vivo in breast tumor xenografts.Materials and MethodsThe adiabatic version of refocused insensitive nuclei enhanced by polarization transfer (BINEPT) MRS was tested at 9.4 Tesla in phantoms and animal models. BINEPT and pulse-acquire (PA) 31P MRS was acquired consecutively from the same orthotopic MCF-7 (n = 10) and MDA-MB-231 (n = 10) breast tumor xenografts. After in vivo MRS measurements, animals were euthanized, tumors were extracted and high resolution (HR)-MRS was performed. Signal to noise ratios (SNRs) and metabolite ratios were compared for BINEPT and PA MRS, and were also measured and compared with that from HR-MRS.ResultsBINEPT exclusively detected metabolites with 1H-31P coupling such as PC, PE, GPC, and GPE, thereby creating a significantly improved, flat baseline because overlapping resonances from immobile and partly mobile phospholipids were removed without loss of sensitivity. GPE and GPC were more accurately detected by BINEPT in vivo, which enabled a reliable quantification of metabolite ratios such as PE/GPE and PC/GPC, which are important markers of tumor aggressiveness and treatment response.ConclusionBINEPT is advantageous over PA for detecting and quantifying the individual phospholipid metabolites PC, PE, GPC, and GPE in vivo at high magnetic field strength. As BINEPT can be used clinically, alterations in these phospholipid metabolites can be assessed in vivo for cancer diagnosis and treatment monitoring.

Highlights

Elevated concentrations of water-soluble phospholipid metabolites such as the phosphomonoesters (PMEs) phosphocholine (PC) and phosphoethanolamine (PE) and the phosphodiesters (PDEs) glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) are a metabolic hallmark of cancer [1,2]. 1H and 31P magnetic resonance spectroscopy (MRS) are able to detect this activated phospholipid metabolism in cancers in vivo, which can be used clinically for cancer diagnosis and treatment monitoring [2]
GPE and GPC were more accurately detected by BINEPT in vivo, which enabled a reliable quantification of metabolite ratios such as PE/GPE and PC/GPC, which are important markers of tumor aggressiveness and treatment response
BINEPT is advantageous over PA for detecting and quantifying the individual phospholipid metabolites PC, PE, GPC, and GPE in vivo at high magnetic field strength

Summary

Introduction

Elevated concentrations of water-soluble phospholipid metabolites such as the phosphomonoesters (PMEs) phosphocholine (PC) and phosphoethanolamine (PE) and the phosphodiesters (PDEs) glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) are a metabolic hallmark of cancer [1,2]. 1H and 31P magnetic resonance spectroscopy (MRS) are able to detect this activated phospholipid metabolism in cancers in vivo, which can be used clinically for cancer diagnosis and treatment monitoring [2]. The total choline (tCho) signal detected by 1H MRS cannot be spectrally resolved into individual metabolites, mainly free choline (Cho), PC and GPC, due to the low spectral resolution in vivo at clinical field strengths of 1.5 and 3 Tesla (T), nor can it be resolved at high field strengths of 4 and 7 T [3,4,5]. Even at high field strength, the detection of individual PE, PC, GPE and GPC is difficult, in heterogeneous cancer tissues in which the homogeneity of the magnetic field is poor [9] Another significant problem for quantitative in vivo detection with 31P MRS is that these signals typically overlap with signals of other molecules with 31P nuclei, such as sugar phosphates and immobile membrane phospholipids (e.g. phosphatidylcholine, phosphatidylethanolamine), which cause a broad, uneven baseline, which in turn severely hampers the accuracy of metabolite measurement and quantification [10]. Accurate measurement and quantification of these phospholipid metabolites is important in the clinic as consistent changes in phospholipid metabolite levels can aid in cancer diagnosis, prognosis, and treatment response monitoring

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Results

Conclusion